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CHAPTER
5
Osteoblast/Osteoclast Development and
Function
in Osteogenesis I
mperfecta
Neal S. Fedarko
Johns Hopkins University, Baltimore, MD, USA
INTRODUCTION
produce a collagen-rich extracellular matrix that subse-
quently becomes mineralized. Mesenchymal progeni-
tor cells give rise to osteoblasts in two distinct types of
bone formation. In intramembranous ossification, mes-
enchymal cells differentiate directly into the osteoblas-
tic lineage. In endochondral ossification, mesenchymal
cells differentiate into perichondral cells and chondro-
cytes and a subsequent chondrocyte hypertrophy drives
differentiation of perichondral cells into osteoblasts. A
number of transcription factors are involved in mesen-
chymal progenitor cell differentiation, including SOX9,
RUNX2 and OSX.
2
SOX9, a transcription factor of the sex-
determining region Y-related high mobility group box
family of proteins, is required for chondrogenesis, and
marks the mesenchymal progenitors that become osteo-
blasts, though SOX9 is not expressed by mature osteo-
blasts.
2
RUNX2 is a central transcription factor for bone
because: (1) RUNX2 expression correlates with osteo-
genesis during development; (2) targeted inactivation of
RUNX2 in mice generates animals lacking osteoblasts;
(3) loss of one RUNX2 allele gives rise to cledocranial
dysplasia syndrome where there is a delay in osteoblast
differentiation in bones forming through intramembra-
nous ossification; and (4) RUNX2 modulates expression
of bone-specific markers such as osteocalcin and bone
sialoprotein.
3-7
Osterix (OSX or SP7) is a transcription
factor expressed specifically by osteoblasts that regu-
lates differentiation. Mice lacking OSX are deficient in
osteoblasts and form no endochondral and intramembra-
neous bone. Because OSX was not expressed in RUNX2-
null mice, while RUNX2 was expressed in OSX-deficient
mice, it has been proposed that OSX acts downstream of
RUNX2.
8
OSX is both a developmental and homeostatic
regulator of osteoblast and osteocyte differentiation and
The major health consequences in osteogenesis
imperfecta (OI) arise from functionally compromised
bone. OI is a heritable disease of the connective tissue
characterized by lower bone mass, bone fragility and
skeletal deformities. Short stature, blue sclerae, lax-
ity of ligaments, non-union of fractures, keloid and
hyperplastic callus formation are additional but vari-
able symptoms.
1
OI is a polygenic disease with a vari-
able phenotype spanning mild to lethal. The majority of
mutations associated with OI occur in the type I collagen
encoding genes (
COL1A1
and
COLIA
2) and give rise to
an autosomal dominant form of the disease. Novel muta-
tions in seven other genes involved in collagen assem-
bly and processing and in two genes involved in cellular
differentiation have recently been associated with auto-
somal recessive forms of OI.
1
Bone forming cells in the
osteoblastic lineage are the most affected targets of these
mutations. Skin and other type I collagen enriched tis-
sues are also affected. Understanding how the genetic
mutations underlying OI translate into the disease phe-
notype has involved studies on the cells affected and the
molecular consequences of identified mutations.
BONE COMPONENTS
Osteoblasts
Normal bone homeostasis involves the coupling of
bone formation and resorption. Bone formation involves
cells in the osteoblastic lineage, while bone resorption
is carried out by osteoclasts (
Figure 5.1
). Osteoblasts
