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protein-protein interactions. These interactions are criti-
cal for the function of collagen fibrils, and for promoting
tissue organization. Ligand sites in proximity to Pro
986
include but are not limited to the fibronectin binding site
and the sequence that mediates α1β1
/
α2β1
/
α1β11 integrin
binding.
62
Ultimately, the disruption of ligand interaction
sites may result in disease.
Recessive OI due to mutations in other collagen
chaperones in the ER did not show Pro
986
3-hydroxyl-
ation deficits and hence those chaperones appear to act
downstream of the prolyl 3-hydroxylation complex.
5,63
Therefore prolyl 3-hydroxylation, prolyl cis-trans isom-
erization and the overall chaperone function played by
the CRTAP
/
P3H1
/
CYPB complex appear to be the very
first essential step for proper collagen modification and
folding in the ER.
While the potential role of ER stress triggered by
unfolded collagen in the pathogenesis of OI has yet
to be demonstrated, recent evidence identified a sig-
nificant reduction of collagen fibrils in the extracellular
matrix of human primary fibroblasts with mutations
in
CRTAP
.
37
This effect contributes to the deposition of
an abnormal matrix that was shown to have abnormal
mineral density distribution
64
and decreased mineral-
ization lag time.
11
These effects likely impact the stoi-
chiometry of matrix non-collagenous proteins and the
normal interaction with integrins and other receptors
that mediate intracellular signals.
References
[10]
CONCLUSION
The study of Crtap and the identification of
CRTAP
mutations in recessive OI led to the discovery of its role
in collagen prolyl 3-hydroxylation and overall bone
formation, the description of its binding partners in
the rER and the identification of mutations in several
new genes involved in collagen modification, process-
ing, folding and transport. Much has been learned in
the past six years about recessively inherited OI and
the new knowledge will contribute to a better over-
all understanding of the pathogenesis of dominant OI
and to the devising of new treatment modalities. The
still unanswered question is whether there are unifying
mechanisms that arise from the pathogenesis of these
forms of OI compared to OI caused by type I collagen,
as they are impossible to distinguish clinically, radio-
logically and histopathologically. Attractive possibilities
include common alteration of fibril packing and assem-
bly, alteration of cell metabolism due to activation of ER
stress and dysregulation of signaling factors between
matrix and the cell.
65
Identifying the dominant mecha-
nism at the tissue level is critical as this will inform tar-
geted therapies that may address the issue of altered
bone quality beyond just bone quantity.
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
