Pathogenesis and pathology of osteoarthritis

SECTION 13 OSTEOARTHRITIS AND RELATED DISORDERS
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 osteoarthrosis, 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 prevalence increases sharply with age it is not part of normal aging. Very
little is known about the underlying causes of OA, and many hypotheses 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 collectively 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 morphologic 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 appreciation of the contribution of all three joint compartments to disease
173
progression, research in OA pathogenesis, biomarkers, and treatment

has broadened immensely and many new potential therapeutic targets
have emerged over the past years.
THE NORMAL JOINT: ANATOMY

PHYSIOLOGYFUNCTION
Understanding of joint dysfunction requires some knowledge of normality and the comparison of the diseased state to the physiologic situation (Fig. 173.2). The most important requirements for normal joint
function are the freedom of the opposed articular surfaces to move pain
freeand largely frictionlesslyover 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
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 provided 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 surfacesin combination with the articular cartilage
determine the absorption properties during movement. Also, the synovial 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 ligaments that provides the mechanical stability of the joints and ultimately 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 synovial 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.
CHAPTER 173 Pathogenesis

and
pathology of
osteoarthritis
OSTEOARTHRITIS
AND RELATED
DISORDERS
Pathogenesis
and pathology of osteoarthritis
Pathogenesis and pathology

of osteoarthritis
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 consists of evenly stained (hyaline) collagen- and proteoglycan-rich extracellular matrix with sparsely distributed cartilage cells (chondrocytes).
The cells represent less than 5% of the total volume of articular cartilage 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.
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 destruction 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
membrane
(Subchondral) bone
Synovial
hyperplasia
(Subchondral)
bone remodelling
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.)
1742
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 supramolecular structures also takes place. For example, destabilization of the collagen network results in microscopically and, finally, macroscopically
visible matrix destruction. Both mechanical wear and enzymatic degradation 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 microscopic (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 chondrocytes. 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 nonweightbearing 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 formation. For example, the exogenous application of transforming growth
factor- (TGF-) 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 different histories, symptoms, and morphologic changes. Common to all
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.
(Courtesy of Felix Eckstein, Salzburg, Austria.)
CHAPTER 173 Pathogenesis and pathology of osteoarthritis
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 secondary (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., preconditions 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 modifications) 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 variability, 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
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., Charcots joint)
Overload causing excessive wear (work, sport, varus or valgus deformity)
Pagets 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 histopathologic 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
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
Mankin 02
OA
Mankin 67
Mankin 35
Mankin 810
Mankin >10
Sup. zone
Mid. zone
Stage 0
Stage I
Stage II
Stage III
Toluidine blue
Toluidine blue
Bone
Toluidine blue
Toluidine blue
Calc. zone
Toluidine blue
Deep zone
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
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Feature
Score
Histologic feature
Cartilage structure
Normal
Superficial fibrillation
Pannus and superficial fibrillation*
Fissures to the middle zone
Fissures to the deep zone
Fissures to the calcified zone
Normal
Diffuse hypercellularity
Cell clusters
Hypocellularity
Normal
Slight reduction
Moderate reduction
Severe reduction
No staining
Total disorganization*
Intact
Tidemark penetrated by vessels
Chondrocytes
Safranin-O staining
Tidemark
*Might best be removed (relates to osteophyte formation).
Might best be supplemented with or duplicated tidemark.

From Mankin HJ, Dorfman H, Lippiello L, etal. Biochemical and metabolic abnormalities in
articular cartilage from osteoarthritic human hips. J Bone Joint Surg Am 1971;53:523-537.
TABLE 173.6 SCORING OF OSTEOARTHRITIS ACCORDING TO

PRITZKER AND COLLEAGUES (2006)
Grade
Histologic properties
Matrix: surface intact (normal architecture)

Cells: intact, appropriate orientation
Matrix: superficial zone intact, edema and/or superficial fibrillation

(abrasion), focal superficial matrix condensation
Cells: cell death, proliferation (cluster formation), hypertrophy
As above:
Matrix: discontinuity at superficial zone (deep fibrillation)
Loss of proteoglycan staining in upper third of cartilage
Focal perichondral increased proteoglycan stain in middle zone
Disorientation of chondron columns
As above:
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
As above:
Cartilage matrix loss with delamination of superficial zone
Excavation with matrix loss from superficial to middle zone
Formation of cysts in the middle layer
Complete matrix loss with denudation of the sclerotic subchondral

bone or fibrocartilage
Microfracture with repair limited to bone surface
Bone remodeling (more than osteophyte formation only) with

microfracture, fibrocartilage, and osseous repair above the
previous surface
From Pritzker KP, Gay S, Jimenez SA, etal. Osteoarthritis cartilage histopathology: grading and
staging. Osteoarthritis Cartilage 2006;14:13-29.
TABLE 173.3 STAGING OF OSTEOPHYTE DEVELOPMENT ACCORDING

TO GELSE AND AIGNER (2003)
Stage 0
(normal)
Normal periosteum
Stage I
Slight thickening of the periosteum

Incipient formation of fibrocartilage (some round cells, some
metachromatic tissue staining of the extracellular matrix)
No/slight active bone formation
Molecular markers:
Focal collagen type II expression
No collagen type X
Stage II
Pronounced thickening of the periosteal layers

Well-established formation of fibrocartilage (many round cells,
strong metachromatic tissue staining of the extracellular matrix)
Some/moderate bone formation
Molecular markers:
Distinct collagen type II expression
No collagen type X
Stage III
Pronounced thickening of the periosteal layers

Well-established formation of fibrocartilage (many round cells,
strong metachromatic tissue staining of the extracellular matrix,
formation of lacunae)
Strong active bone formation
Molecular markers:
Distinct collagen type II expression
Collagen type X expression in basal areas
Collagen type VI: intermixed with collagen types I, III, and V in
the intercellular matrix
Stage IV
Significant thickening of the periosteal layer

Apparent formation of fibrocartilage with partial hyalinization of
the extracellular matrix (chondrocyte-like cells in lacunae,
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 173.2 GRADING OF OSTEOARTHRITIS ACCORDING TO

MANKIN AND COLLEAGUES (1971)
From Gelse K, Soeder S, Eger W, etal. Osteophyte development-molecular characterization of

differentiation stages. Osteoarthritis Cartilage 2003;11:141-148.
TABLE 173.4 GRADING SCHEME ORIGINALLY SUGGESTED BY OUTERBRIDGE

FOR MACROSCOPIC CHANGES SEEN ON THE PATELLA
Grade I
Softening and swelling of the cartilage
Grade II
Fragmentation and fissuring in an area 0.5 inch in diameter
Grade III
Area more than half an inch in diameter is involved
Grade IV
Erosion of cartilage down to bone
From Outerbridge RE. The etiology of chondromalacia patellae. J Bone Joint Surg Br
1961;43:752-757.
TABLE 173.5 STAGING OF JOINT DESTRUCTION ACCORDING TO OTTE (1969)

Grade
Morphology
Normal
Superficial fibrillation, no cartilage loss
II
Cartilage lesions (without full-thickness defects): deep fibrillation,

fissures to middle zone and/or partial cartilage matrix loss
III
Cartilage lesions (without full thickness defects): fissures to deep zone

and partial cartilage matrix loss
IV
Complete cartilage loss (at least focally)
From Otte P. Die konservative Behandlung der Hft-und Kniearthrose und ihre Gefahren. Dtsch
Med Jahresschr 1969;20:604-609.
1745
TABLE 173.7 OARSI TERMINOLOGY OF OSTEOARTHRITIC JOINT DEGENERATIONA PROPOSAL FOR A CONSENSUS
Preferred term
Definition
Synonym
Superficial zone
Includes the surface and upper zones
Surface zone
Cartilage zone immediately subjacent to the joint surface.

Collagen fibers are aligned parallel to surface (without cells)
This zone might be not present in normal cartilage samples/in some species.
Lamina splendens
Upper zone
Collagen fibers are aligned parallel to surface. Chondrocytes, elongated and

flattened, are aligned parallel to collagen fibers and to joint surface.
Horizontal zone/layer
Tangential zone/layer
Superficial zone/layer
Middle zone
Zone subjacent to upper zone.

Collagen fibers are aligned intermediately between upper and deep zone alignments.
Chondrocytes present in groups (chondrons) aligned parallel to collagen fibers.
Transitional zone/layer
Intermediate zone/layer
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
Penetration
Advancement
Duplication/multiplication
Zone of increased calcification at border of uncalcified and calcified cartilage
Calcification front
Ligne bordant (increased basophilic stain)
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
Surface
Into the superficial zone
Into the middle zone
Into the deep zone
Full depth
Loss of articular cartilage tissue including superficial and at least portions of deeper
cartilage layers
Loss
Ulceration
Abrasion
Delamination
Flaking
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 nomenclature is proposed by the Osteoarthritis Research Society International
(OARSI) (Table 173.7).4
TYPING AND GRADING OF SYNOVIAL

MEMBRANE ALTERATIONS IN OSTEOARTHRITIS
1746
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 specimens, 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
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 pathogenesis is the inflammatory OA synoviopathy, which displays moderately 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
Normal
Hyperplastic
synoviopathy
Inflammatory
synoviopathy
Fibrotic
synoviopathy
Detritus-rich
synoviopathy
Villous hyperplasia
++(+)
++(+)
++(+)
++(+)
Synovial liningproliferation
++
++
++(+)
Synovial liningactivation
++
Fibrinous exudate
(+)
++(+)
Capsular fibrosis
(+)
+++
+++
(Macromolecular) cartilage and bone debris
(+)
+++
Granulocytic infiltrate
Lymphoplasmocellular infiltratediffuse
++
(+)
+(+)
Lymphoplasmocellular infiltrateAggregates/follicles
++
(+)
(+)
Bold italics = key diagnostic criteria.

From Oehler S, Neureiter D, Meyer-Scholten C, etal. Subtyping of osteoarthritic synoviopathy. Clin Exp Rheumatol 2002;20:633-640.
appears to correlate directly with interleukin (IL)-1 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 presence 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 macromolecular 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 synoviopathy 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,
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 differentiation. 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 additionally 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 mesenchymal precursor cells for filling up cartilage defects).
TABLE 173.8 MAJOR HISTOPATHOLOGIC FEATURES OF THE FOUR PATTERNS OF OA-ASSOCIATED SYNOVIOPATHY IN
COMPARISON TO EACH OTHER AND TO NORMAL SYNOVIAL MEMBRANE
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 pathophysiology as well as assist in the development of disease-modifying
therapeutic agents and biologic markers for diagnosing and constructing 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 impossible and a number of models employing various species are currently
in use. These include spontaneous as well as induced (surgically, enzymatically/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 mechanisms of disease. Given this heterogeneity of the OA disease process,
identification of an appropriate disease-mechanismoriented model
may be a more realistic goal and better suited to a particular investigation 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
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 inflammationinflammatory 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
Osteophyte
Normal
Stage 0
Stage I
Stage II
Stage III
Stage IV
Articular
cartilage
Growth
plate
GAGs
Aggrecan
Col1
Col6
interterritorial
Col6
pericellular
Col2a
Fig. 173.7 Osteophyte development can be

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
formed cartilage, but no (endochondral) bone
formation is observed (c, h, k). Stage III (early
osteophytes) shows an arrangement as the fetal
growth plate cartilage with hypertrophic
differentiation in the deepest cartilage layers and
active bone formation underneath (d, i, k). Stage IV
(mature osteophytes) shows a structure most
resembling hyaline articular cartilage physiologically
covering the joint surfaces (e, j, k). Normal periosteum
is shown in a and f (a to e, H&E; f to j, toluidine blue
staining). (Reprinted with permission from Gelse K,
Soeder S, Eger W, etal. Osteophyte developmentmolecular characterization of differentiation stages.
Osteoarthritis Cartilage 2003;11:141-148.)
Col2B, Col11
Col 10
PATHOGENETIC CONCEPTS OF OSTEOARTHRITIS

OA is a heterogeneous condition and most likely many different causes
exist that initiate or at least promote the disease process. Consequently, 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 concepts is provided.
Extracellular matrix
functional element
Articular cartilage
Chondracytes
reactive element
The articular cartilage and the

extracellular matrix
Articular cartilage is a highly specialized and uniquely designed biomaterial (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 immediate to the cells, the interterritorial matrix compartment represents
the major portion of the cartilage matrix far off the cells and the territorial matrix the (not really well defined and characterized) cell-associated 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 noncollagenous 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, etal. Osteoarthritis:
pathobiologytargets and ways for therapeutic intervention. Adv Drug Deliv Rev
2006;58:128-149.)
collagen II fibrils also contain many non-collagenous protein components such as small proteoglycans and cartilage matrix proteins. The
non-fibrillar component of hyaline articular cartilage consists predominantly 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
elasticity as water molecules are drawn back into the matrix on unloading 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
COOH
NH2
Chondrocyte
Type XI
Type IX
Type X
Type VI
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 interterritorial 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 signaling 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 turnover 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

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.
One major threat to the cartilage matrix and thus to the integrity of
articular cartilage are matrix-degrading enzymes destroying the collagen 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 biomechanical function is largely due to the destruction and loss of the (inter)
territorial cartilage matrix. So far, our knowledge focuses on degradation 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 characteristic 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 firstthe loss of proteoglycans or the loosening of the collagen
networkbecause both do eventually influence the other as well. Loosening 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
THE STRUCTURE OF AGGRECAN

G1
E1
G2
KS- rich
domain
E2 (C5- rich domain)
G3
Ig fold
NH2
Lectin
binding
NH2 COOH
Proteoglycan
tandem repeat
Link protein
1750
Keratan sulfate
N-linked oligosaccharides
O-linked oligosaccharides
Chondroitin sulfate
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),
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
double loop structure (proteoglycan tandem repeat
[PTR]). In addition, both G1 and LP show an
additional loop structure (immunoglobulin fold [Ig
fold]) that can selectively interact with H hyaluronic
acid to form aggregates. The G3 domain contains a
lectin-binding region.
Osteoarthritis:
Imbalance of cartilage matrix turnover
IGF
BMP
...
Il-2
TNFa
...
Anabolism
Aggrecan
(collagen type II)
Collagen type VI
Collagen type IX
Link protein
...
Catabolism
Collagenases
Aggrecanases
MMP-1
MMP-3
(MMP-8)
MMP-14
MMP-13
ADAMTS-1
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-1 and TNF- 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 metalloproteinases including matrix metalloproteinases (MMPs), as well as adamalysins 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 cartilage. These damaged components threaten the functional integrity of
the extracellular matrix and the articular cartilage, in particular if challenged 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 degeneration 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 crosslinking). 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 disintegration. Also, the aggrecan molecules change over age. Aggrecan monomers and polymers get smaller and have fewer sugar side chains.
Interestingly, this is not only related to accumulating molecular degradation 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, nonenzymatic 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. Pseudogout 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 concentration 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 firstthe cell
and matrix degradation or the crystal formation. Most likely they
promote each other with metabolic disturbance leading to cellular
degeneration and vice versa.
THE HALLMARK OF OA CARTILAGE DEGENERATION IS

A LOSS OF CARTILAGE MATRIX HOMEOSTASIS
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 generally 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 morphology 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
TABLE 173.9 DIFFERENCES BETWEEN KNEE AND ANKLE JOINT STABILITY,

MOTION, AND CARTILAGE
Feature
Knee
Ankle
Joint stability
Relatively unstable
Highly stable
Non-congruent
Highly congruent
Flexion/extension
Flexion/extensor
Joint motion
Rotation
Cartilage
Cellularity
Same
Same
Cartilage thickness
2-6mm
1-1.5mm
Superficial chondrons
Single cells
Clusters of 2-4 cells
Sulfated glycosaminoglycan
content
Lower
Higher
Water content
Higher
Lower
Collagen content
Same
Same
Dynamic stiffness
Lower
Higher
Hydraulic permeability
Higher
Lower
Peak stress with 65% final

strain
11MPs
16MPs
In explants
Higher
Lower
In alginate
Same
Same
Proteoglycan half-life
22.68 days
16.58 days
Protein synthesis
Lower
Higher
In alginate
11pg/mL
56pg/mL
In explants
6pg/mL
35pg/mL
Proteoglycan synthesis
(anti-anabolic)
Low dose (1nM)
High dose (100nM)
Proteoglycan loss
(catabolic)
Significant at 7 days
Not significant
after 28 days
Attempted repair
No significant rebound
Significant rebound
Upregulation of
collagen degradation
Upregulation of
matrix synthesis
Glycosaminoglycan synthesis
IC30 for IL-1 reduction of

proteoglycan synthesis
Influence of Fn-fs on
(Response to anabolic factors

after catabolic stimulation)
Response to degeneration
From Eger W, Schumacher BL, Mollenhauer J, etal. Human knee and ankle cartilage explants:
catabolic differences. J Orthop Res 2002;20:526-534.
matrix provides the mechanical properties of the cartilage tissue.

However, the cells (i.e., the chondrocytes) represent the only vital
element of the cartilage tissue, although they represent only about two
to three volume percent of the articular cartilage in the adult. Thus,
besides changes in the extracellular matrix changes within the cells
also are obviously potential causes of the OA disease process and the
study of the chondrocyte cell phenotype/behavior (Fig. 173.12) can
provide substantial scientific insights into the disease mechanisms
of OA.
The developmental history as a model of

chondrocyte reactivity in the adult
1752
A very important and interesting aspect of cellular behavior in the adult

organism is the recapitulation of molecular mechanisms that occurred
during fetal development (Fig. 173.13). This phenomenon is also true
for OA chondrocytes. In fact, many of the biologic changes that occur

in OA cells mimic a differentiation pattern characteristic of fetal skeletogenesis. This includes changes not only in cellular phenotypes and
in anabolic and catabolic events but also in other basic mechanisms
during the disease process such as matrix calcification, apoptosis, and
proliferation. Thus these (evolutionary and developmental) comparisons are attractive for explaining chondrocyte behavior and disease
pathways in the adult, but uncoordinated degenerative events should
not be mistaken for tightly regulated developmental processes (Fig.
173.14). Both scenarios presumably involve similar molecular and
regulatory events, but just as in a jigsaw puzzle the assembly is the
challenge.
The OA chondrocyte phenotype

Chondrocytes in normal adult articular cartilage are stable, postmitotic, differentiated cells that maintain tissue homeostasis by synthesizing very low levels of extracellular matrix components to replace
damaged molecules, thus preserving the structural integrity of the
cartilage matrix. The cells are the major regulators of matrix anabolism
and catabolism of articular cartilage. One well-documented change in
OA cartilage is the induction of an activated cellular phenotype within
the chondrocytes whereby matrix anabolism is strongly stimulated.
Nevertheless, the chondrocytes fail to compensate for matrix damage
induced externally (e.g., by mechanical stress or enzymatic degradation
through synovial proteases). Additionally, the chondrocytes do play an
active role in the degradative process themselves, a phenomenon
termed chondrocytic chondrolysis.12 During chondrocytic chondrolysis,
OA chondrocytes activate or upregulate the expression of many matrixdegrading proteases such as the MMPs, which are largely responsible
for the breakdown of the collagenous and non-collagenous cartilage
matrix components. This elevated proteolytic activity is not sufficiently
counterbalanced by an increase of the chrondrocyte anabolic activity.
This is particularly true for the upper zones of damaged cartilage (the
progression zone), in which the anabolic activity even drops again
severely.13
Activation of inflammatory signaling

In addition to local and/or general inflammatory responses within the
synovial membrane, the activation of inflammatory (signaling) pathways within the chondrocytes themselves appears to play a crucial role
in OA disease progression. Activation of such processes is independent
of direct inflammatory cell infiltrates (i.e., lymphocytes, granulocytes,
plasma cells), which are not present in OA articular cartilage. Activated
inflammatory signaling pathways have been shown to induce catabolic
responses in chondrocytes, namely, matrix degrading proteases such
as MMP-13, MMP-1, and others. One of the most prominent catabolic
cytokines in OA is the proinflammatory cytokine IL-1. Elevated levels
of IL-1 are found in synovial fluids of patients suffering from rheumatoid arthritis and, to a lesser extent, in synovial fluid from OA patients.
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 cartilage from the synovial space. IL-1 significantly affects gene expression
patterns within articular chondrocytes via multiple intracellular pathways, particularly the MAP kinases and NF-B pathways (Fig. 173.15).15
IL-1 downregulates the expression of the major cartilage matrix components, aggrecan and collagen type II, and, thus, counteracts the
effects of anabolic factors on matrix synthesis. Additionally, IL-1
induces the expression of matrix degrading enzymes such as MMP-1,
MMP-3, MMP-13, or ADAMTS-4, which are all potential major
players in the destruction of cartilage matrix components. Besides
these direct effects, IL-1 also induces other cytokines with synergistic
(catabolic) effects such as IL-6 and leukemia inducing factor (LIF),
further expanding its versatile effects on cartilage tissue homeostasis.
Oxygen, reactive oxygen species, and reactive

nitrogen species
Articular cartilage is an avascular tissue and its nutrition is mainly
supplied by the synovial fluid. Because of the rather long diffusion
CELL BIOLOGY OF OA
Synovial factors Matrix alterations
Aggrecan
Fibronectin
Autocrine and
paracrine factors
SS
Changes in phenotype to:

Dedifferentiated cells
Hypertrophic cells
Precursor cells
Proliferation and/or
(apoptotic) death
Chondrocyte
Type II collagen
(Pre)senescence
Anabolic
activation
Catabolic activation
THE DEVELOPMENTAL MODEL OF CHONDROCYTE BEHAVIOR

APPLIED TO OA IN THE ADULT
Osteoarthritis
Developmental model: endochondral ossification
Pathomechanisms
Development steps
Differentiation
Chondrogenesis
Marker genes
Epichondral
Anabolism
Link protein
Matrix synthesis
Proliferation
Proliferation
Catabolism
Matrix degradation
Calcification
Hypertrophy
Calcification
Cell death/apoptosis
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
induce a plethora of abnormal cellular responses made
apparent by the changes in anabolism, catabolism, and
phenotype that have been demonstrated in the cells. Also,
chondrocyte numbers are modified by proliferation or
apoptosis. In addition, cells might become presenescent,
leading to an overall loss of chondrocyte function. In this
schematic, an OA chondrocyte is embedded in a
cartilaginous extracellular matrix of type II collagen,
aggrecan, and fibronectin, for simplicity. Other collagens,
proteoglycans, and noncollagenous proteins are also present
at varying levels. (Reprinted with permission from Aigner T,
Soder S, Gebhard PM, etal. Mechanisms of disease: role of
chondrocytes in the pathogenesis of osteoarthritisstructure,
chaos and senescence. Nat Clin Pract Rheumatol
2007;3:391-399.)
COL2A
SOX9
COL2/9/11
aggrecan
Resting
Proliferative
COL10
ssDNA
Ki-67
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, etal. Mechanisms
of disease: role of chondrocytes in the pathogenesis of osteoarthritis-structure, chaos and senescence. Nat Clin
Pract Rheumatol 2007;3:391-399.)
1753
1754
RNA IN SITU HYBRIDIZATION FOR MARKER GENES AND

OA RELEVANT PROTEASES IN THE TIBIA OF NEWBORN MICE
Cartilage
synthesis
Resting
chondrocytes
Proliferating
chondrocytes
Cartilage
maturation
and degradation
Hypertrophic
chondrocytes
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 researchpotentials 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
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 physiologically 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-1 (HIF-1), which has key functions in controlling 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 activation, 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, adhesion molecules, and matrix components. However, in pathologic conditions, 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 implicatedbesides metalloproteinasesin 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 important 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 inducible NOS (iNOS) and produce significant amounts of NO. The
mechanisms by which NO could contribute to OA pathogenesis are
still hypothetical. NO inhibits actin polymerization, which affects cell

adhesion, signaling from extracellular matrix, and phagocytosis. Furthermore, 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 biomechanical 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. Obviously, 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 mechanoreceptors such as integrins initiate intracellular signaling cascades, triggering 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 explanation, 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 indirectly on chondrocytes leading to the increased risk for developing
OA.19 Several studies suggest that so-called adipokines, which are proteins 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
IL 1
IL 1-R
MAPKKKK
NIK
MAPKKK/TAK1/TAB1
MAPKK
NFB
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-B 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 inflammationinflammatory 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
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 apoptosis 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
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 1-integrinmediated 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- (TNF-) 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 apoptosis 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 pathogenesis 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 promoting effects on the other.
SCHEMATIC REPRESENTATION OF THE INTERLEUKIN-1 (IL-1)

SIGNALING PATHWAY
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 chondrocytes in vivo obviously classic cellular (replicative) senescence does not
play a role in general. More attractive, however, is the concept of progressive cellular senescence, which is precipitated by steadily increasing 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 relevance for cells if they are proliferating, because a large portion of these
molecules are re-synthesized during replication. However, this constant molecular renewal is missing in post-mitotic cells. Thus, postmitotic 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-acceptable cell damage may be an important permissive factor at this stage.
1755
CHONDROCYTE BEHAVIOR
1756
Coordinated processes
Un-coordinated
Functional
Dysfunctional
Matrix
turnover repair
Cellular dysfunction
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 downregulation of RhoB in OA chondrocytes might be a prerequisite for the sustained 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 symptomatic disease as in OA cartilage. Although all individuals are susceptible 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 cartilage 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 chondrocyte 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 Alzheimers 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
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 fibrosis. However, although its clinical importance is clear, the role of
synovial inflammation in the pathogenetic process of cartilage destruction 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 arthritis, 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 hyperplasia 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 particular 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-), 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 associates33 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 produces 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
INTERACTION ACTION BETWEEN SYNOVIUM AND CARTILAGE IN OA
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 inflammationinflammatory changes in
osteoarthritic synoviopathy. In: Buckwalter JA, Lotz M, Stoltz JF, eds.
Osteoarthritis, inflammation and degradation: a continuum. Amsterdam:
IOS Press, 2007:219-230.)
Joint space
Cytokines
e.g., IL-1, TNF
Growth
factors
Cartilage
Early
Late
Synthesis
of matrix
molecules
Synthesis
of matrix
molecules
e.g., TGF beta

BMP
Active
enzymes
TIMP
Latent
enzymes
MMP, ADAMTS
Chondrocyte
Activation
Synovial
activation
OA synovial fluid. The fact that TNF- is less abundant is in line with
the observation that TNF- can be found only in a limited number of
OA cases. Also, members of the TGF- superfamily are found in OA
synovium. Synovial tissues from patients with OA express and secrete
TGF-, mainly TGF-1. 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 catabolic 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 destruction: 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 chondrometaplastic 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
Matrix
degradation
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.
Synovium
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 articular cartilage are always exposed to mechanical stress from loading,
shearing, stretching, or hydrostatic pressure. This results in continuous 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 chondrocytes via mechanoreceptors (e.g., integrins) and thus transmitted to
the intracellular compartment. Here they can trigger a variety of cellular 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 ones 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 quadriceps and radiographic as well as symptomatic OA has been demonstrated, which most likely results from increased load being applied to
articular cartilage in case of muscular weakening. Thus, musclestrengthening 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 stability is the proprioception. It is based on specialized nerve endings known
as mechanoreceptors, which are located in the muscles and the ligaments and are essential for fine tuning of muscular movement. Proprioception 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.
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 concepts 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 insufficiency 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 radiographic 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
process. It is the molecular phenotype of the resident chondrocytes that

determines the homeostasis of the cartilage matrix. The cellular reaction 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 oxidative 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 manipulating these molecular networks in the context of OA.
Epigenetics
Clearly, one major issue during disease progression is a severe alteration 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 expression levels, namely, methylation of genes coding for cytokines, growth
factors, and so on.43 In fact, first experimental data indicate that differences 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 chondrocytes 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 epigenetic disregulation in OA chondrocytes is clearly one potentially
important new research topic for understanding the cellular (dis)behavior during the disease process.
CONCLUSION
The most common and generally accepted theory of the pathogenic
mechanisms of primary OA involves the cumulative effects of continuous 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 premature 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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REFERENCES
Full references for this chapter can be found on www.expertconsult.com.
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SECTION 13 OSTEOARTHRITIS AND RELATED DISORDERS

Thomas Aigner and Nicole Schmitz

(OA) is pathologically primarily characterized by focal

progression, research in OA pathogenesis, biomarkers, and treatment

THE NORMAL JOINT: ANATOMY

CHAPTER 173 Pathogenesis