5-azacytidine-induced protein 2 (AZI2) regulates bone mass by fine-tuning osteoclast survival [Immunology]

February 17th, 2015 by Maruyama, K., Fukasaka, M., Uematsu, S., Takeuchi, O., Kondo, T., Saitoh, T., Martino, M., Akira, S.

5-azacytidine-induced protein 2 (AZI2) is a TNFR-associated factor family member-associated NF-κB activator binding kinase 1 binding protein that regulates the production of IFNs. A previous in vitro study showed that AZI2 is involved in dendritic cell differentiation. However, the roles of AZI2 in immunity and its pleiotropic functions are unknown in vivo. Here we report that AZI2 knockout mice exhibit normal dendritic cell differentiation in vivo. However, we found that adult AZI2 knockout mice have severe osteoporosis, due to increased osteoclast longevity. We revealed that the higher longevity of AZI2-deficient osteoclasts is due to an augmented activation of proto-oncogene tyrosine-protein kinase (c-Src), which is a critical player in osteoclast survival. We found that AZI2 promotes c-Src activity, by inhibiting the heat shock protein 90 (Hsp90)-a chaperone involved in c-Src dephosphorylation. Furthermore, we demonstrated that AZI2 indirectly inhibits c-Src, by interacting with the Hsp90 co-chaperone Cdc37. Strikingly, administration of a c-Src inhibitor markedly prevented bone loss in AZI2 knockout mice. Together, these findings indicate that AZI2 regulates bone mass by fine-tuning osteoclast survival.