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pathway, the reduced levels of secreted and processed
normal collagen give rise to an altered extracellular
matrix structure and component stoichiometry. This
altered extracellular matrix, in turn, fails to convey the
normal feedback signals that would promote differenti-
ation. For example, by analogy to the TSP-2 null mouse
(where the absence of thrombospondin led to increased
osteoblast proliferation and increased bone formation),
increased levels of thrombospondin in OI extracellu-
lar matrix may be associated with the decreased pro-
liferation and reduced amounts of bone being formed.
A number of transgenic knockouts of matrix compo-
nents have recently been described that share similar
phenotypes.
148-152
For example, the phenotype of the
osteonectin knockout
148
is reminiscent of the pheno-
type for the biglycan knockout
150
with a subtle presen-
tation and a phenotype more evident at older ages (an
aging but not a developmental phenotype). Defects
in the ratio and composition of matrix proteins in the
knockouts result in collagen fibril defects (osteonectin,
decorin and biglycan bind collagen) which could in
turn affect the cell. In OI, the levels of not only type I
collagen, but also other matrix components, are altered.
Thus, feedback from the extracellular matrix to the cell
could be drastically altered.
The feedback system could include disrupted growth
factor/cytokine sequestration in an OI altered extracellu-
lar matrix and subsequent deficient growth factor recep-
tor signaling. Normal receptor recognition of matrix
components and subsequent signal transduction may be
perturbed in OI.
43,45
An OI perturbed signaling pathway
might involve collagen interaction with alpha2beta1 inte-
grin that activates MAPK that then phosphorylates and
activates RUNX2.
153-155
Reduced type I collagen in the
matrix in OI would then lead to reduced RUNX2 acti-
vation and activity. The deficit in extracellular feedback
ultimately leads to a failure to alter specific transcrip-
tion factor expression and maintain the differentiation
program.
A second possible pathway involves a failure to accu-
mulate differentiated, mature osteoblasts because the
necessity of chronically diverting resources to the error
checking and editing machinery and stress responses
subverts cell survival. The cell must respond to a muta-
tion in its most abundant product. Error checking mech-
anisms in the cell include chaperone and/or protein
disulfide isomerase target binding and sequestration
in the endoplasmic reticulum as well as intracellular
(proteasomes) and extracellular (protease) degradation
of abnormal collagen.
156,157
Induction of an endoplas-
mic reticulum stress-specific unfolded protein response
involves upregulation of chaperones and caspases that
promote apoptosis.
158
Mature osteoblasts do not accumu-
late because they are more likely to undergo apoptosis in
response to chronic stress. Identifying and distinguishing
between these different pathways that translate the dis-
tinct genetic events to a molecular, cellular and physi-
ological phenotype provides a robust framework for
translational research in OI.
References
