2. Academic Validation
  3. HSP90β promotes osteoclastogenesis by dual-activation of cholesterol synthesis and NF-κB signaling

HSP90β promotes osteoclastogenesis by dual-activation of cholesterol synthesis and NF-κB signaling

  • Cell Death Differ. 2022 Oct 5. doi: 10.1038/s41418-022-01071-3.
Hui-Min Cheng 1,  Mingming Xing 1,  Ya-Ping Zhou 1,  Weitao Zhang 1,  Zeyu Liu 1,  Lan Li 1,  Zuguo Zheng 1,  Yuanchen Ma 2,  Pingping Li 3 4,  Xiaoxuan Liu 1,  Ping Li 1,  Xiaojun Xu 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China.
  • 2 Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, No.106, Zhongshan Second Road, Yuexiu District, Guangzhou, 510000, China.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
  • 4 Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, 100050, China.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China. xiaojunxu2000@163.com.
  • 6 Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, No.106, Zhongshan Second Road, Yuexiu District, Guangzhou, 510000, China. xiaojunxu2000@163.com.
PMID: 36198833 DOI: 10.1038/s41418-022-01071-3
Abstract

Heat shock protein 90β (Hsp90β, 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 Hsp90β in vivo functions using tissue specific knockout mice are still lacking. Here, we showed that Hsp90β exerted paralogue-specific role in osteoclastogenesis. Using myeloid-specific Hsp90ab1 knockout mice, we provided the first genetic evidence showing the in vivo function of Hsp90β. Hsp90β binds to Ikkβ and reduces its ubiquitylation and proteasomal degradation, thus leading to activated NF-κB signaling. Meanwhile, Hsp90β increases Cholesterol biosynthesis by activating Srebp2. Both pathways promote osteoclastogenic genes expression. Genetic deletion of Hsp90ab1 in osteoclast or pharmacological inhibition of Hsp90β alleviates bone loss in ovariectomy-induced mice. Therefore, Hsp90β is a promising druggable target for the treatment of osteoporosis.

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