Mechanism of growth deficiency in dominant forms of osteogenesis imperfecta

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PROJECT SUMMARY Osteogenesis imperfecta (OI), known as a brittle bone disease, is a genetic disorder typically caused by autosomal dominant mutations in one of the two genes that encode type l collagen (Col1). In addition to bone fragility, growth deficiency is a critical musculoskeletal issue in OI. There is no cure for OI. While bisphosphonates are the standard treatment to strengthen bones, there is no reliably effective treatment for growth impairment. One of the major hurdles preventing the development of such treatments is that the mechanism of how a mutation in Col1 causes growth deficiency has not been elucidated. Given that treatments to improve osteoblast function were not effective for resolving bone length deficiency, cell types other than osteoblasts might be involved in OI growth retardation. We and others found abnormalities in the growth plate, where longitudinal bone growth occurs, including increased total height, decreased chondrocyte turnover and fewer proliferating chondrocytes, suggesting that mutated Col1 somehow affects chondrocytes in the growth plate. Thus, understanding the mechanism underlying chondrocyte defects is critical to develop treatments for OI growth deficiency. In this proposal, we will focus on dominant OI using G610C mice harboring Col1 mutation because 85-90% of OI are autosomal dominant forms. Our data demonstrated that OI HCs began to express Col1 as they mature along with the enlarged endoplasmic reticulum (ER), suggesting that OI HCs are exposed to higher ER stress similar to OI osteoblasts. Our preliminary studies demonstrated that G610C OI chondrocytes had a lower ability to express hypertrophic phenotypes in pellet cultures and an ER stress reducer ameliorated this defect, suggesting that ER stress may cause dysfunction not only in osteoblasts but also in HCs in OI. Indeed, it has been shown that induction of ER stress in HCs causes HC dysfunction and results in growth deficiency. Collectively, these findings provide rigorous premises for our highly innovative hypothesis that HC dysfunction induced by ER stress plays a pivotal role in growth deficiency of dominant OI. This hypothesis will be addressed by experiments supporting the following specific aims: (1) to characterize ER stress occurring in HCs in G610C OI mice, (2) to determine HC dysfunction in G610C OI mice, and (3) to determine ER stress in HCs from dominant OI patients with distinct mutations. The completion of these aims will determine whether growth deficiency in dominant OI is a consequence of HC dysfunction caused by ER stress. The outcome of this innovative project has potential to change our understanding of OI by redefining OI not only as “bone disease” but also as “cartilage disease”, and by providing approaches focused on chondrocytes, rather than osteoblasts or osteoclasts in developing therapeutic strategies for growth impairment in OI.