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

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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Fig. 1: Hsp90β is upregulated during osteoclastogenesis.
Fig. 2: Osteoclast Hsp90ab1 deletion reduces osteoclastogenesis.
Fig. 3: Hsp90ab1 deletion improves ovariectomy-induced bone loss by inhibiting osteoclast activity.
Fig. 4: Osteoclast Hsp90ab1 deletion attenuates NF-κB signaling.
Fig. 5: Pathological up-regulation of Hsp90ab1 is transcriptionally regulated by c-Jun.
Fig. 6: Corylin inhibits RANKL-induced osteoclastogenesis and bone resorption in vitro.
Fig. 7: Corylin inhibits NF-κB activity.
Fig. 8: Corylin improves ovariectomy-induced bone loss.

Data availability

All data in this study are provided in the paper and Supplementary Materials. Additional data related to this study may be obtained from the authors.

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Acknowledgements

We thank the State Key Laboratory of Natural Medicines, China Pharmaceutical University for providing experimental instruments. We thank Prof. Chaojun Li (Nanjing Medical University) for providing LysM-Cre mice.

Funding

This work was supported by National Key Research & Development Program of China for International S&T Cooperation Projects (2018YFE0117800), National Natural Science Foundation of China (81773957), CAMS Innovation Fund for Medical Sciences (2016-I2M-4-001), Beijing Outstanding Young Scientist Program (BJJWZYJH01201910023028), the Chinese Academy of Medical Sciences (CAMS) Central Public-interest Scientific Institution Basal Research Fund (2018RC350004, 2017PT31046).

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XX, H-MC, ZZ performed research design. H-MC, MX, Y-PZ performed animal experiment. H-MC, MX, WZ, ZL, LL acquired the data. H-MC, MX analyzed the data. XX, H-MC drafted and revised the manuscript. YM, PL, XL, PL provided technical and material support. All authors contributed to the preparation of the manuscript.

Corresponding author

Correspondence to Xiaojun Xu.

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The authors declare no competing interests.

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All animal experiments were approved by the Laboratory Animal Management Committee of Jiangsu Province and the Institutional Animal Care and Use Committee of China Pharmaceutical University (Nanjing, China). This clinical study was approved by the Ethnic Committee of Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences) and the Affiliated Nanjing Hospital, Nanjing Medical University, and written informed consents were obtained from the patients before procedure [31].

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Cheng, HM., Xing, M., Zhou, YP. et al. HSP90β promotes osteoclastogenesis by dual-activation of cholesterol synthesis and NF-κB signaling. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01071-3

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