SECTION 13  OSTEOARTHRITIS AND RELATED DISORDERS
Pathogenesis and pathology
of osteoarthritis
Thomas Aigner and Nicole Schmitz
 Osteoarthritis (OA) is pathologically primarily characterized by focal
cartilage damage, bone sclerosis, and some sort of synoviopathy.
 Osteoarthritic changes within the articular cartilage can be
categorized by typing, staging, and grading of the lesions.
 OA is strongly associated with age, but bone and cartilage changes
in OA are different from those of normal aging.
 There are many different hypotheses trying to explain cartilage and
joint degeneration, including chronic mechanical (over)load, matrix
proteolysis, age-induced changes of the cartilage matrix and the
chondrocytes, as well as increasing damage to the genomic DNA of
the chondrocytes, leading to a deranged cellular phenotype.
 Proinflammatory cytokines as well as the activation of cellular
inflammatory signaling pathways including interleukin-1 and the
MAP kinases likely play an important role in OA pathogenesis.
 Biomechanical factors are essential in the pathogenesis of OA.
Altered joint biomechanics are generated by joint incongruity,
laxity, muscle weakness, and impaired proprioception in addition
to trauma and heavy physical load.
 Despite the fact that presumably a high variety of different
phenomena contribute to the pathogenesis of OA, premature
aging of the chondrocytes and the matrix presumably plays a
crucial role in its initiation and progression; thus, OA might be in
analogy the “Morbus Alzheimer” of the joint.
INTRODUCTION
Osteoarthritis (OA), also known as degenerative joint disease or osteo-
arthrosis, is the most common form of arthritis and the leading source
of physical disability with severely impaired quality of life in people in
industrialized nations. Although derived from the Greek words osteon
for bone, arthron for joint, and the suffix -itis for inflammation, the
site of most pronounced structural alterations is not the bone but the
joint cartilage, and severe inflammation is seen in only few patients.
OA is generally considered as a disease of the elderly, progressively
causing loss of joint function, but although it is true that OA preva-
lence increases sharply with age it is not part of normal aging. Very
little is known about the underlying causes of OA, and many hypoth-
eses regarding its pathogenesis have been proposed over time. Genetic
defects causing malfunction of structural genes give rise to premature
and often severe OA in certain families, but in the majority of OA cases
no such defects have been identified. A number of risk factors are
known that apart from age include heredity, malalignment of the
articulating surfaces, obesity, metabolic diseases, and joint trauma.
Each can make contributions to the initiation and progress of the
disease in different compartments of the joint. Biochemical processes
involving cartilage, bone, and synovium eventually intertwine and col-
lectively damage all three joint compartments. This results in articular
cartilage breakdown, osteophyte formation, subchondral bone sclerosis,
bone marrow lesions, and alterations of the synovium on both mor-
phologic and biochemical levels, often causing, for example, episodic
synovitis (Fig. 173.1). Advances in molecular biology raise hopes that
new therapeutic targets will be identified that will allow more than just
symptomatic therapy. Joint replacement is still the unsurpassed therapy
for advanced and incapacitating OA. However, with increasing appre-
ciation of the contribution of all three joint compartments to disease
173
OSTEOARTHRITIS
CHAPTER 173  ●  Pathogenesis
AND RELATED
progression, research in OA pathogenesis, biomarkers, and treatment
has broadened immensely and many new potential therapeutic targets
have emerged over the past years.
and
DISORDERS
THE NORMAL JOINT: ANATOMY—
pathology  of
PHYSIOLOGY—FUNCTION
Understanding of joint dysfunction requires some knowledge of nor-
mality and the comparison of the diseased state to the physiologic situ-
Pathogenesis
ation (Fig. 173.2). The most important requirements for normal joint
osteoarthritis
function are the freedom of the opposed articular surfaces to move pain
free—and largely frictionlessly—over each other within the required
range of motion as well as the correct distribution of load across joint
tissues. Thus, pathology in many cases might be caused by acute or
chronic mechanical overloading, systematic mal-loading, or habitual
and pathology of osteoarthritis
underloading, leading to disuse atrophy.
The correct functioning of the joint is largely dependent on its
design. Joints are highly specialized organs whose properties are pro-
vided by the articular cartilage and its extracellular matrix that, under
physiologic conditions, is capable of sustaining high cyclic loading.
Articular cartilage covers the joint surfaces and is mainly responsible
for the unique biomechanical properties of the joints. Joints are,
however, complex composites of different types of connective tissue,
including subchondral bone, cartilage surfaces, ligaments, and the joint
capsule. The bony backbone defines the shape of the joint and the
articulating surfaces—in combination with the articular cartilage—
determine the absorption properties during movement. Also, the syno-
vial capsule and, in particular, the synovial membrane (i.e., the synovial
lining cell layer) vastly contribute to the physiologic functioning of the
articulating joints. It is the synovial capsule together with the liga-
ments that provides the mechanical stability of the joints and ulti-
mately determines their flexibility and range of motion. The synovial
membrane, containing high metabolically active surface cells, the 
synoviocytes, plays a crucial role in nourishing the chondrocytes as
well as maintaining the normal metabolic milieu within the joints by
removing metabolites and matrix degradation products from the syno-
vial space. Also, synoviocytes produce large amounts of important
mediators (cytokines and growth factors), matrix degrading enzymes,
as well as hyaluronic acid and other factors such as lubricin/superficial
zone protein, which provide the joint surfaces with its lubrication
capacity. All these factors enable maintaining the local milieu of the
synovioarticular joint organ.
Together all different tissues with their own functional capacities
permit correct functioning and integrity of the joints.
PATHOLOGY
Macroscopically, normal hyaline articular cartilage is a rather unruffled
white to yellowish overlay coating the articulating joint surface (Figs.
173.3e and 173.4a). The synovial fluid makes it to appear slippery and
provides its gliding properties. Microscopically, hyaline cartilage con-
sists of evenly stained (“hyaline”) collagen- and proteoglycan-rich extra-
cellular matrix with sparsely distributed cartilage cells (“chondrocytes”).
The cells represent less than 5% of the total volume of articular carti-
lage but are of obvious importance for the maintenance of the tissue.
Chondrocytes are surrounded in most parts by a specialized pericellular
matrix forming a biomechanical and biochemical interface between the
rigid interterritorial matrix and the cells. The mechanical properties of 1741
 articular cartilage largely depend on the biochemical composition of
the extensive interterritorial (extracellular) cartilage matrix.
SECTION 13  ●  OSTEOARTHRITIS AND RELATED DISORDERS
Macroscopically, OA cartilage is often yellowish or brownish, is
typically soft, and is often swollen. The surface shows roughening in
the early stages and overt fibrillation and matrix loss in the later stages
until the eburnated subchondral bone plate is visible (see Fig. 173.3f,
g). These changes can be seen and graded radiographically (see Fig.
173.3a-d) and can be visualized in more detail on the histologic level
(see Fig. 173.4). Thus, microscopically, the surface shows undulations
(roughening) in the early and overt fissures and splits as well as matrix
loss in the later disease stages (see Fig. 173.4b) until the subchondral
bone plate becomes visible (see Fig. 173.4e). Besides the total destruc-
tion of matrix areas, also the degradation of matrix molecules plays an
important role preceding and driving the final loss of the respective
SCHEMATIC VIEW OF THE MAIN STRUCTURES
OF A HEALTHY (LEFT) AND DEGENERATE OA (RIGHT) JOINT
Articular cartilage
Destructed
cartilage
Joint capsule Capsular fibrosis
Osteophyte
formation
Synovial
Synovial
membrane hyperplasia
(Subchondral)
bone remodelling
(Subchondral) bone
and sclerosis
Fig. 173.1  Schematic view of the main structures of a healthy (left) and
degenerated OA (right) joint. In OA the articular cartilage is lost or severely
thinned, the (subchondral) bone is sclerotic, the joint capsule is thickened, and
the synovial membrane is activated. (Courtesy of E. Bartnik, Frankfurt.)
Fig. 173.2  The images show coronal magnetic resonance imaging datasets of the knee acquired using a fast
low-angle shot (FLASH) or spoiled gradient-recalled-echo sequence (SPGR). This imaging sequence has been
extensively validated for detecting cartilage lesions and for performing quantitative measures of cartilage
volume and thickness. The left image shows a healthy knee with normal cartilage thickness, the right image a
knee with OA. Note the osteophytes and the extensive cartilage loss in the lateral femorotibial compartment.
1742 (Courtesy of Felix Eckstein, Salzburg, Austria.)
matrix areas (see Fig. 173.4d, e: loss of toluidine blue staining reflecting
the loss of proteoglycans in damaged cartilage areas). Apart from the
degradation of molecular components, destabilization of supramolecu-
lar structures also takes place. For example, destabilization of the col-
lagen network results in microscopically and, finally, macroscopically
visible matrix destruction. Both mechanical wear and enzymatic deg-
radation appear to play a pivotal role during the disease process.
Together, these cause the destruction of the cartilage matrix on the
molecular (e.g., proteoglycan depletion) and the macromolecular (e.g.,
network loosening), explaining the changes observed on the micro-
scopic (e.g., fissures) and the macroscopic level (e.g., cartilage tear).
At the margins of joints frequently (osteo)cartilaginous outgrowths
appear (chondro-osteophytes). They are best considered as a process of
secondary chondroneogenesis in the adult. Osteophytes derive from
mesenchymal precursor cells within periosteal or synovial tissue and
often merge with or overgrow the original articular cartilage. Thus, in
this process, mesenchymal precursor cells differentiate into chondro-
cytes. A similar, but less structured process is observed in the areas of
the eburnated bone, in which the articular cartilage is completely torn
off. Here, mesenchymal multipotential stem cells of the bone marrow
undergo also chondrogenic differentiation: metaplastic cartilage in
forms of nodules or “tufts” is found either within the bone marrow or
at the naked bone surface.
Osteophytes could be considered as endogenous repair attempts in
degenerating joints and might be a physiologic response to mechanical
overloading by increasing the articulating joint surface, thus having a
supportive function. However, they are mainly found in non–weight-
bearing areas and their mechanical stability and biologic benefit are
questionable. To date, the molecular mechanisms in the development
of osteophytes are largely unknown. Mechanical or biochemical stimuli
could play a central role. However, most osteophytes do not take part
in the articulating process and are subsequently not exposed to major
mechanical load. Thus, it is more likely that growth factors play a
dominant role in the induction and promotion of osteophyte forma-
tion. For example, the exogenous application of transforming growth
factor-β (TGF-β) and bone morphogenetic protein-2 (BMP-2) into knee
joints of adult mice leads to significant osteophyte formation.
TYPING, STAGING, AND GRADING OF JOINT
CARTILAGE ALTERATIONS IN OSTEOARTHRITIS
Overall, the classification of OA cartilage degeneration is rather
complex because all patients present with at least to some extent dif-
ferent histories, symptoms, and morphologic changes. Common to all

a b
e f
Fig. 173.3  Knee: (a) grade 0 normal, (b) grade 1 lateral tibiofemoral narrowing, (c) grade 3 lateral tibiofemoral narrowing, and
(d) grade 3 lateral tibiofemoral narrowing. (e, f ) Macroscopic appearance of femoral condyles of a normal (e) and severely
damaged (f ) knee. (g) Arthroscopic image of a cartilage defect of the femoral condyle within the knee joint. (a-d, from Altman
RD, Gold GE. Atlas of individual radiographic features in osteoarthritis, revised. Osteoarthritis Cartilage 2007;15[Suppl A]:A1-A56; g,
courtesy of Dr. W. Eger, Rummelsberg.)
of them is some sort of structural joint (cartilage) damage, pain, and
limitation in joint movement.
Obviously, many other tissues apart from the articular cartilage are
involved in this process, but, traditionally, the cartilage has been used
to score OA severity (at least as long as structural changes are assessed).
In general, the process of joint destruction can always be evaluated for
the pathogenesis (“typing”), for its extent (“staging”), and for the degree
of the most extensive focal damage (“grading”).
“Typing” is mostly related to “primary” (i.e., idiopathic) and “sec-
ondary” (i.e., “caused by”) OA. Primary OA is most frequently observed.
Whereas the addition “primary” implies that there is no obvious cause,
still minor preexisting conditions also exist in this condition (i.e., “pre-
conditions” or “risk factors”). The major causes leading to secondary
OA joint degeneration are listed in Table 173.1. “Grading” and
“staging” have been much more under debate, also regarding the basic
meaning of both words: “grading” should refer to the evaluation of
histologic changes at one (or the worst) site of joint destruction,
whereas “staging” should refer to the overall disease process (in analogy
to “grading” and “staging” in tumor pathology). Both represent an
attempt to score processes relevant to the disease.
The grading system most commonly used (partly with minor modi-
fications) is the histochemical-histologic grading system by Mankin
and coworkers in 1971 (Table 173.2; Fig. 173.5).1 Despite repetitive
criticism that the Mankin score shows a high interindividual variabil-
ity, this might be related to the training status of the involved scoring
people. However, clearly some of the subcategories of the Mankin score
do not belong to primary cartilage degeneration but describe features
observed in secondary cartilage formation (i.e., osteophyte formation:
see Table 173.3) and should be excluded in future scoring attempts. A
staging system used internationally is that of Outerbridge (Table
173.4), while another has been established in Germany by Otte (Table
173.5; see Fig. 173.5).2 The Outerbridge system was primarily described
for the patella but later successfully applied to other joints. Whereas
Mankin addresses the piece of cartilage under the microscope, the
CHAPTER 173  ●  Pathogenesis and pathology of osteoarthritis
c d
g
TABLE 173.1  TYPING OF JOINT DESTRUCTION
Primary
No (major) causative reason known
Secondary
Articular gout
Bone infarction
Endocrine disorders (e.g., hyperparathyroidism)
Hemophilia
Intra-articular infections
Joint instability (e.g., meniscus lesions)
Neuropathy (e.g., Charcot’s joint)
Overload causing excessive wear (work, sport, varus or valgus deformity)
Paget’s disease
Psoriatic arthritis
Rheumatic disease
Trauma
staging systems look at the whole joint surface mostly macroscopically
(but if needed the worst lesion can be evaluated histologically). At the
site of the highest cartilage damage, grading and staging are closely
correlated. Clearly, a pure macroscopic staging system is too rough for
scientific purposes and, thus, a new staging system has been proposed
by Pritzker and colleagues (Table 173.6)3 that combines histopatho-
logic grading parameters with the extension of the lesions. Doubtless,
along with new scientific insights and more extensive and specified
medical options, we will need more elaborated and validated “grading”
and “scoring” systems, and this will be a major task in the near future.
Of crucial importance will be the use of a defined and unified
nomenclature to make studies, descriptions, and results comparable,
whereas at the moment many similar-sounding terms are used for
partly different phenomena and differently sounding words for the 1743
 SECTION 13  ●  OSTEOARTHRITIS AND RELATED DISORDERS

a b c

d e f

Fig. 173.4  Conventional histology shows fibrillation and matrix loss in OA cartilage (b) compared with normal cartilage (a). In
severely damaged areas nearly all articular cartilage is destroyed (e). Also a moderate (d) to severe (e) loss of proteoglycans is
found, as visualized by toluidine blue staining. Besides changes in articular cartilage, also changes in the subchondral bone
are prominent, namely, thickening of the subchondral bone plate (f, OA; c, normal).

Grading according to Mankin

Normal OA
Mankin 0–2 Mankin 3–5 Mankin 6–7 Mankin 8–10 Mankin >10

Sup. zone

Mid. zone

Deep zone

Calc. zone
Toluidine blue

Toluidine blue

Toluidine blue

Toluidine blue
Toluidine blue

Bone

Stage 0 Stage I Stage II Stage III Stage IV

Staging according to Otte

Fig. 173.5  The grading system according to Mankin and colleagues (1971)1 compared with the staging system
according to Otte (1969).2

1744
 TABLE 173.2  GRADING OF OSTEOARTHRITIS ACCORDING TO TABLE 173.3  STAGING OF OSTEOPHYTE DEVELOPMENT ACCORDING
MANKIN AND COLLEAGUES (1971) TO GELSE AND AIGNER (2003)

CHAPTER 173  ●  Pathogenesis and pathology of osteoarthritis

Feature Score Histologic feature Stage 0 Normal periosteum
(normal)
Cartilage structure 0 Normal
Stage I Slight thickening of the periosteum
1 Superficial fibrillation Incipient formation of fibrocartilage (some round cells, some
2 Pannus and superficial fibrillation* metachromatic tissue staining of the extracellular matrix)
No/slight active bone formation
3 Fissures to the middle zone
Molecular markers:
4 Fissures to the deep zone Focal collagen type II expression
No collagen type X
5 Fissures to the calcified zone
Stage II Pronounced thickening of the periosteal layers
Chondrocytes 0 Normal
Well-established formation of fibrocartilage (many round cells,
1 Diffuse hypercellularity strong metachromatic tissue staining of the extracellular matrix)
2 Cell clusters Some/moderate bone formation
Molecular markers:
3 Hypocellularity Distinct collagen type II expression
Safranin-O staining 0 Normal No collagen type X

1 Slight reduction Stage III Pronounced thickening of the periosteal layers

Well-established formation of fibrocartilage (many round cells,
2 Moderate reduction strong metachromatic tissue staining of the extracellular matrix,
3 Severe reduction formation of lacunae)
Strong active bone formation
4 No staining
Molecular markers:
5 Total disorganization* Distinct collagen type II expression
Collagen type X expression in basal areas
Tidemark 0 Intact
Collagen type VI: intermixed with collagen types I, III, and V in
1 Tidemark penetrated by vessels† the intercellular matrix

*Might best be removed (relates to osteophyte formation). Stage IV Significant thickening of the periosteal layer
†
Might best be supplemented with “or duplicated tidemark.” Apparent formation of fibrocartilage with partial hyalinization of
From Mankin HJ, Dorfman H, Lippiello L, et al. Biochemical and metabolic abnormalities in the extracellular matrix (chondrocyte-like cells in lacunae,
articular cartilage from osteoarthritic human hips. J Bone Joint Surg Am 1971;53:523-537.
strong metachromatic tissue staining of the extracellular matrix)
Some active bone formation
Molecular markers:
Ubiquitous presence of collagen type II
Collagen type X in basal areas
Collagen type VI: mostly pericellular
TABLE 173.6  SCORING OF OSTEOARTHRITIS ACCORDING TO
PRITZKER AND COLLEAGUES (2006) From Gelse K, Soeder S, Eger W, et al. Osteophyte development-molecular characterization of
differentiation stages. Osteoarthritis Cartilage 2003;11:141-148.
Grade Histologic properties

0 Matrix: surface intact (normal architecture)

Cells: intact, appropriate orientation
TABLE 173.4  GRADING SCHEME ORIGINALLY SUGGESTED BY OUTERBRIDGE
1 Matrix: superficial zone intact, edema and/or superficial fibrillation FOR MACROSCOPIC CHANGES SEEN ON THE PATELLA
(abrasion), focal superficial matrix condensation
Cells: cell death, proliferation (cluster formation), hypertrophy Grade I Softening and swelling of the cartilage

2 As above: Grade II Fragmentation and fissuring in an area ≤ 0.5 inch in diameter

Matrix: discontinuity at superficial zone (deep fibrillation) Grade III Area more than half an inch in diameter is involved
± Loss of proteoglycan staining in upper third of cartilage
± Focal perichondral increased proteoglycan stain in middle zone Grade IV Erosion of cartilage down to bone
± Disorientation of chondron columns From Outerbridge RE. The etiology of chondromalacia patellae. J Bone Joint Surg Br
3 As above: 1961;43:752-757.
Matrix: vertical fissures into middle zone and branched fissures
± Loss of proteoglycan staining into lower two thirds of cartilage
± New collagen formation cells: cell death, regeneration,
hypertrophy in cartilage domains adjacent to fissures TABLE 173.5  STAGING OF JOINT DESTRUCTION ACCORDING TO OTTE (1969)
4 As above:
Grade Morphology
Cartilage matrix loss with delamination of superficial zone
Excavation with matrix loss from superficial to middle zone 0 Normal
± Formation of cysts in the middle layer
I Superficial fibrillation, no cartilage loss
5 Complete matrix loss with denudation of the sclerotic subchondral
II Cartilage lesions (without full-thickness defects): deep fibrillation,
bone or fibrocartilage
fissures to middle zone and/or partial cartilage matrix loss
± Microfracture with repair limited to bone surface
III Cartilage lesions (without full thickness defects): fissures to deep zone
6 Bone remodeling (more than osteophyte formation only) with
and partial cartilage matrix loss
microfracture, fibrocartilage, and osseous repair above the
previous surface IV Complete cartilage loss (at least focally)

From Pritzker KP, Gay S, Jimenez SA, et al. Osteoarthritis cartilage histopathology: grading and From Otte P. Die konservative Behandlung der Hüft-und Kniearthrose und ihre Gefahren. Dtsch
staging. Osteoarthritis Cartilage 2006;14:13-29. Med Jahresschr 1969;20:604-609.
1745
 TABLE 173.7  OARSI TERMINOLOGY OF OSTEOARTHRITIC JOINT DEGENERATION—A PROPOSAL FOR A CONSENSUS
SECTION 13  ●  OSTEOARTHRITIS AND RELATED DISORDERS

Preferred term Definition Synonym

Superficial zone Includes the surface and upper zones

Surface zone Cartilage zone immediately subjacent to the joint surface. Lamina splendens
Collagen fibers are aligned parallel to surface (without cells)
This zone might be not present in normal cartilage samples/in some species.
Upper zone Collagen fibers are aligned parallel to surface. Chondrocytes, elongated and Horizontal zone/layer
flattened, are aligned parallel to collagen fibers and to joint surface. Tangential zone/layer
Superficial zone/layer
Middle zone Zone subjacent to upper zone. Transitional zone/layer
Collagen fibers are aligned intermediately between upper and deep zone alignments. Intermediate zone/layer
Chondrocytes present in groups (chondrons) aligned parallel to collagen fibers. Middle zone
Deep zone Zone subjacent to mid zone and above calcified cartilage. Radial zone/layer
  Upper deep Collagen fibers are aligned predominantly perpendicular to joint surface.
  Lower deep Chondrocytes within chondrons are aligned parallel to collagen fibers and
perpendicular to joint surface.
Tidemark Zone of increased calcification at border of uncalcified and calcified cartilage Calcification front
Penetration Ligne bordant (increased basophilic stain)
Advancement
Duplication/multiplication
Calcified cartilage Zone between tidemark and the subarticular bone plate Calcified zone
Surface undulations Surface irregularities that do not involve discontinuity of articular surface Roughening
Unevenness
Fissure Vertical cracks, irregularities or discontinuities of cartilage matrix Cleft
Crack
  Superficial Restricted to surface and the superficial zone Flaking
Fraying
  Middle Restricted down to the middle zone Fibrillation
  Deep Restricted down to the deep zone Fissuring
Simple Unbranched fissure
Complex Branched fissure
Split/Splitting Horizontal (0°-60° to cartilage surface) matrix cleft/separation
Erosion Loss of articular cartilage tissue including superficial and at least portions of deeper Loss
Surface cartilage layers Ulceration
Into the superficial zone Abrasion
Into the middle zone Delamination
Into the deep zone Flaking
Full depth Spallation
Excavation
Eburnation Smooth shiny bone surface indicative of exposed bone at articular surface Denudation

From Pritzker K, Aigner T, in press.

same (e.g., fissuring, clefting, flaking). Therefore, a consensus nomen-
clature is proposed by the Osteoarthritis Research Society International
(OARSI) (Table 173.7).4
TYPING AND GRADING OF SYNOVIAL
MEMBRANE ALTERATIONS IN OSTEOARTHRITIS
Clinically relevant OA joint disease is invariably associated with some
sort of synovial pathology. This reflects the notion that there is a direct
relation between clinical symptoms and the synovial reaction in OA
and most likely these changes in the synovial membrane are at least
partly involved in the progression of the disease. In OA synovial speci-
mens, in principle, four different types of OA synoviopathies are found:
hyperplastic, inflammatory, fibrotic, and detritus-rich synoviopathy
(Table 173.8).5
Detritus-rich synovitis, which is found in end-stage OA disease, is
due to abundant macromolecular cartilage and bone detritus (i.e., bone
1746 and cartilage fragments attached to or incorporated into the synovial
membrane; Fig. 173.6h, i) in addition to abundant molecular debris
that is not visible microscopically. Besides the debris, a significant
amount of fibrinous exudate is found at the surface of the synovial
membrane. This exudate may be combined with incorporated fibrin,
reflecting longer ongoing fibrinous exudation already being organized
(i.e., resorbed). Detritus-rich synoviopathy usually contains a minor
inflammatory cell infiltrate consisting of lymphocytes and granulocytes
as well as some foreign-body giant cells.
Another form of OA synoviopathy found in late-stage disease,
fibrotic OA synoviopathy (capsular fibrosis) (see Fig. 173.6e),5 is mainly
characterized by the shortening and thickening of the joint capsule,
which is partly responsible for some symptoms, in particular joint
stiffness, seen in OA patients.
The most interesting of the OA synoviopathies in terms of patho-
genesis is the inflammatory OA synoviopathy, which displays moder-
ately extensive lymphocytic infiltrates (see Fig. 173.6f, g). It is intriguing
to speculate whether this condition reflects some kind of autoimmune
aspect that may be occurring, at least in this subset of OA patients.
Interestingly, the lymphocytic infiltrate in the subsynovial stroma
 TABLE 173.8  MAJOR HISTOPATHOLOGIC FEATURES OF THE FOUR PATTERNS OF OA-ASSOCIATED SYNOVIOPATHY IN
COMPARISON TO EACH OTHER AND TO NORMAL SYNOVIAL MEMBRANE
Villous hyperplasia
Synovial lining—proliferation
Synovial lining—activation
Fibrinous exudate
Capsular fibrosis
(Macromolecular) cartilage and bone debris
Granulocytic infiltrate
Lymphoplasmocellular infiltrate—diffuse
Lymphoplasmocellular infiltrate—Aggregates/follicles
Bold italics = key diagnostic criteria.
From Oehler S, Neureiter D, Meyer-Scholten C, et al. Subtyping of osteoarthritic synoviopathy. Clin Exp Rheumatol 2002;20:633-640.
appears to correlate directly with interleukin (IL)-1β in the synovial
fluid as well as matrix metalloproteinase-1 (MMP-1) expression by
synoviocytes, suggesting a direct stimulatory role of the inflammatory
cells on the activity of the synovial lining cells. In any case, the pres-
ence of inflammation in a significant portion of OA patients clearly
points to the option of anti-inflammatory therapy at least for some
subsets of OA patients.
In early OA, mostly hyperplastic OA synoviopathy is found (see Fig.
173.6d). This pattern shows only moderate synovial hyperplasia with
or without cellular activation but without significant capsular fibrosis
or thickening and without significant inflammatory infiltrates or mac-
romolecular detritus. Overall, three forms of alterations of the synovial
surface can be observed:
1. Increased cytoplasmic volume of the usually flat synovial lining
cells. These cells may even become cuboidal or even cylindrical,
suggesting that they have been activated in some way (see Fig.
173.6c).
2. The under normal conditions single (flat) cell layer of synovial
lining cells (see Fig. 173.6a, b) can proliferate to form as many
as five cell layers
3. The whole synovial surface, including the underlying stroma,
can become hyperplastic and form the classic synovial villi.
Synovial hyperplasia per se can be found in all forms of OA synovi-
opathy and in chronic synovitis. Thus, villous hyperplasia is largely a
non-specific feature of chronic synovial alteration and activation.
So far, no well-established scoring system is available for human
OA synoviopathy. Recently, a simple scoring system was proposed by
Krenn and colleagues to separate inflammatory and non-inflammatory
synovial alterations mainly based on the intensity of inflammatory
infiltrates, synovial and stromal activation.6 In 2002 we proposed a
scoring system specifically for OA synoviopathy basically dividing the
OA-associated synoviopathies into four categories (see Table 173.7):
hypertrophic, fibrotic, inflammatory, and detritus-rich. These can
always be subdivided into mild, moderate, and strong depending on
the intensity of changes present.5 This presumably reflects the different
roles of OA synoviopathy and its implications for the clinical picture.
Whatever scoring system is used, importantly one should average the
changes present in the overall joint and not just rely on one particular
region, because synovial changes are notoriously heterogenous within
affected joints.
EVALUATION OF REGENERATIVE CARTILAGE
FORMATION IN OSTEOARTHRITIC JOINTS
(CHONDRO-OSTEOPHYTE FORMATION)
Central for the basic understanding of osteophytic tissue is the analysis
of the developmental steps during osteophyte formation. Thus,
CHAPTER 173  ●  Pathogenesis and pathology of osteoarthritis
Hyperplastic Inflammatory Fibrotic Detritus-rich
Normal synoviopathy synoviopathy synoviopathy synoviopathy
− ++(+) ++(+) ++(+) ++(+)
− + ++ ++ ++(+)
− + ++ + +
− − (+) + ++(+)
− − (+) +++ +++
− − (+) − +++
− − − − +
− − ++ (+) +(+)
− − ++ (+) (+)
although it is clear that osteophyte development is a continuous
process and many osteophytes show different steps in various portions
at the same time, one can define basic steps based on the cellular
phenotype and the matrix composition of the predominating tissue
(Fig. 173.7; see Table 173.3).7,8 Initially, mesenchymal precursor cells
derived either from periosteum or synovium initiate chondrogenic dif-
ferentiation. This results in fibrocartilage composed of both fibrous and
cartilaginous matrix components. In early osteophytes, endochondral
ossification is initiated. The deepest cell layer becomes hypertrophic
and resembles very much the lowest cells found in the fetal growth
plate. Mature osteophytes are characterized by the predominance of a
hyaline-cartilage-like extracellular matrix. At a first glance, mature
osteophytes can, macroscopically and histologically, easily be mistaken
for original articular cartilage. Although hyaline zones in osteophytes
resemble articular cartilage in terms of structural composition, there
are, nevertheless, certain differences such as a more random cellular
arrangement, the lack of a distinct tidemark, and a missing linear
subchondral bone plate.
Understanding osteophyte formation and classifying its maturation
stage is on the one hand interesting per se for understanding changes
going on in the chondro-osseous department in OA joints, but addi-
tionally osteophyte formation represents an interesting in-vivo model
system to understand and evaluate processes occurring after many
modern cartilage repair strategies (e.g., transplantation of mesenchy-
mal precursor cells for filling up cartilage defects).
ANIMAL MODELS OF OSTEOARTHRITIS
Animal model systems represent an important adjunct and substitute
for studies of OA in humans. They provide means to study OA patho-
physiology as well as assist in the development of disease-modifying
therapeutic agents and biologic markers for diagnosing and construct-
ing a prognosis for the disease. OA is a heterogeneous condition leading
to pain and reduced joint function due to a structurally damaged joint.
Not surprisingly, for such a heterogeneous disorder, identification of
an optimal model system for the human disease is difficult or impos-
sible and a number of models employing various species are currently
in use. These include spontaneous as well as induced (surgically, enzy-
matically/chemically, mechanically, and genetically) models (see
Chapter 172). Unfortunately, all the models differ somehow and no
gold standard has yet been identified. Different subsets of human
patients have disease etiologies that vary, for instance, genetic versus
traumatic causes, and, in this regard, can manifest different mecha-
nisms of disease. Given this heterogeneity of the OA disease process,
identification of an appropriate disease-mechanism–oriented model
may be a more realistic goal and better suited to a particular investiga-
tion than the “universal model” that has not yet been identified.
Rather, as a consequence of this disease heterogeneity in the human,
a plethora of models is required. 1747
 SECTION 13  ●  OSTEOARTHRITIS AND RELATED DISORDERS

a b c

d e f

g h i

Fig. 173.6  (a, b) Normal synovial membrane shows a rather flat surface with a flat layer of inactive, non-proliferated layer of
synoviocytes. In contrast, OA synoviocytes are at least in some cases severely activated and proliferated (c) similar to the
situation found in rheumatoid arthritis. Most cases of late-stage OA synovial specimens show a moderate to abundant
synovial hyperplasia (d, e) and often some sort of capsule thickening (e). A minority of cases of OA synovial membranes show
mild to moderate (f, g) inflammatory infiltrates usually lying in aggregates around blood vessels (f ). In part of the cases
lymphoid follicles also are found (g). End-stage rapid progressive cartilage destruction leads to detritus-rich synovitis with
cartilage and bone fragments incorporated in fibrinous exudate (i, van Gieson stain) or the synovial stroma (h). (Reprinted with
permission from Aigner T, van der Kraan P, van den Berg W. Osteoarthritis and inflammation—inflammatory changes in
osteoarthritic synoviopathy. In: Buckwalter JA, Lotz M, Stoltz JF, eds. Osteoarthritis, inflammation and degradation: a continuum.
Amsterdam: IOS Press, 2007:219-230.)

1748
 CHAPTER 173  ●  Pathogenesis and pathology of osteoarthritis
Fig. 173.7  Osteophyte development can be a b c d e
subdivided into four stages with different structural
organization although many osteophytes show
different stages simultaneously in different areas.
Stage I (early chondrophytes) shows first chondrocytic
differentiation of previously undifferentiated
mesenchymal precursor cells (b, g, k). Stage II
(chondrophytes) shows extensive areas of newly f g h i j
formed cartilage, but no (endochondral) bone
formation is observed (c, h, k). Stage III (early
osteophytes) shows an arrangement as the fetal Normal Osteophyte
growth plate cartilage with hypertrophic Articular Growth
Stage 0 Stage I Stage II Stage III Stage IV cartilage plate
differentiation in the deepest cartilage layers and
active bone formation underneath (d, i, k). Stage IV
(mature osteophytes) shows a structure most GAGs
resembling hyaline articular cartilage physiologically
covering the joint surfaces (e, j, k). Normal periosteum Aggrecan
is shown in a and f (a to e, H&E; f to j, toluidine blue
staining). (Reprinted with permission from Gelse K,
Col1
Soeder S, Eger W, et al. Osteophyte development-
Col6
molecular characterization of differentiation stages. interterritorial
Osteoarthritis Cartilage 2003;11:141-148.) Col6
pericellular
Col2a

Col2B, Col11

Col 10

PATHOGENETIC CONCEPTS OF OSTEOARTHRITIS Extracellular matrix Chondracytes

functional element Articular cartilage reactive element
OA is a heterogeneous condition and most likely many different causes
exist that initiate or at least promote the disease process. Conse-
quently, many different hypotheses for the pathogenesis of OA have
been brought forward. Presumably, many of them reflect part of the
mechanisms important for the initiation and progression of joint
degeneration. Here a rough overview of the relevant pathogenetic con-
cepts is provided.

The articular cartilage and the

extracellular matrix
Articular cartilage is a highly specialized and uniquely designed bioma-
terial (see Chapter 8). It is largely an avascular, aneural, and alymphatic
matrix that is synthesized by the sparsely distributed resident cells—
the chondrocytes. The cartilage matrix can be subdivided according to
different cartilage zones based on the arrangement of the cells and the
matrix fibrils (i.e., superficial, radial, deep, and calcified). Also, the
cartilage matrix can be split up in different compartments depending
on its relationship to the cells: whereas the pericellular matrix is imme-
diate to the cells, the interterritorial matrix compartment represents
the major portion of the cartilage matrix far off the cells and the territo-
rial matrix the (not really well defined and characterized) cell-associ-
ated compartment in between (Fig. 173.8).
At the supramolecular level, the interterritorial cartilage matrix
consists of two basic components: a fibrillar and an extrafibrillar matrix
(see Fig. 173.8). The fibrillar matrix is a network consisting mainly of
collagen II together with other collagens, predominantly IX, XI, and
XVI (Fig. 173.9). Collagen XI is located in the core of the collagen II
fibrils and is thought to be involved in fibril initiation and limiting
fibril diameter. Collagen IX is located periodically along the surface of
collagen II fibrils in antiparallel direction and might be responsible for
crosslinking the collagen network with itself but also to the noncol-
lagenous matrix. The function of collagen XVI, which is also present
in articular cartilage, is so far unknown. Of note, the so-called type
Fig. 173.8  Articular cartilage mainly consists of extracellular matrix (more than
95% of tissue volume), its functional element. Interspersed in between the
abundant matrix are the cells, the chondrocytes, which are, however, the living
(i.e., reacting) element of the articular cartilage tissue. (Reprinted with
permission from Aigner T, Sachse A, Gebhard PM, et al. Osteoarthritis:
pathobiology—targets and ways for therapeutic intervention. Adv Drug Deliv Rev
2006;58:128-149.)
collagen II fibrils also contain many non-collagenous protein compo-
nents such as small proteoglycans and cartilage matrix proteins. The
non-fibrillar component of hyaline articular cartilage consists predomi-
nantly of highly sulfated aggrecan monomers (Fig. 173.10), which are
attached to hyaluronic acid and form very large aggregates. In terms of
the physical properties of the cartilage matrix, tensile strength comes
from the collagen network, which hinders expansion of the viscoelastic
aggrecan component and, thus, provides compressive stiffness of the
tissue. On the other hand, the aggrecan-hyaluronan aggregates bind
high amounts of intercellular water owing to their extensive fixed 1749
 charges and are responsible for the elasticity of the tissue. Thus, under
compression, the cartilage matrix is compliant but rapidly regains its
SECTION 13  ●  OSTEOARTHRITIS AND RELATED DISORDERS
elasticity as water molecules are drawn back into the matrix on unload-
ing by the strongly hydrophilic aggrecan aggregates.
The territorial matrix is defined as the cell-associated matrix located
between the pericellular and the interterritorial matrix compartments,
but no real specific biochemical characterization is available so far.
CARTILAGE COLLAGENS
Type II
NH2 COOH
Chondrocyte
Type XI
Type IX
Type X
Type VI
Fig. 173.9  Cartilage collagens. The different collagen types synthesized by
chondrocytes. The chondrocyte, depicted on the left side of the figure,
constitutively produces three collagen types: type II, type XI, and type IX. These
three collagens, shown inside the bracket, are incorporated into the same
collagen fibril. The proportions of these collagens in the fibrils change with
age. The other two collagen types, type X and type VI (marked with dashed
arrows), are not made by all chondrocytes. Type X collagen is synthesized only
by the hypertrophic chondrocytes in growth-plate cartilage or in articular
cartilage near the tidemark and through the calcified cartilage. Type VI
collagen is not synthesized in embryonic cartilage but appears in mature
cartilage. The levels of both type X and type VI collagen in articular cartilage
appear to increase in OA. All the cartilage collagens are synthesized as
molecules containing at least two different kinds of domains, triple helical and
non-helical. The helical regions are depicted as three-chained coils, and the
non-helical regions are contiguous small boxes. In some collagen types (II and
XI) the non-helical regions (yellow) are removed as fibrils are formed. The other
collagen types (IX, X, and VI) retain their non-helical regions and are shown as
one solid color through the entire molecule. Type IX collagen is also a
proteoglycan and contains one glycosaminoglycan chain (small orange kinked
chain). Disulfide bonds between two collagen chains are shown as red boxes.
All the molecules and their domains are drawn approximately to scale as a
linear representation of their respective molecular weights.
THE STRUCTURE OF AGGRECAN
KS- rich
G1 E1 G2 domain E2 (C5- rich domain)
Ig fold
NH2
NH2 COOH
Proteoglycan
tandem repeat
Keratan sulfate
Link protein N-linked oligosaccharides
1750
Clearly, it shares most of its basic composition with the interterritorial
matrix to which it shows no clear border separating them from each
other.
The pericellular cartilage matrix demonstrates in many respects a
very distinct composition compared with the territorial and interter-
ritorial cartilage matrices. In terms of structural collagens, type VI
collagen (see Fig. 173.9) is the predominant collagen present, which in
hyaline articular cartilage is concentrated within the pericellular
matrix. Ultrastructural studies have shown a physical overlap of the
type VI collagen network with the type II collagen positive matrix,
which supports the concept that type VI collagen is a central molecular
component forming a mechanical interface between the rigid type II
matrix and the (softer) cells. Additionally, type VI collagen presumably
plays some role in cell anchoring and cell-matrix interaction and signal-
ing together with other molecules present in the pericellular cartilage
matrix.
Most of the cartilage matrix is formed during fetal development and
the phase of skeletal growth until the closure of the growth plates at
the end of adolescence. In fact, the collagen backbone appears to show
virtually no turnover during life at least in the (inter)territorial matrix
compartments. However, other matrix components, namely, the large
aggregating proteoglycan aggrecan and the small proteoglycans as well
as some collagen types (e.g., types VI and IX) show a significant turn-
over throughout life. This physiologic turnover is highly relevant for
the maintenance of the cartilage matrix integrity on the molecular, and
in particular also the macromolecular, level.
Pathologic matrix degradation
One major threat to the cartilage matrix and thus to the integrity of
articular cartilage are matrix-degrading enzymes destroying the colla-
gen network as well as the interlying proteoglycans (Fig. 173.11).
Besides direct degradation of molecular components, destabilization of
the supramolecular structures also takes place and plays an important
role in the loosening of the overall matrix architecture.
The destruction of articular cartilage and the loss of its biomechani-
cal function is largely due to the destruction and loss of the (inter)
territorial cartilage matrix. So far, our knowledge focuses on degrada-
tion processes of the two major components of the interterritorial
cartilage matrix, the collagen network and the interwoven proteoglycan
aggregates. Loss of aggrecan and its fixed (negative) charges is charac-
teristic of the early stages of cartilage degeneration, whereas the overall
content of collagen remains rather constant nearly throughout the
disease process. Still, loosening of the collagen network is a major
feature also in early cartilage degeneration. So far, it is unknown what
happens first—the loss of proteoglycans or the loosening of the collagen
network—because both do eventually influence the other as well. Loos-
ening of the collagen network leads to a loss of proteoglycans, and a
loss of proteoglycans leads to a mechanical overload and, thus, damage
and loosening of the collagen network. In particular, the latter appears
to be responsible for the hyperhydration of articular cartilage in the
early phases of the disease process, macroscopically visible as softening
Fig. 173.10  The structure of aggrecan. In aggrecan
the three globular domains (G1, G2, and G3) are
separated by two extended segments (E1 and E2),
G3
which carry the glycosaminoglycans chondroitin
sulfate (CS, in the CS-rich domain) and keratan
sulfate (KS, in the KS-rich domain, but some also in
the E1 segment and within the CS-rich domain).
Furthermore, the core protein is substituted with
N- and O-linked oligosaccharides. The G1 and G2
domains, as well as the link protein (LP), contain a
Lectin double loop structure (proteoglycan tandem repeat
binding [PTR]). In addition, both G1 and LP show an
additional loop structure (immunoglobulin fold [Ig
fold]) that can selectively interact with H hyaluronic
O-linked oligosaccharides
acid to form aggregates. The G3 domain contains a
Chondroitin sulfate lectin-binding region.

THE HALLMARK OF OA CARTILAGE DEGENERATION IS
A LOSS OF CARTILAGE MATRIX HOMEOSTASIS
Osteoarthritis:
Imbalance of cartilage matrix turnover
IGF Il-2β
BMP TNFa
... ...
Anabolism Catabolism
Aggrecan Collagenases Aggrecanases
(collagen type II) MMP-1 MMP-3
Collagen type VI (MMP-8) MMP-14
Collagen type IX MMP-13 ADAMTS-1
Link protein ADAMTS-4
Gelatinase
... ADAMTS-5
MMP-2
MMP-9
Fig. 173.11  The hallmark of OA cartilage degeneration is a loss of cartilage
matrix homeostasis. The insufficiency of anabolic factors such as insulin-like
growth factor-I (IGF-I) and BMPs in combination with an increased influence of
catabolic factors such as IL-1β and TNF-α result in an overexpression of matrix
degrading proteases (collagenases, aggrecanases, and gelatinases). The
catabolic activity of these enzymes cannot be compensated by the concurrent
increase in anabolic activity (i.e., expression of aggrecan and collagen types II,
VI, and others).
and swelling of the OA articular cartilage. Degradation processes
appear to be specifically prominent in the surface zone and around the
chondrocytes in OA cartilage. Enhanced levels of many metalloprotein-
ases including matrix metalloproteinases (MMPs), as well as adamaly-
sins such as ADAMs (a disintegrin and metalloproteinase) and
ADAMTSs (a disintegrin and metalloproteinase with thrombospondin
type-1 motifs) are the most likely candidate enzymes responsible for
the increased matrix degradation in OA cartilage.9 So far it is rather
enigmatic which proteases are really crucial for the degradation of the
various cartilage matrix components, although MMP-13 is certainly a
top candidate for primary collagen type II fibril degradation, MMP-2
(gelatinase A) is a good candidate for subsequent cleavage of denatured
collagen fibrils (“gelatins”), whereas ADAMTS-4 and ADAMTS-5 are
favored to be the major aggrecanases responsible for the proteoglycan
breakdown.
Age-induced degenerative changes of the
cartilage matrix
Clearly, the extracellular cartilage matrix is different depending on the
age of the individual. One obvious reason for this is the continuous
loading and intermittent overloading during life. Thus, damaged matrix
molecules due to continuous mechanical forces, but also degradative
enzymatic activity, which are not sufficiently replaced as part of a
permanent physiological turnover, accumulate over time in any tissue,
but in particular in the mechanically heavily challenged articular car-
tilage. These damaged components threaten the functional integrity of
the extracellular matrix and the articular cartilage, in particular if chal-
lenged by further mechanical stress. However, beyond the classic wear
and tear concept, which certainly holds true for some aspects of OA,
a second theory for explaining the association between cartilage degen-
eration and aging of its matrix focuses on well-known age-related
changes in the extracellular matrix of articular cartilage, modulating
its biomechanical properties and integrity.
Besides pure degradation of matrix components, also molecular
modifications are of high relevance for the functional integrity of the
cartilage matrix: thus, the collagen network stiffens due to increased
covalent cross-linking of the single collagen chains (pyridinium cross-
linking). This makes the fibrillar network more rigid and less flexible
for physiologic deformation occurring during (physiologic) joint loading
and movement. In consequence, the collagen network is prone to
microfracturing during compression and, thus, molecular disintegra-
tion. Also, the aggrecan molecules change over age. Aggrecan mono-
CHAPTER 173  ●  Pathogenesis and pathology of osteoarthritis
mers and polymers get smaller and have fewer sugar side chains.
Interestingly, this is not only related to accumulating molecular deg-
radation but also newly synthesized aggrecan aggregates appear to be
smaller in the aged tissue, thus carrying less fixed charges. Although
the molecular mechanisms driving this decline are so far unclear,
severely reduced sugar side chains significantly limit the ability of
aggrecan to bind water and, thus, to maintain the elasticity of the
articular cartilage matrix.
The time-dependent formation of advanced glycation end products
is another interesting phenomenon involving post-translational, non-
enzymatic protein and lipid modifications that contribute to changes
in matrix biochemistry and chondrocyte biology in aging cartilage. The
accumulation of advanced glycation end products has been shown to
increase the stiffness of the collagen network and can downregulate the
anabolic activity of chondrocytes, further imbalancing cartilage tissue
homeostasis.
Crystal deposition disease
One interesting phenomenon frequently observed within the articular
tissues of degenerated joints is the deposition of anorganic crystals. In
general, there are two major forms of crystal deposition disease in the
articulating joints: deposition of sodium urate crystals (i.e., gout [see
Chapter 183]) and the deposition of basic calcium phosphate (BCP) or
calcium pyrophosphate dihydrate (CPPD) (so-called pseudogout or
chondrocalcinosis [see Chapters 186 and 187]). Both forms can cause
significant symptomatic disease, but gout is clearly usually sympto­
matic and pseudogout, in most cases, a clinically silent process. Pseu-
dogout is strongly associated with (OA) cartilage degeneration and can
be detected on routine radiography and by conventional polarizing
microscopy. Several studies have demonstrated a relation between the
prevalence of crystal occurrence and severity as well as progression of
OA. So far four factors have been identified that play a role in this type
of crystal formation: (1) overproduction of the anionic component
pyrophosphate by the chondrocytes, (2) increased calcium concentra-
tion in the cartilage of OA patients, (3) changes in the pericellular
matrix milieu, and (4) the involvement of matrix vesicles that have
been shown to produce CPPD crystals in vitro.10 Overall, the cause and
the relevance of chondrocalcinosis continue to be ambiguous: clearly,
it is well correlated to the degeneration of the articular cartilage and it
is thought to be related to a metabolic imbalance within the cells and
the tissue, most likely the articular cartilage and the chondrocytes.
However, so far it remains largely unclear what comes first—the cell
and matrix degradation or the crystal formation. Most likely they
promote each other with metabolic disturbance leading to cellular
degeneration and vice versa.
Role of biochemical differences
An interesting feature of OA is that not all joints are affected equally.
Although knee and hip joints are most often involved, ankles are gener-
ally spared in symptomatic OA. Although it is obvious that there are
anatomic differences between the ankle and knee joint, this alone does
not explain why the knee is more susceptible to OA. Studies comparing
knee and ankle cartilage have identified several biochemical differences
that might be of additional relevance (Table 173.9): (1) differences in
biochemical composition and biomechanical properties of the matrix
resulting in higher dynamic stiffness of the ankle cartilage, (2) decreased
response to catabolic factors such as interleukin-1 (IL-1), and (3) more
efficient synthetic matrix repair with an increase in collagen type II
synthesis and aggrecan turnover seen in ankle lesions.11 Taken together
it seems that there are differences not only in the anatomy and mor-
phology of the joints and its cartilage but also in the cellular phenotype
chondrocytes themselves, which may explain why some joints are less
prone to develop OA than others.
The articular cartilage and chondrocytes
The articular cartilage consists mostly of extracellular matrix. This
matrix is the functional element of the cartilage tissue, that is, the 1751
 for OA chondrocytes. In fact, many of the biologic changes that occur
TABLE 173.9  DIFFERENCES BETWEEN KNEE AND ANKLE JOINT STABILITY, in OA cells mimic a differentiation pattern characteristic of fetal skel-
MOTION, AND CARTILAGE
SECTION 13  ●  OSTEOARTHRITIS AND RELATED DISORDERS

etogenesis. This includes changes not only in cellular phenotypes and

Feature Knee Ankle in anabolic and catabolic events but also in other basic mechanisms
during the disease process such as matrix calcification, apoptosis, and
Joint stability Relatively unstable Highly stable proliferation. Thus these (evolutionary and developmental) compari-
Non-congruent Highly congruent sons are attractive for explaining chondrocyte behavior and disease
pathways in the adult, but uncoordinated degenerative events should
Joint motion Flexion/extension Flexion/extensor
not be mistaken for tightly regulated developmental processes (Fig.
Rotation 173.14). Both scenarios presumably involve similar molecular and
Cartilage regulatory events, but just as in a jigsaw puzzle the assembly is the
challenge.
  Cellularity Same Same
  Cartilage thickness 2-6 mm 1-1.5 mm
The OA chondrocyte phenotype
  Superficial chondrons Single cells Clusters of 2-4 cells
Chondrocytes in normal adult articular cartilage are stable, postmi-
  Sulfated glycosaminoglycan Lower Higher totic, differentiated cells that maintain tissue homeostasis by synthe-
content sizing very low levels of extracellular matrix components to replace
  Water content Higher Lower damaged molecules, thus preserving the structural integrity of the
cartilage matrix. The cells are the major regulators of matrix anabolism
  Collagen content Same Same
and catabolism of articular cartilage. One well-documented change in
  Dynamic stiffness Lower Higher OA cartilage is the induction of an activated cellular phenotype within
  Hydraulic permeability Higher Lower the chondrocytes whereby matrix anabolism is strongly stimulated.
Nevertheless, the chondrocytes fail to compensate for matrix damage
  Peak stress with 65% final 11 MPs 16 MPs induced externally (e.g., by mechanical stress or enzymatic degradation
strain through synovial proteases). Additionally, the chondrocytes do play an
Glycosaminoglycan synthesis active role in the degradative process themselves, a phenomenon
  In explants Higher Lower
termed chondrocytic chondrolysis.12 During chondrocytic chondrolysis,
OA chondrocytes activate or upregulate the expression of many matrix-
  In alginate Same Same degrading proteases such as the MMPs, which are largely responsible
Proteoglycan half-life 22.68 days 16.58 days for the breakdown of the collagenous and non-collagenous cartilage
matrix components. This elevated proteolytic activity is not sufficiently
Protein synthesis Lower Higher
counterbalanced by an increase of the chrondrocyte anabolic activity.
IC30 for IL-1 reduction of This is particularly true for the upper zones of damaged cartilage (the
proteoglycan synthesis “progression zone”), in which the anabolic activity even drops again
  In alginate 11 pg/mL 56 pg/mL severely.13
  In explants 6 pg/mL 35 pg/mL
Influence of Fn-fs on Activation of inflammatory signaling
  Proteoglycan synthesis Low dose (1 nM) High dose (100 nM)
In addition to local and/or general inflammatory responses within the
(anti-anabolic) synovial membrane, the activation of inflammatory (signaling) path-
ways within the chondrocytes themselves appears to play a crucial role
  Proteoglycan loss Significant at 7 days Not significant in OA disease progression. Activation of such processes is independent
(catabolic) after 28 days of direct inflammatory cell infiltrates (i.e., lymphocytes, granulocytes,
Attempted repair No significant rebound Significant rebound plasma cells), which are not present in OA articular cartilage. Activated
inflammatory signaling pathways have been shown to induce catabolic
(Response to anabolic factors
after catabolic stimulation)
responses in chondrocytes, namely, matrix degrading proteases such
as MMP-13, MMP-1, and others. One of the most prominent catabolic
Response to degeneration Upregulation of Upregulation of cytokines in OA is the proinflammatory cytokine IL-1. Elevated levels
collagen degradation matrix synthesis of IL-1 are found in synovial fluids of patients suffering from rheuma-
From Eger W, Schumacher BL, Mollenhauer J, et al. Human knee and ankle cartilage explants:
toid arthritis and, to a lesser extent, in synovial fluid from OA patients.
catabolic differences. J Orthop Res 2002;20:526-534. Although polymerase chain reaction (PCR)-based studies could not
confirm an increased expression of IL-1 mRNA in OA chondrocytes,14
there might still be increased levels of IL-1 protein diffused into carti-
lage from the synovial space. IL-1 significantly affects gene expression
patterns within articular chondrocytes via multiple intracellular path-
matrix provides the mechanical properties of the cartilage tissue. ways, particularly the MAP kinases and NF-κB pathways (Fig. 173.15).15
However, the cells (i.e., the chondrocytes) represent the only vital IL-1 downregulates the expression of the major cartilage matrix com-
element of the cartilage tissue, although they represent only about two ponents, aggrecan and collagen type II, and, thus, counteracts the
to three volume percent of the articular cartilage in the adult. Thus, effects of anabolic factors on matrix synthesis. Additionally, IL-1
besides changes in the extracellular matrix changes within the cells induces the expression of matrix degrading enzymes such as MMP-1,
also are obviously potential causes of the OA disease process and the MMP-3, MMP-13, or ADAMTS-4, which are all potential major
study of the chondrocyte cell phenotype/behavior (Fig. 173.12) can players in the destruction of cartilage matrix components. Besides
provide substantial scientific insights into the disease mechanisms  these direct effects, IL-1 also induces other cytokines with synergistic
of OA. (catabolic) effects such as IL-6 and leukemia inducing factor (LIF),
further expanding its versatile effects on cartilage tissue homeostasis.
The developmental history as a model of
chondrocyte reactivity in the adult Oxygen, reactive oxygen species, and reactive
A very important and interesting aspect of cellular behavior in the adult nitrogen species
organism is the recapitulation of molecular mechanisms that occurred Articular cartilage is an avascular tissue and its nutrition is mainly
1752 during fetal development (Fig. 173.13). This phenomenon is also true supplied by the synovial fluid. Because of the rather long diffusion
 CELL BIOLOGY OF OA

CHAPTER 173  ●  Pathogenesis and pathology of osteoarthritis

Fig. 173.12  Cell biology of OA: how do chondrocytes react?
OA chondrocytes are exposed to severely abnormal
extracellular stimuli, including autocrine and paracrine
factors, synovial factors, and altered matrix constituents, that Synovial factors Matrix alterations
induce a plethora of abnormal cellular responses made Aggrecan Link protein
apparent by the changes in anabolism, catabolism, and Fibronectin
phenotype that have been demonstrated in the cells. Also, Autocrine and S–S
paracrine factors
chondrocyte numbers are modified by proliferation or
apoptosis. In addition, cells might become presenescent, Changes in phenotype to:
leading to an overall loss of chondrocyte function. In this • Dedifferentiated cells
schematic, an OA chondrocyte is embedded in a • Hypertrophic cells
cartilaginous extracellular matrix of type II collagen, • Precursor cells
aggrecan, and fibronectin, for simplicity. Other collagens,
proteoglycans, and noncollagenous proteins are also present
at varying levels. (Reprinted with permission from Aigner T, Proliferation and/or
(apoptotic) death Chondrocyte
Soder S, Gebhard PM, et al. Mechanisms of disease: role of
Type II collagen
chondrocytes in the pathogenesis of osteoarthritis—structure,
chaos and senescence. Nat Clin Pract Rheumatol (Pre)senescence
2007;3:391-399.)
Anabolic Catabolic activation
activation

THE DEVELOPMENTAL MODEL OF CHONDROCYTE BEHAVIOR

APPLIED TO OA IN THE ADULT

Osteoarthritis Developmental model: endochondral ossification

Pathomechanisms Development steps Marker genes
Epichondral COL2A
Differentiation Chondrogenesis SOX9
COL2/9/11
aggrecan
Matrix synthesis Resting
Anabolism

Proliferation Proliferation
Proliferative
Catabolism Matrix degradation
Hypertrophy COL10 ssDNA
Calcification Calcification Ki-67
Cell death/apoptosis Cell death/apoptosis Hypertrophic

MMP-13
Bone

Fig. 173.13  The developmental model of chondrocyte behavior applied to OA in the adult. One way to
interpret cellular behavior in adult disease is to investigate whether it shows similarities to developmental or
evolutionary processes. Several processes that occur in OA are also known to have occurred during fetal
chondroneogenesis, including changes in the chondrocytic phenotype (differentiation), matrix anabolism
and catabolism, (apoptotic) cell death, proliferation, and matrix calcification. The analysis of events during
fetal development allows us to identify marker genes that can assist in the identification of the molecular
context of a gene in the adult chondrocyte. For example, expression of Sox9 indicates differentiation to the
chondrocyte phenotype, type IIA collagen (COL2A) is a chondroprogenitor cell marker, and type X collagen
(COL10) is a marker of hypertrophic chondrocytes. Ki-67 indicates cell proliferation whereas the onset of
MMP-13 expression suggests increased matrix catabolism potentially linked to hypertrophic differentiation.
ssDNA indicates apoptotic DNA fragmentation, whereas aggrecan, COL2, COL9, and COL11 indicate anabolic
cell activity (the synthesis of new cartilage matrix). Despite the appeal of a comparative approach, one
should be cautious not to mistake uncoordinated degenerative processes for highly structured
developmental processes. COL2/2A/9/10/11, collagen type II/IIA/IX/X/XI; MMP, matrix metalloproteinase;
ssDNA, single-stranded DNA. (Reprinted with permission from Aigner T, Soder S, Gebhard PM, et al. Mechanisms
of disease: role of chondrocytes in the pathogenesis of osteoarthritis-structure, chaos and senescence. Nat Clin
Pract Rheumatol 2007;3:391-399.)

1753
 RNA IN SITU HYBRIDIZATION FOR MARKER GENES AND
OA RELEVANT PROTEASES IN THE TIBIA OF NEWBORN MICE
SECTION 13  ●  OSTEOARTHRITIS AND RELATED DISORDERS

Resting
Cartilage chondrocytes
synthesis

Proliferating
chondrocytes

Hypertrophic
Cartilage chondrocytes
maturation
and degradation

Bone

Sox9 Ihh Col10a1 MMP13 MMP9

Fig. 173.14  RNA in-situ hybridization for marker genes and OA relevant proteases in the tibia of newborn mice. Anabolic and
catabolic events in the growth plate of the primary ossifying skeleton are at least in part separated. Sox9 mRNA expression
marks the zone of proliferation, which differs from the region of terminal chondrocyte maturation characterized by the
expression of Ihh as a marker for the prehypertrophic chondrocyte and Col10A1 as a specific marker for the entire
hypertrophic cartilage. (Reprinted with permission from Aigner T, Gerwin N. Growth plate cartilage as developmental model in
osteoarthritis research—potentials and limitations. Curr Drug Targets 2007;8:377-385.)

distance the partial pressure of oxygen is very low in healthy cartilage
and presumably even further decreased in OA. Thus, chondrocytes  adhesion, signaling from extracellular matrix, and phagocytosis. Fur-
live in a hypoxic environment with an O2 tension around 6% at
the joint surface to as low as 1% in the deep layers of the articular
cartilage. Even though the oxygen level in articular cartilage is physi-
ologically very low, a certain level of oxygen availability appears to be
essential also for chondrocytes. One major factor in the chondrocytes’
adaption to hypoxia has been found to be the transcription factor
hypoxia-inducible factor-1α (HIF-1α), which has key functions in con-
trolling energy generation, cell survival and even influences matrix
synthesis.16
During normal (oxygen) metabolism so-called reactive oxygen
specias (ROS) are formed as natural byproducts.17 They are involved in
the control of various aspects of biologic processes, including cell acti-
vation, proliferation, and (apoptotic) cell death. Especially, low levels
of ROS have been reported to act as a second messenger in (physiologic)
intracellular cell signaling involved in the regulation of the expression
of a wide variety of gene products, including cytokines, MMPs, adhe-
sion molecules, and matrix components. However, in pathologic condi-
tions, including inflammatory joint diseases, elevated production of
ROS in combination with depletion of antioxidants has been observed
within the cells and causally implicated in the progression of these
diseases. Such an imbalance between oxidants and antioxidants leading
to cellular or tissular structural and/or functional changes is referred
to as “oxidative stress.” At this time, our knowledge on the redox state
of cartilage in pathologic circumstances remains fragmented. However,
ROS have been implicated—besides metalloproteinases—in the process
of matrix and cell component degradation in OA. ROS may directly
oxidize nucleic acids, transcriptional factors, membrane phospholipids,
intracellular and extracellular components leading to impaired biologic
activity, cell death, and breakdown of matrix components. Perhaps
most importantly, ROS are the major cause of DNA damage within
the genome.
Besides ROS, reactive nitrogen species (RNS) also might be impor-
tant in the pathogenesis of OA.18 RNS are derived from nitric oxide
(NO), which is produced in small amounts by nitric oxide synthase
(NOS) and performs important functions in many physiologic proc­
esses. Human chondrocytes cultured from OA patients express induc-
ible NOS (iNOS) and produce significant amounts of NO. The
1754 mechanisms by which NO could contribute to OA pathogenesis are
still hypothetical. NO inhibits actin polymerization, which affects cell
thermore, it has been found that NO can inhibit matrix synthesis and
promote cell death of chondrocytes mediated by caspase-3 and tyrosine
kinase activation. However, the concept that NO is a promoter of cell
death itself so far remains unproven. Thus, RNS as well as ROS are
exciting areas of future research in the pathogenesis and molecular
biology of OA.
Obesity and adipokines
Being overweight is a strong risk factor for the development of knee
OA and less so for the hand and the hip. Two main theories have been
proposed to explain this association between obesity and OA: the bio-
mechanical and the systemic/metabolic.
The biomechanical hypothesis proposes that obesity leads to an
increased loading of the (knee) joints beyond their capabilities (due to
the increased body weight). Although it is known that moderate loading
is beneficial for chondrocyte physiology and cartilage (matrix) integrity,
excessive stress disrupts the homeostasis of the cartilage matrix. Obvi-
ously, mechanical overload represents a direct physical insult to the
cartilage matrix. Additionally, mechanical forces are transmitted to the
cells and transformed into intracellular signals. Sensitive mechanore-
ceptors such as integrins initiate intracellular signaling cascades, trig-
gering a variety of cellular responses, including the release of paracrine
or autocrine factors. With increased mechanical stress through, for
example, being overweight, cells are overstrained and fail to perform
adequately. Although this theory sounds like a straightforward explana-
tion, epidemiologic studies have also shown a significant correlation
between hand OA and obesity, which cannot be completely explained
by mechanical stress. Therefore, the systemic/metabolic hypothesis
proposes that metabolic factors related to obesity act directly or indi-
rectly on chondrocytes leading to the increased risk for developing
OA.19 Several studies suggest that so-called adipokines, which are pro-
teins synthesized and secreted mostly by adipocytes, are the major
factors linking obesity to OA. Leptin, the prototypic adipokine, has
been found in cartilage of OA patients and shows biologic activity on
chondrocytes. It has been shown to act as a proinflammatory cytokine
and a catabolic factor in cartilage metabolism via induction of MMPs.
Conversely, it might also demonstrate anabolic effects through the

SCHEMATIC REPRESENTATION OF THE INTERLEUKIN-1 (IL-1)
SIGNALING PATHWAY
IL 1
IL 1-R
MAPKKKK
NIK MAPKKK/TAK1/TAB1
MAPKK
NFΚB
JNK p38 ERK
c-jun, ATF, SAP-1, ELK, ...
Catabolic genes
Catabolism
Fig. 173.15  Schematic representation of the interleukin-1 (IL-1) signaling
pathway. IL-1 signals through four major cellular signaling pathways including
the three major MAP kinases (ERK, JUN, and P38) as well as the NF-κB cascade.
This explain the high pleomorphism of genes influenced by IL-1 stimulation in
chondrocytes. (Reprinted with permission from Aigner T, van der Kraan P, van den
Berg W. Osteoarthritis and inflammation—inflammatory changes in osteoarthritic
synoviopathy. In: Buckwalter JA, Lotz M, Stoltz JF, eds. Osteoarthritis, inflammation
and degradation: a continuum. Amsterdam: IOS Press, 2007:219-230.)
stimulation of proteoglycan and collagen synthesis and the induction
of growth factors.
A third (indirect) effect of obesity is certainly also the induction of
a (latent) diabetic metabolic state in the obese patients over time,
enhancing, for example, advanced glycation end products formation
within the cartilage matrix and leading to all their detrimental  play a role in general. More attractive, however, is the concept of “pro-
effects on matrix mechanoproperties and cell behavior as discussed
earlier.
The concept of progressive (apoptotic) cell loss
One of the most simple explanations for OA cartilage degeneration
would be a mere loss of viable chondrocytes due to cell death during
the disease process. Because the chondrocytes are the only source of
matrix component synthesis in articular cartilage, any significant cell
loss would immediately result in a distortion of cartilage matrix
homeostasis. Cell death can, in principle, be divided into apoptosis and
necrosis. Apoptosis has evolved as a mechanism to eliminate surplus,
abnormal, or dysfunctional cells whose survival and proliferation would
be detrimental. Apoptosis is thus normally a beneficial process,
although aberrant apoptosis can occur in pathologic states and apop-
tosis is clearly disadvantageous when it leads to the elimination of
healthy cells.
Many studies have addressed whether cell death plays a role in the
pathology of OA,20 because articular chondrocytes cannot self-renew
and cell loss would therefore be permanent and detrimental. Also
emptying of cellular lacunae (within the cartilage matrix) is a seemingly
obvious histologic feature of OA cartilage.21 However, opinions on the
CHAPTER 173  ●  Pathogenesis and pathology of osteoarthritis
prevalence and importance of chondrocyte death for OA pathology
differ widely,22 and most likely apoptotic cell death is a rather rare
event.23,24 Also, lacunar emptying appears to be largely a technical
artifact (mainly due to cell shrinkage) except in late-stage disease when
in fact there is enhanced cell loss.23
Apoptosis is a complex cellular process, and the factors responsible
for apoptotic cell death in articular cartilage are largely unknown.25
Because β1-integrin–mediated cell-matrix interactions provide survival
signals for chondrocytes, reduction in extracellular matrix integrity due
to degradation may be partly responsible for chondrocyte death in vivo.
In cultured chondrocytes, treatment with Fas ligand (or anti-Fas), NO
donors, tumor necrosis factor-α (TNF-α) or IL-1, taurosporin, ceramide,
or retinoic acid has been shown to induce apoptosis, but it is uncertain
to which of these factors articular chondrocytes are sufficiently exposed
to in the body. Certainly, chondrocytes become somewhat fragile if the
(peri-)cellular matrix is removed or deranged26 as in OA cartilage.27,28
In fact, degradation products of pericellular matrix components 
such as fibronectin might directly induce cellular death programs in
chondrocytes.
Altogether, the experimental evidence clearly suggests that apopto-
sis occurs in OA cartilage, but at a very low rate at least in the earlier
stages. The relative contribution of apoptotic cell death to the patho-
genesis of OA is difficult to assess because of the chronic nature of the
disease process. Also, it is difficult to assess whether apoptosis is
primary or secondary to cartilage matrix destruction. There is a good
likelihood that, at least in later-stage disease, chondrocyte death and
matrix loss form a vicious cycle, the progression of one having promot-
ing effects on the other.
The aging chondrocyte: genomic integrity and
the chaotic phenotype
It has been known for a very long time that age is the most prominent
risk factor for OA, but the explanations for this clear and strong 
association have changed over time.29 Besides the classic hypothesis
of continuing wear and tear, the aging of matrix and cells are pre­
sumably very important etiopathogenetic factors for explaining this
relationship.
The senescence theory of OA postulates that the chondrocytes
become senescent due to cellular stress and/or (focal) proliferation,
finally leading to a failure of the cells to fulfill their essential functions
(e.g., in maintaining proper matrix turnover). In general, cellular 
aging is associated with a number of changes that may undermine the
ability of cells to maintain tissue homeostasis and culminate in cellular
senescence. Senescence occurs in cultures of continuously dividing
somatic cell populations, including chondrocytes, after a limited
number of population doublings and is presumably due to telomere
erosion (replicative senescence). In post-mitotic cells such as chondro-
cytes in vivo obviously classic cellular (replicative) senescence does not
gressive” cellular senescence, which is precipitated by steadily increas-
ing damage to the genomic DNA mostly due to oxidative stress. Thus,
oxidatively damaged molecules (DNA, proteins, lipids) accumulate
with aging and are thought to gradually derange cellular functions.
Accumulation of damaged molecules is usually of only limited rele-
vance for cells if they are proliferating, because a large portion of these
molecules are re-synthesized during replication. However, this con-
stant molecular renewal is missing in post-mitotic cells. Thus, post-
mitotic cells accumulate (oxidatively) damaged molecules significantly
with time.
Substantial DNA damage in addition to other cellular degenerative
alterations is known to occur in OA chondrocytes.30 These effects
would be expected to lead to apoptotic cell death in most cell types. As
alluded to earlier, however, apoptosis appears to occur rather rarely in
OA cartilage. Instead, the chondrocytes remain in a pre-apoptotic or
para-apoptotic state with an uncoordinated pattern of gene expression,
as shown in many in-vivo studies of chondrocyte behavior (Fig. 173.16).
In this respect, the downregulation of molecules that are usually
responsible for regulating cell integrity and/or removal after non-accept-
able cell damage may be an important permissive factor at this stage. 1755
 CHONDROCYTE BEHAVIOR
SECTION 13  ●  OSTEOARTHRITIS AND RELATED DISORDERS

Coordinated processes Un-coordinated

Functional Dysfunctional

Matrix Cellular dysfunction

turnover – repair Cell death/apoptosis

Fig. 173.16  Chondrocyte behavior. Articular chondrocytes in the normal joint behave in a
very structured manner: they react to extracellular stimuli (e.g., joint loading, matrix
changes, and exposure to cytokines and growth factors) according to their internal,
predetermined program. In OA cartilage degeneration, chondrocytes are exposed to
abnormal stimuli such as non-physiologic loading conditions, byproducts of matrix
destruction (e.g., fibronectin and collagen fragments), and cytokines and growth factors
that are not normally expressed in normal cartilage. This exposure leads to structured/
deterministic cellular reactions, some of which are functionally positive for the tissue (e.g.,
anabolism), others of which are dysfunctional/detrimental (e.g., increased matrix
catabolism and cell death). Potentially even more problematic for preserving tissue
homeostasis are the unstructured/stochastic reaction patterns typically seen in OA
chondrocytes, which lead to a significant microheterogeneity of cellular reaction patterns.

For example, the expression of the small GTPase RhoB, a molecule
that is constitutively expressed by normal articular chondrocytes, is
significantly downregulated in OA cartilage.31 RhoB is involved in
cytoskeletal organization, cell transformation, and survival, but, most
importantly, appears to be required for the apoptotic response at least
in some cell types. One intriguing speculation is that the downregula-
tion of RhoB in OA chondrocytes might be a prerequisite for the sus-
tained pre-apoptotic or para-apoptotic phenotype of OA chondrocytes
despite the substantial DNA damage that in normal cells would lead
to apoptotic cell death.
Clearly, aging chondrocytes differ from normal cartilage cells, and,
to a greater degree, chondrocytes from OA cartilage are likely to show
signs of degeneration. However, aging does not inevitably lead to OA
and not all aged chondrocytes show losses of function. On the other
hand, even in “normal” joints of elderly people the cartilage no longer
looks juvenile. The major difference between normal aged cartilage and
OA cartilage is that lesions do not progress and do not result in symp-
tomatic disease as in OA cartilage. Although all individuals are sus-
ceptible to the same age-related changes, these appear to progress faster
in some individuals (i.e., patients with primary OA) than others. Thus,
OA shows “premature” or accelerated degeneration of articular carti-
lage due to a premature senescence of the chondrocytes that maintain
its structural integrity. By analogy to neurodegenerative disorders one
could name OA the “Morbus Alzheimer” of articular cartilage and
chondrocytes.29
This analogy is particularly intriguing as OA, and to a lesser extent
aged chondrocytes show discoordinate reaction patterns (see Fig.
173.16), which are most likely to be related to a disturbance of the
“cellular brain,” the gene regulation machinery. Also, cartilage and
brain share an important similarity: both have “(very) old” largely
postmitotic cells (i.e., basically no cell supply and proliferation after
puberty) and, thus, show hardly any regeneration capacity. However,
cartilage has an additional problem in that it lacks the plasticity of the
neuronal network. As discussed earlier, a functionally intact chondro-
cyte cannot adequately replace a dysfunctional chondrocyte located at
a distance from it. Obviously, additional research will be needed to
determine whether accelerated cell aging processes account for the
phenotype of the disease or, as is the case in Alzheimer’s disease, there
are additional features that would allow one to take new therapeutic
approaches. Even if cell aging is an inevitable feature of OA (e.g., for
limiting tumorigenic capacity), these processes can be used to identify
1756 and manipulate the causes of premature chondrocyte degeneration.
The synovial membrane
The two main clinical symptoms of OA, pain and joint stiffness, are
both significantly related to synovial inflammation and capsular fibro-
sis. However, although its clinical importance is clear, the role of
synovial inflammation in the pathogenetic process of cartilage destruc-
tion remains largely unknown (Fig. 173.17).32
The synovial (inflammatory) reaction observed in OA joint disease
has been primarily considered to be a secondary effect resulting from
the release of cartilage debris from the damaged articular cartilage. This
is in contrast to the situation found for example in rheumatoid arthri-
tis, which is considered to originate from a synovial inflammatory
autoimmune reaction with secondary cartilage destruction. However,
inflammatory reactions in the synovial membrane do occur to some
degree in all OA joints. Also, the fact that most OA patients display 
a minor elevation of C-reactive protein within the serum suggests 
that the inflammatory component plays some role within the disease
process.
Synoviocyte activation and proliferation as well as synovial hyper-
plasia presumably all represent reactive changes responding to increased
demands for clearance of molecular debris in the synovial fluid of the
joint. This also explains the increase in the amount of CD68-positive
type A synoviocytes, which have phagocytic capacity, in the synovial
lining layer.
Although a cellular inflammatory component is missing in particu-
lar cases of early OA, synovial hyperplasia and activation is likely to
generate significant problems for the articular cartilage homeostasis.
Synoviocytes are able to secrete not only matrix-degrading proteases
(e.g., MMPs) but also catabolic cytokines (e.g., IL-1, TNF-α), inducing
inflammatory signaling pathways within the chondrocytes themselves
(see Fig. 173.15).
Many studies have found elevated MMP levels in synovial fluid of
OA patients, namely, collagenase and stromelysin. Davidson and asso-
ciates33 showed upregulation in OA synovium compared with synovium
from patients with fracture of the femoral neck of MMP-9, MMP-11,
MMP-13, MMP-16, and MMP-28 and ADAMTS-2, ADAMTS-10, and
ADAMTS-16.
Not only proteases, cytokines, and growth factors but also other
factors are expressed by inflamed OA synovium. OA synovium pro-
duces increased amounts of ROS, such as NO, peroxynitrite, and
superoxide anion.
IL-1 is also synthesized in substantial quantities in OA synovial
tissues, and this may be a major source of the increased IL-1 levels in

Fig. 173.17  Interaction action between synovium and cartilage in OA.
Molecular detritus from the cartilage activates the synovial lining cells.
The synovial lining cells produce cytokines, growth factors, and (latent)
enzymes. Synoviocyte-derived cytokines and growth factors further
activate the chondrocytes. Enzymes produced by the synovial lining cells
can directly degrade matrix molecules if not inactivated by inhibitors in
the synovial fluid. Latent enzymes can be activated in the milieu of the
OA cartilage. (Reprinted with permission from Aigner T, van der Kraan P, van
den Berg W. Osteoarthritis and inflammation—inflammatory changes in
osteoarthritic synoviopathy. In: Buckwalter JA, Lotz M, Stoltz JF, eds.
Osteoarthritis, inflammation and degradation: a continuum. Amsterdam:
IOS Press, 2007:219-230.)
OA synovial fluid. The fact that TNF-α is less abundant is in line with
the observation that TNF-α can be found only in a limited number of
OA cases. Also, members of the TGF-β superfamily are found in OA
synovium. Synovial tissues from patients with OA express and secrete
TGF-β, mainly TGF-β1. Expression of BMP-2 and BMP-4 was reduced
in OA synovial tissue compared with controls. Vascular endothelial
growth factor (VEGF) as well as basic fibroblast growth factor (bFGF)
have been detected in OA synovium, and immunoreactivity increased
with higher histologic inflammation grade.
Altogether, the synovial reaction is clearly of major importance to
the symptoms of OA but also involved in its progression. The latter
effect is presumably most of all mediated by the secretion of cartilage
matrix degrading proteases as well as chondrocyte-modulating cata-
bolic cytokines.
The subchondral bone
Another important tissue, which is often neglected in OA research, is
the subchondral bone,34 which undergoes severe thickening (sclerosis),
in particular in the subchondral bone plate (compare Fig. 173.4f with
normal bone shown in Fig. 173.4c). Although it is not yet clear whether
changes within this tissue precede changes in the articular cartilage
(i.e., increased subchondral bone mass or stiffness as a risk factor for
OA) or whether subchondral bone changes are secondary adaptation
processes after changes in the biomechanical properties of the overlying
articular cartilage. That both are closely related is suggested by the fact
that the cartilage marker cartilage oligomeric matrix protein (COMP)
and the bone marker bone sialoprotein (BSP) increased concomitantly
in persons with early stages of what later developed into radiographic
OA. Already in early stages this tissue compartment shows significant
changes in terms of increased thickness of the subchondral bone plate
as well as of adjacent bone trabeculae. In later stages, severe remodeling
processes take place in particular in areas of advanced cartilage destruc-
tion: apart from extensive bone sclerosis, significant aseptic bone
necrosis is a common feature of late-stage OA joints. In areas of total
cartilage destruction (i.e., the eburnated bone plate), synovial fluid gets
access to the bone marrow and presumably leads to the bone cysts
frequently seen in late stage disease. Growth factors from the synovial
fluid are probably involved in inducing fibrocytic and even chondro-
metaplastic changes, which lead to the “cartilage nodules” or “tufts”
characteristic for late-stage disease. At least in moderate to advanced
lesions, the changes in the subchondral bone represent one tissue
responsible for the joint pain and, thus, are an interesting target tissue
for symptomatic treatment in these patients. Also, modification of
bone remodeling might be an interesting way to prevent osteophyte
INTERACTION ACTION BETWEEN SYNOVIUM AND CARTILAGE IN OA
CHAPTER 173  ●  Pathogenesis and pathology of osteoarthritis
Synovium Joint space Cartilage
Early Late
Cytokines Synthesis Synthesis
of matrix ↑ of matrix ↓
e.g., IL-1, TNF
molecules molecules
e.g., TGF beta
Growth
BMP
factors
Active Chondrocyte
enzymes TIMP
Latent MMP, ADAMTS
enzymes
Activation
Matrix
degradation
Synovial
activation Degradation products
formation as well as subchondral stiffening, which as such has the
potential to enhance the progression of cartilage destruction.
One interesting notion that would fit the mechanical interrelation
between cartilage and subchondral bone outlined earlier is the inverse
correlation of osteoporotic bone changes and OA. Whereas this was
supported by data of several initial studies, more recent work reported
partly contradicting (supporting and rejecting) data. Therefore, future
more extensive studies have to be done to further elucidate this
phenomenon.
Continuous loading and mechanic stress?
The most long-standing theory in the pathogenesis of primary OA
involves the cumulative (detrimental) effects of continuous mechanical
wear and tear on articular cartilage. Joints and, in particular, the articu-
lar cartilage are always exposed to mechanical stress from loading,
shearing, stretching, or hydrostatic pressure. This results in continu-
ous microtrauma to the cartilage and repetitive damage to the cartilage
extracellular matrix (see Chapter 6). Actually, pathologically increased
mechanical stress has been linked to decreased matrix synthesis and
the induction of proinflammatory genes. This might be explained by
the fact that mechanical signals are directly transmitted to the chon-
drocytes via mechanoreceptors (e.g., integrins) and thus transmitted to
the intracellular compartment. Here they can trigger a variety of cel-
lular responses by modulation of gene expression. One factor in the
pathogenesis might be oxidants produced by chondrocytes in that
process that causes oxidative damage accumulating over a lifetime.
Thus, either cellular overstress or just continuous loading cycles might
result in the loss of extracellular matrix integrity and function and in
slowly progressing destruction of the tissue and the cells.
A more sophisticated explanation of the involvement of loading in
the degeneration process is based on the fact that joints and joint
geometry are remodeled over one’s lifetime and a redistribution of load
might lead to increased stress in formerly unloaded and, therefore,
atrophic cartilage areas. This age-related load redistribution could also
explain why cartilage in the elderly is incapable of withstanding
mechanical forces.
Neuromuscular function and proprioception—
roles in joint homeostasis
Joint stability is dependent on several neuromuscular factors, including
strength and coordination of the joint-related muscles as well as the
ability to sense the position and movement of the limb, the so called
proprioception.35 The quadriceps femoris is one of the major muscles 1757
 involved in providing knee joint stability. An association of weak quad- process. It is the molecular phenotype of the resident chondrocytes that
riceps and radiographic as well as symptomatic OA has been demon- determines the homeostasis of the cartilage matrix. The cellular reac-
SECTION 13  ●  OSTEOARTHRITIS AND RELATED DISORDERS

strated, which most likely results from increased load being applied to
articular cartilage in case of muscular weakening. Thus, muscle-
strengthening seems to have a preventive effect for OA. Whether the
knee joint also benefits from quadriceps strengthening after the onset
of OA remains so far unclear. Another important factor for joint stabil-
ity is the proprioception. It is based on specialized nerve endings known
as mechanoreceptors, which are located in the muscles and the liga-
ments and are essential for fine tuning of muscular movement. Pro-
prioception declines with age, and a further decrease is seen in patients
with OA. However, it is unclear whether impaired proprioception in
OA contributes or results from the disease.
tion pattern of the chondrocytes in OA cartilage degeneration, however,
is poorly understood, mainly because many of the involved genes are
not yet identified and characterized. This exactly is one of the strengths
of the gene expression chip technology.41,42 In fact, a lot of studies have
been performed during the past decade using the array-chip technology
and quite a few interesting genes and gene clusters were found42: this
included in addition to known candidate gene groups such as anabolic
and catabolic genes also new gene networks, such as a cluster of oxida-
tive defense genes (e.g., superoxide dismutase-2 [SOD2]—the major
mitochondrial ROS scavenger) and others. Further studies have to
validate the relevance of these findings for understanding and manipu-
lating these molecular networks in the context of OA.

GENETICS, FUNCTIONAL GENOMICS,

AND EPIGENETICS
Genetics
No doubt, OA, like nearly all other diseases, is initiated and progresses
dependent on the genetic background of the individual. Therefore, the
potential of genetics for elucidating the pathogenesis of OA is the
subject of intensive investigation at the moment (see Chapter 174).
Clearly, tools have been emerging rapidly in this area of research and
the first hot candidate genes have been identified, such as frizzled
related protein 336 and asporin.37 However, clear-cut pathogenetic con-
cepts have not emerged for any of the suggested genes. Methods for
dissecting the complex interplay between genes and environment are
still to be developed and refined. One major difficulty is to separate
genes that influence the development of the joints (thus leading, for
example, to a mechanical weakness) from genes leading to an insuffi-
ciency of the cells to maintain adequate repair and joint homeostasis
later in life, which are finally relevant for preventing and treating OA.
Another reason for the complexity of the interpretation of genetic data
is that many of the genes detected are likely to be linked to other organ
systems such as neuronal crosslinking, muscle strength, and mental
perception. All these will have roles in OA development and disease
manifestation without being related to cartilage physiology and
pathobiology.
It has been known for some time that “OA runs in families,” but
to what extent this is due to shared genetic influences or shared family
environment is still uncertain. The disease is clearly multifactorial and
polygenetic, that is, it results from the interaction of several, possibly
many, genes. This fact, combined with the late onset of the disease,
which makes linkage studies almost impossible, has made the task of
identifying susceptibility genes very difficult. Classic twin studies have
estimated the influence of genetic factors to be 39% to 65% for radio-
graphic OA of the hand and knee, about 60% for OA of the hip, and
up to 70% for OA of the spine.38 In contrast, the Farmington study, a
multigenerational cohort study of hand OA, estimated heritability to
be only 28% to 34%.39 Overall, the strongly varying results of these
studies point to a considerable heterogeneity of the genetics of OA.
Also, it seems that different combinations of different susceptibility
genes may apply to different forms of OA.40
Functional genomics
One major change in OA research in recent years has been the shift
from investigating primarily biochemical aspects of articular cartilage
matrix destruction to studying the molecular aspects of the disease
Epigenetics
Clearly, one major issue during disease progression is a severe altera-
tion of the gene expression phenotype of the articular chondrocytes.
Besides gene regulation by ordinary transcription factors, epigenetic
gene regulation may play an important role in determining gene expres-
sion levels, namely, methylation of genes coding for cytokines, growth
factors, and so on.43 In fact, first experimental data indicate that dif-
ferences in the methylation status within disease-relevant promoters
are likely to induce/repress respective gene expression.44,45 This is,
however, not true for all genes. Thus, for example, no changes in the
methylation levels of the aggrecan gene in aged and diseased chondro-
cytes were found.46 Also, no de novo methylation of the p21(WAF1/
CIP1)-promoter-CpG island is involved in this process, although
p21(WAF1/CIP1) is known to be regulated by methylation, for example,
in oncogenesis.47 The overall genome-wide methylation level remains
unchanged between normal and diseased and aged chondrocytes,
although this does not exclude differences in methylation levels for
selected promoter regions. Altogether data are sparse so far and epi-
genetic disregulation in OA chondrocytes is clearly one potentially
important new research topic for understanding the cellular (dis)behav-
ior during the disease process.
CONCLUSION
The most common and generally accepted theory of the pathogenic
mechanisms of primary OA involves the cumulative effects of continu-
ous mechanical wear and tear on articular cartilage. In the model of
biochemical cartilage degeneration, the initiation and progression of
primary OA is linked to time/age-related modifications of resident
cartilage matrix components as well as age-dependent changes in the
properties of newly synthesized and secreted matrix components,
which together culminate in a structurally and functionally inferior
cartilage matrix. In addition to the extracellular cartilage matrix, the
chondrocytes are viewed as major contributors to disease, progression
and premature aging of the chondrocytes appears to be important in
the pathogenesis of OA. Unfortunately, the underlying causes of pre-
mature aging are largely unknown at the moment and are therefore
important areas for future research. Of interest, modern aging research
points out that aging is not an inevitable event, at least not with respect
to the period between 50 and 70 years of age, but rather an interesting
target for therapeutic intervention. Thus, anti-aging strategies might
well complement present therapeutic approaches related to anabolism,
catabolism, apoptosis, and inflammation processes, all of which are
known to be relevant in OA.

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