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HSP90 Exacerbates Bone Destruction in Rheumatoid Arthritis by Activating TRAF6/NFATc1 Signaling

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Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by a notably high disability rate, primarily attributed to cartilage and bone degradation. The involvement of heat shock protein 90 (HSP90) as a molecular chaperone in the inflammatory response of RA has been established, but its role in bone destruction remains uncertain. In the present study, the expression of HSP90 was augmented in osteoclasts induced by the receptor activator of nuclear factor-κB ligand. Additionaly, it was observed that the outcomes revealed a noteworthy inhibition of osteoclast formation and differentation when triptolide was utilized to hinder the expression of HSP90. Furthermore, the positive influence of HSP90 in osteoclast differentiation was substantiated by overexpressing HSP90 in osteoclast precursor cells. Mechanically, HSP90 significantly activated the TNF receptor-associated factor 6 (TRAF6)/Nuclear factor of activated T cells 1 (NFATc1) signaling axis, accompanied by markedly promoting osteoclast differentiation. This effect was consistently observed in the destructive joint of rats with collagen-induced arthritis, where HSP90 effectively activated osteoclasts and contributed to arthritic bone destruction by activating the TRAF6/NFATc1 signaling. Overall, the findings of this study provide compelling evidence that HSP90 exacerbates bone destruction in RA by promoting osteoclast differentiation through the activation of TRAF6/NFATc1 signaling, and interference with HSP90 may be a promising strategy for the discovery of anti-arthritic bone destruction agents.

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DATA AVAILABILITY

Data are available from the corresponding author on reasonable request.

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ACKNOWLEDGMENTS

This study was supported by the National Natural Science Foundation of China (Grant number: 82174042), Scientific and technological innovation project of China Academy of Chinese Medical Sciences (Grant number: CI2021A03806), Special Funds for Basic Research Operations of Public Welfare Research Institutes (Grant number: ZZ13-YQ-043), Beijing Natural Science Foundation of China (Grant number: 7202142), and Special Funds for Basic Research Operations of Public Welfare Research Institutes (Grant number: ZXKT21016 and ZXKT20014).

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Authors and Affiliations

  1. Institute of Chinese Materia Medica, China, Academy of Chinese Medicine Sciences , Beijing, China

    Qian Wang, Xiangying Kong, Wanyi Guo, Liling Liu, Yage Tian, Xueying Tao, Na Lin & Xiaohui Su

  2. School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, China

    Qian Wang

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  1. Qian Wang
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Contributions

Xiaohui Su and Na Lin contributed to the study conception and design. Qian Wang, Wanyi Guo, Liling Liu, and Xueying Tao performed the experiments and analyzed the data. Qian Wang drafted the manuscript. Xiangying Kong and Yage Tian contributed to the discussion of this study and the revision of this manuscript. Xiaohui Su and Na Lin wrote and revised the manuscript, conducted the project administration, and Xiaohui Su acquired the funding grants. All authors read and approved the manuscript.

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Correspondence to Na Lin or Xiaohui Su.

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This study was approved by approved by the Institutional Animal Ethics Committee of China Academy of Chinese Medical Sciences.

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Wang, Q., Kong, X., Guo, W. et al. HSP90 Exacerbates Bone Destruction in Rheumatoid Arthritis by Activating TRAF6/NFATc1 Signaling. Inflammation 47, 363–375 (2024). https://doi.org/10.1007/s10753-023-01914-2

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