REGγ is essential to maintain bone homeostasis by degrading TRAF6, preventing osteoporosis

Primary osteoporosis, manifesting as decreased bone mass and increased bone fragility, is a "silent disease" that is often ignored until a bone breaks. Accordingly, it is urgent to develop reliable biomarkers and novel therapeutic strategies for osteoporosis treatment. Here, we identified REGγ as a potential biomarker of osteoporotic populations through proteomics analysis. Next, we demonstrated that REGγ deficiency increased osteoclast activity and triggered bone mass loss in <i>REGγ</i> knockout (KO) and bone marrow-derive macrophage (BMM)-conditional <i>REGγ</i> KO mice. However, the osteoclast activity decreased in BMM-conditional <i>REGγ</i> overexpression mice. Mechanistically, we defined that REGγ-20S proteasome directly degraded TRAF6 to inhibit bone absorption in a ubiquitin-independent pathway. More importantly, BMM-conditional <i>Traf6</i> KO with <i>REGγ</i> KO mice could "rescue" the osteoporosis phenotypes. Based on NIP30 (a REGγ "inhibitor") dephosphorylation by CKII inhibition activated the ubiquitin-independent degradation of TRAF6, we selected TTP22, an inhibitor of CKII, and defined that TTP22 could alleviate osteoporosis in vitro and in vivo. Overall, our study reveals a unique function of NIP30/REGγ/TRAF6 axis in osteoporosis and provides a potential therapeutic drug TTP22 for osteoporosis.