Collagen Structure, Folding and Function - Osteogenesis Imperfecta - page 72

model has not been considered a prime contender for
explaining bone pathology caused by Gly substitutions,
because no upregulation of BiP by these mutations has
been detected. 86 BiP upregulation is a commonly used
indicator of canonical UPR signaling activation in ER
stress response to protein misfolding, 78 but the ER stress
response to misfolding of procollagen triple helix might
be different. 80 Recent studies show that aggregation of
some misfolded proteins, 171 including procollagen with
Gly substitutions, 91 might trigger a different pathway of
ER stress response, which does not involve upregulation
of BiP and activation of UPR. Severe dilation of fibroblast
ER cisternae in Brtl mouse skin 89 without BiP upregula-
tion 90 confirms that this ER stress response is likely to be
an important factor in at least some OI cases.

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CONCLUSION

In summary, the relationship between type I collagen
biology and OI pathophysiology might be represented
by categorizing the latter based on disruptions in type
I collagen homeostasis as: (1) insufficient collagen pro-
duction; (2) extracellular collagen malfunction; and (3)
osteoblast malfunction resulting from abnormal pro-
collagen folding and / or trafficking. We must stress that
these disruptions are interrelated and all of them are
likely to contribute to OI. By somewhat reductionist
discussion of the corresponding concepts, we intend
only to highlight the aspects of type I collagen biology
that might be important for better understanding OI
and developing therapeutic strategies for this devastat-
ing disorder. Our emphasis on procollagen folding and
ER stress stems from the belief that targeting osteoblast
malfunction offers the best hope for new pharmaco-
logical treatments of the most common forms of severe
OI, providing an alternative to much more challenging
gene therapy and stem cell transplantation. We hope
that the present review makes the case for a more care-
ful analysis of this idea.

Acknowledgment
This work was funded by the Intramural Research Program, NICHD,
NIH.

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