Pin1 regulates osteoclast fusion through suppression of the master regulator of cell fusion DC-STAMP.

Cell fusion is a fundamental biological event that is essential for the development of multinucleated cells such as osteoclasts. Fusion failure leads to the accumulation of dense bone such as in osteopetrosis, demonstrating the importance of fusion in osteoclast maturity and bone remodeling. In a recent study, we reported that Pin1 plays a role in the regulation of bone formation and Runx2 regulation. In this study, we explored the role of Pin1 in osteoclast formation and bone resorption. Pin1 null mice have low bone mass and increased TRAP staining in histological sections of long bones, compared to Pin1 wild-type mice. In vitro osteoclast forming assays with bone marrow-derived monocyte/macrophage revealed that Pin1-deficient osteoclasts are larger than wild-type osteoclasts and have higher nuclei numbers, indicating greater extent of fusion. Pin1 deficiency also highly enhanced foreign body giant cell formation both in vitro and in vivo. Among the known fusion proteins, only DC-STAMP was significantly increased in Pin1(-/-) osteoclasts. Immunohistochemistry showed that DC-STAMP expression was also significantly increased in tibial metaphysis of Pin1 KO mice. We found that Pin1 binds and isomerizes DC-STAMP and affects its expression levels and localization at the plasma membrane. Taken together, our data indicate that Pin1 is a determinant of bone mass through the regulation of the osteoclast fusion protein DC-STAMP. The identification of Pin1 as a factor involved in cell fusion contributes to the understanding of osteoclast-associated diseases, including osteoporosis, and opens new avenues for therapeutic targets.