Development of Bone and

Cartilage: Function and Repair

Department of Anatomy and Cell Biology

Fayez F. Safadi, Ph.D.

fsafadi@temple.edu

X (2-5655)
 Osteogenesis – Two Processes

 Intramembranous – Bone tissue is formed

directly in primitive connective tissue
(mesencyhme).
 Endochondral – Bone tissue replaces a
hyaline cartilage template.
 Regulation of Mesenchymal Cell
Differentiation and Skeletal Patterning
 Mesenchymal cell differentiation into osteoblasts regulated
by Core Binding Factor-a1 (CBFA1)/RUNX2; differentiation
into chondrocytes regulated by SOX9.

 Skeletal patterning controlled by a multitude of signaling

molecules and transcription factors, including wnt and
hedgehog signaling factors, homeobox (HOX) transcription
factors, members of the transforming growth factor-
TGF and fibroblast growth factor (FGF) families.

 For limb morphogenesis, wnt7a is important for

dorsal/ventral patterning, FGF4 for proximal/distal
patterning, and sonic hedgehog for posterior/anterior
patterning.
Intramembranous Bone Formation
Intramembranous Bone Formation
Endochondral Bone Formation
 Endochondral Bone Formation

Steps in endochondral
bone formation lead
from mesenchymal
condensations to
cartilage synthesis,
chondrocyte
differentiation and
death, and
replacement by bone.

From mesenchymal condensation to

hyaline cartilage model
Endochondral Bone Formation

Chondrocyte
hypertrophy

Cartilage
mineralizes

Replaced
by bone
Endochondral Bone Formation
Endochondral Bone Formation
Endochondral Ossification
Endochondral Bone Formation
 Local Regulators of Endochondra
?? Ossification

 Indian hedgehog (Ihh) protein is

produced by proliferating
chondrocytes; stimulates the
synthesis and secretion of
parathryroid hormone related
protein (PTH-RP) and regulates
formation of the periosteal bone
collar.

 PTH-RP stimulates chondrocyte

proliferation and inhibits their
differentiation into hypertrophic
chondrocytes.

 Hypertrophic chondrocytes
secrete type X collagen, a marker
of terminal differentiation and
vascular endothelial growth factor
(VEGF), an inducer of vascular
invasion.
Bone Remodeling – Woven vs.
Lamellar Bone
 Aberrant Regulation of
Endochondral Ossification
 Example of
consequences
caused when a
growth factor
important for
regulation of
endochondral
bone formation
is functionally
inactivated.
Joints
 Definition

Articulations: The site where 2 or more bones

meet

Joints are the weakest part of the skeleton

 Synovial Joints
Articulating bones are separated by
a fluid-containing joint cavity
 Synovial (Diarthrosis/True joints):
Unite two bone ends covered by articular
cartilage
Surrounded by a thick articular capsule
Examples: appendicular skeleton and
vertebral joints
 Structure of Synovial Joints
Articular Cartilage
Synovial (joint) cavity
Articular Capsule
Two layers around cavity
Outer fibrous continuous with periosteum
Inner synovial
Synovial Fluid
Derived from filtration through the capillaries and
fills the space of the capsule
Viscous
It consists of hyaluronic acid and functions as a lubricant

Reinforcing Ligaments
Some have fatty Pads or articular Discs
Synovial Joints
Rheumatoid Arthritis

Panus
Mechanism of Rheumatoid Arthritis
 Erosive Arthritis Develops in the
Complete Absence of TNF
TNF-deficient mice with SCW-induced arthritis

SCW = streptococcal cell wall

van den Berg W. Semin Arthritis Rheum. 2001;30(suppl 2):7-16.
 IL-1 Mediates the Development of
Erosive Disease
Control mice with SCW- IL-1 -deficient mice with
induced arthritis SCW-induced arthritis

SCW = streptococcal cell wall

van den Berg W. Semin Arthritis Rheum. 2001;30(suppl 2):7-16.
RANKL, OPG: Key Components of Bone
Erosion
 Bone erosion is mediated by activated osteoclasts
 Osteoprotegerin ligand (RANKL):
–induces osteoclast differentiation
–is crucial for osteoclast activation
–is identical to receptor activator of NF- B ligand
(RANK-L)
–is identical to osteoclast differentiating factor
 Osteoprotegerin (OPG) binds RANKL, thus inhibiting
bone resorption
 RANKL/OPG balance determines relative degree of
erosion
 Regulation of Osteoclast Differentiation by Osteoblasts
M-CSF:
Macrophages colony
stimulating factor

RANK:
Receptor for activation
of nuclear factor kappa B

RANKL: Receptor
for activation of nuclear
factor kappa B ligand
Fracture Repair
Inflammatory Phase
Repair Phase
Remodeling Phase
 Factors Influencing the Rate of
Fracture Healing

Local Factors Systemic Factors

 Severity of Trauma  Hormones
 Blood Supply  Nutrition
 Mobility  Disease
 Infection
 Disease