PREPARED BY:

Sanish Basnet
BVSc&A.H., 8th Semester
AFU, Rampur, Chitwan, Nepal
1. :

Bones: Theyre alive.-Mark

Johnson, University of Missouri-Kansas City

Bone is defined as highly specialized rigid mineralized connective tissue forming

supportive framework of body characterized by its rigidity, hardness and power of
regeneration and repair. It protects the
vital organs, provides environment for
marrow (both blood forming and fat
storage),produce red and white blood
cells, maintains calcium hemostasis
and acid base balance, reservoir for
growth factors and cytokines(Taichman
, 2005).
Bone constantly undergoes remodeling
(reshaping) or shape shifting during an
individuals life to help it adapt to
changing biochemical forces, as well as
to remove old micro damaged bone and
replace it with new, mechanically
stronger bone (Clarke, 2008).
Bone is the mineralized osseous tissue, also called bone tissue, that gives it rigidity
and a honeycomb-like three-dimensional internal structure.
Bone is a dynamic tissue which adapts to load variations. This adjustment occurs
through continuous structural remodeling. Bone is a dynamic, living tissue; not the
and dry, lifeless structure with 30 % composed of living tissue, cells, and blood
vessels (goes in and out carrying oxygen and nutrients and taking away debris and
wastes). About 45 % is mineral (Calcium and phosphorous) giving rigidity.
1.1. Two types of bone:
1) Cortical bone: makes up 80 % of skeletal mass, but accounts for only a small
portion of total bone turnover. The basic unit of Compact Bone is an
"osteon", which is also known as a "Haversian System".
Haversian System consists of four parts:
Central tube (Haversian canal-contains nerves and blood vessels), Lamellae
(Concentric rings giving hardness and strength), Lacunae (bone cells) and
Canaliculi (route for nutrients to reach osteocytes)

2) Trabecular (Calcaneus) bone: represents 20 % of skeletal mass, but due to its

large surface- to - mass ratio, a far greater % (80%) of bone turnover.
Contains lamellae, osteocytes, lacunae and canaliculi. The spaces between
the trabeculae of some spongy bones are filled with red bone marrow.
Based on the pattern of collagen forming the osteoid, two types of bone are
identied: woven bone, which is characterized by a haphazard organization of
collagen bers (Eriksen et al. ,1994), and lamellar bone, which is characterized
by a regular parallel alignment of collagen into sheets.
2. Bone cells:
4 different cell types are found in developing bone:
Osteoprogenitor cells
Osteoblasts
Osteocytes
Osteoclasts

Osteoprogenitor cells
Bone is derived from mesenchyme cells. After birth, flattened, poorly-
differentiated, mesenchyme-like cells, are found in the periosteum and
endosteum. These cells can divide (mitosis) and differentiate into bone
cells (osteogenic potential) and as a result are known as osteoprogenitor
cells.

Osteoblasts
The first cells to develop from the osteoprogenitor cells are the osteoblasts
and are involved in the formation of bone and are found on the boundaries of
developing and growing bone. The cells are oval, with a large eccentric
nucleus and are very active in synthesizing and secreting the components of
 the bone matrix and have well-developed rough endoplasmic reticulum
(RER), Golgi bodies and granules. The collagen fibers are synthesized and
secreted by the osteoblasts. The matrix closest to the osteoblasts is not yet
calcified and is known as osteoid or prebone. This osteoid is rich in
collagen fibers.
Osteocytes
Osteocytes are mature bone cells that develop from osteoblasts and are
located in lacunae within the bony matrix. Osteocytes have cytoplasmic
processes located in canaliculi, which penetrate the bony matrix.
Osteoclasts
Osteoclasts are the largest of the bone cells (20-100m diameter) and are
multinuclear (with up to 50 nuclei). Osteoclasts are involved in bone
resorption and can be found on the eroding surfaces of bone, often in
cavities known as Howship's lacunae. These cells are metabolically very
active, possess large numbers of mitochondria (resulting in the acidophilia of
regular staining) and have well-developed Golgi bodies.
Osteoclasts originate from monocytes and are included in the mononuclear
phagocyte system.
 Development of Bone:
The process of formation of bone is called osteogenesis or ossification by cells
called osteoblasts.
Three basic steps involved in osteogenesis are:
Synthesis of extracellular organic matrix (osteoid)
Matrix mineralization leading to the formation of bone
Remodeling of bone by the process of resorption and reformation
Two types of ossification:
Intramembranous Ossification: characterized by laying down of bone into
the primitive connective tissue (mesenchyme) resulting in the formation of
bones (skull, clavicle, mandible)
Intracartilaginous or Endochondral Ossification: a cartilage model acts as a
precursor (e.g., femur, tibia, humerus, radius)
A. Intramembranous ossification
Steps of intramembranous ossification includes:
1. Formation of ossication center
2. Calcication
3. Formation of trabeculae
4. Development of periosteum
B. Endochondral Ossification
It occurs in long bones and most of the rest of the bones in the body and it
involves an initial hyaline cartilage which continues to grow.
It is also an essential process during the growth of the length of long bones
and the natural healing of bone fractures (Brighton and Hunt, 1986; Netter
1987 ; Brighton et al. , 1973 ).
Steps involved in process includes:
1. Development of cartilage model
2. Growth of cartilage model
3. Development of the primary ossication center
4. Development of the secondary ossication center
5. Formation of articular cartilage and epiphyseal plate
The following steps are followed in the conversion of cartilage to bone:

1. Zone of reserve cartilage: This region, farthest from the marrow cavity, consists
of typical hyaline cartilage that as yet shows no sign of transforming into bone.
2. Zone of cell proliferation: A little closer to the marrow cavity, chondrocytes
multiply and arrange themselves into longitudinal columns of flattened lacunae
3. Zone of cell hypertrophy: the chondrocytes cease to divide and begin to
hypertrophy (enlarge), much like they do in the primary ossification center of the
fetus. The walls of the matrix between lacunae become very thin
4. Zone of calcification: Minerals are deposited in the matrix between the columns
of lacunae and calcify the cartilage.
5. Zone of bone deposition: Within each column, the walls between the lacunae
break down and the chondrocytes die. This converts each column into a
longitudinal channel, which is immediately invaded by blood vessels and marrow
from the marrow cavity. Osteoblasts line up along the walls of these channels
and begin depositing concentric lamellae of matrix, while osteoclasts dissolve
the temporarily calcified cartilage
BONE REMODELLING:
The bodys skeleton changes constantly. In a process called remodeling, old
bone breaks down so that new bone can take its place.
Bone remodeling (or bone metabolism) is a lifelong process where mature bone
tissue is removed from the skeleton (a process called bone resorption) and new bone
tissue is formed (a process called ossification or new bone formation).

Remodeling involves continuous removal of discrete packets of old bone,

replacement of these packets with newly synthesized proteinaceous matrix,
and subsequent mineralization of the matrix to form new bone
(FernndezTresguerres-Hernndez-Gil et al. 2006; Fraher ,1993)
These processes also control the reshaping or replacement of bone during
growth and following injuries like fractures but also microdamage (prevents
accumulation of bone microdamage through replacement of old bone with the
new one) (Turner ,1998)
The bone remodeling cycle involves a series of highly regulated steps that
depend on the interactions of two cell lineages, the mesenchymal osteoblastic
lineage and the hematopoietic osteoclastic lineage (Fraher, 1993).
Wolffs Law:
Developed by the German anatomist and surgeon Julius Wolff (18361902) in the 19th
century, states that bone in a healthy person or animal will adapt to the loads under
which it is placed.

Bone will remodel itself over time to

become stronger if loading on
particular bone increases. The
trabeculae undergo adaptive
changes followed by secondary
changes to external cortical portion
of bone. Bone on the other hand
becomes less denser and weaker
due to lack of stimulus required for
continued remodeling resulting
osteopenia known as Stress
Shielding.
Mediators of Remodeling:
Osteoclasts: the only cells that are known to be capable of resorbing bone

Osteoblasts: bone building through increased formation of osteoid

RANK: The cell surface receptor called RANK (for receptor activator of
NFkB) prods osteoclast precursor cells to develop into fully differentiated
osteoclasts when RANK is activated by its cognate partner RANK ligand
(RANKL)
RANKL and macrophage CSF (M-CSF) are two cytokines that are critical
for osteoclast formation produced mainly by marrow stromal cells.
Osteoclastogenesis requires the presence of stromal cells and osteoblasts in
bone marrow (Teitelbaum and Ross 2003; Cohen 2006) .

Osteoprotegerin
Also known as osteoclast inhibiting factor (OCIF) or osteoclast binding
factor (OBF), is a key factor inhibiting the differentiation and activation of
osteoclasts, and is, therefore, essential for bone resorption.
Osteoprotegerin is another protein released by osteoblasts that acts as a
decoy to prevent RANK and RANKL from coming in contact (Asagiri and
Takayanagi 2007; Boyle et al. 2003; Gori et al. 2000; Lacey et al. 1998).

Parathyroid hormone (PTH), calcitriol, and other hormones such as

growth hormone, glucocorticoids, thyroid hormones, and sex hormones
Remodeling Phases:

Six phases namely,

Quiescent: is the state/phase of the bone when at rest. The factors that
initiate the remodeling process remain unknown
Activation: Activation of the bone surface prior to resorption, through the
retraction of the bone lining cells and the digestion of the endosteal
membrane by collagenase action.The initial activation stage involves
recruitment and activation of mononuclear monocyte-macrophage osteoclast
precursors from the circulation (Bruzzaniti and Baron 2007; Roodman et al.
1992 ) , resulting in interaction of osteoclast and osteoblast precursor cells.
Resorption: Osteoclasts then begin to dissolve the mineral matrix and
decompose the osteoid matrix completed by macrophages and release of
growth factors-, platelet derived growth factor(PDGF) and insulin-like
growth factor I and II. It takes approximately 2-4 weeks during each
remodeling cycle.
Reversal: Bone resorption transitions to bone formation. At the completion
of bone resorption, resorption cavities contain a variety of mononuclear
 cells, including monocytes, osteocytes released from bone matrix, and
preosteoblasts, recruited to begin new bone formation.
Formation: Once osteoclast gets resorbed cavity of bone, they detach from
bone surface and are replaced by cells of osteoblast lineage initiating bone
formation.
Mineralization: Begins 30 days after deposition of osteoid, and ending at 90
days in trabecular and at 130 days in cortical bone. The quiescent or at rest
phase then again begins.
When the cycle is completed, the amount of bone formed should equal
the amount of bone resorbed.
Regulating Factors of Remodeling
1. Genetic Factors: 60 and 80 % of this bone mass is genetically determined
2. Mechanical Factors: Remodeling is regulated by mechanical loading
3. Vascular / Nerve Factors: Vascularization is fundamental for normal bone
development, supplying blood cells, oxygen, minerals, ions, glucose,
hormones, and growth factors.
4. Nutritional Factors: Minerals especially Calcium sources
5. Hormonal Factors:
Thyroid Hormones: stimulate bone resorption and formation and are critical for
maintenance of normal bone remodeling (Kawaguchi et al. 1994)
Parathyroid Hormone (PTH). It controls the homeostasis of calcium by direct
action on the bone and the kidneys and indirectly on the intestine. Continual
supply of PTH would stimulate bone resorption through the synthesis of a
factor favoring osteoclastogenesis (RANKL)
Calcitonin: inhibitor of bone resorption
1,25 (OH )2 , Vitamin D3 or Calcitriol: Favors intestinal resorptions of Ca
Androgens: anabolic effect on bone through the stimulation of the osteoblast
receptors.
Estrogens: closure of growth plates and increases number of osteoblast cells
Progesterone: anabolic effect
Insulin: stimulates matrix synthesis
Glucocorticoids: Glucocorticoids are necessary for bone cell differentiation
Growth Hormone: acts directly on the osteoblasts with hormone receptors
 Bone Healing

Conclusion
Far from inert and lifeless, bone is a dynamic living tissue capable of growth and
repair since bone tissue is continually being formed and resorbed/ reabsorbed
through processes of remodeling and reorganization. There are living cells (collagen,
and various cells like osteoblast, osteoclast, osteocytes etc.) and non-living; minerals (calcium,
Phosphorus, carbonates, water etc.) and has a blood supply and nerve innervations.

Similar to most of other tissue, bone also can repair itself if gets injured by healing
of bone tissue via impact, induction, inflammation, soft callus, ossification, and
remodeling. The bone over the life period is undergoing constant changes of modeling and
remodeling. Re-modeling occurs at many simultaneous sites throughout the body where bone is
experiencing growth, mechanical stress, micro-fractures, or breaks and also removal of old and
damaged bone cells by new ones. The bone also maintains its cellular structure and adapts to its
changing surrounding and changes according to pressure as stated by Wolffs law i.e. adapts to
bear the increase or decrease in work load. The healing process of bone fractures are similar to
other dynamic tissue, bones are supplied with blood vessel (Nutrient artery, Metaphyseal artery,
periosteal artery). Thus bone can be considered as living dynamic tissue.
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