HSP90ß promotes osteoclastogenesis by dual-activation of cholesterol synthesis and NF-κB signaling.

ABSTRACT

Heat shock protein 90ß (Hsp90ß, encoded by Hsp90ab1 gene) is the most abundant proteins in the cells and contributes to variety of biological processes including metabolism, cell growth and neural functions. However, genetic evidences showing Hsp90ß in vivo functions using tissue specific knockout mice are still lacking. Here, we showed that Hsp90ß exerted paralogue-specific role in osteoclastogenesis. Using myeloid-specific Hsp90ab1 knockout mice, we provided the first genetic evidence showing the in vivo function of Hsp90ß. Hsp90ß binds to Ikkß and reduces its ubiquitylation and proteasomal degradation, thus leading to activated NF-κB signaling. Meanwhile, Hsp90ß increases cholesterol biosynthesis by activating Srebp2. Both pathways promote osteoclastogenic genes expression. Genetic deletion of Hsp90ab1 in osteoclast or pharmacological inhibition of Hsp90ß alleviates bone loss in ovariectomy-induced mice. Therefore, Hsp90ß is a promising druggable target for the treatment of osteoporosis.