Mechanistic and Therapeutic Studies of Initiation and Expansion for Genetic and Acquired Heterotopic Ossification

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Project Summary/Abstract Heterotopic ossification (HO) refers to extraskeletal pathological bone formation that occurs as a common complication after injury or as a manifestation of particular genetic disorders. However, limited by poor understanding of the underlying cellular and molecular mechanisms, there is currently no effective treatment and surgical eviction often results in recurrence. The overall goal of the project is to investigate cellular and molecular mechanisms underlying HO initiation and expansion and identify potential treatment targets for genetic and acquired HO. Our preliminary data suggests that in mouse models of progressive osseous heteroplasia (POH), a human disease caused by null mutations in GNAS that encodes Gαs, progressive expansion of ectopic bone was due to recruitment of surrounding wild-type cells. Mechanistically, Gnas-/- mesenchymal cells differentiate into osteoblasts and recruit wild-type cells to form bone by activating YAP, a transcription factor that regulates expression of Sonic hedgehog (Shh), which encodes a secreted ligand in the Hh family. Secreted SHH further induces YAP activation, thereby resulting in additional Shh expression and osteoblast differentiation in surrounding wild type cells. In human samples with acquired HO, upregulated YAP and HH signaling were also found, indicating the clinical importance of our findings. In our unpublished preliminary studies, we found upregulated Wnt5a expression in Gnas-/- SMPs in vitro and in HO lesions of POH mouse models in vivo. WNT5a not only regulates stem cell proliferation and enhances repopulation, but also plays an essential role in long bone and cartilage development during embryogenesis. Importantly, we found that Wnt5a expression was also controlled by YAP activation and was required for HO in both genetic and acquired HO. These findings lead to a central hypothesis that YAP and WNT5a are activated in a positive feedback loop to recruit progenitor cells for osteoblast differentiation in soft tissues, thereby promoting HO formation in both genetic and acquired HO mouse models. We will test these hypotheses in three aims. The first aim is to clarify the relationship between YAP and Wnt5a expression in ectopic bone formation in POH and test whether YAP and WNT5a interact in a positive feedback loop. The second aim is to illuminate the molecular mechanism in response to YAP and WNT5a in ectopic bone formation. The third aim is to investigate the contribution of WNT5a to ectopic bone formation in fibrodysplasia ossificans progressiva (FOP) and trauma-induced HO models. Taken together, these proposed studies will yield novel insights into a common cellular and molecular mechanism underlying initiation and expansion of distinct HO forms and highlight the importance of rare genetic disease studies in identifying a shared core pathological mechanism underlying a class of diseases.