A Novel Role of Protecadherin-7 in Regulation of Pydc3 Expression and the IFN-β Response During Osteoclast Differentiation.

Protocadherin-7 (Pcdh7) is a member of the protocadherin family, a subgroup of the cadherin superfamily. We previously demonstrated that Pcdh7 functions as a signaling receptor in osteoclast differentiation. In this study, we investigated the potential gene regulatory role of Pcdh7 in this process and identified Pyrin domain-containing protein 3 (Pydc3) as a key mediator of Pcdh7-mediated regulation of osteoclast differentiation. Differential gene expression analysis comparing wild-type (Pcdh7(+/+)) and Pcdh7-deficient (Pcdh7(-/-)) cells revealed a significant upregulation of Pydc3 in Pcdh7(-/-) cells. RNAi-mediated knockdown of Pydc3 rescued the impaired osteoclast differentiation in Pcdh7(-/-) cells, whereas overexpression of Pydc3 suppressed osteoclast differentiation in Pcdh7(+/+) cells, suggesting that Pydc3 negatively regulates osteoclast differentiation. Additionally, Pcdh7(-/-) cells showed elevated expression of interferon response genes and increased production of interferon-β (IFN-β). Neutralization of IFN-β signaling using anti-IFN-β and/or anti-interferon alpha and beta receptor 1 (IFNAR1) antibodies significantly restored osteoclast differentiation in Pcdh7(-/-) cells. Collectively, these findings uncover a novel role for Pcdh7 in osteoclast differentiation through regulation of Pydc3 expression and IFN-β production.