Inflammation leads to systemic osteoporosis or local bone destruction, however, the underlying molecular mechanisms are still poorly understood. In this study, we report that PRL2 is a negative regulator of osteoclastogenesis and bone absorption. Mice with PRL2 deficiency exhibit a decrease in bone volume and an increase in osteoclast numbers. PRL2 negatively regulates RANKL-induced reactive oxygen species production through the activation of RAC1, thus PRL2 deficient osteoclast precursors have both increased osteoclast differentiation ability and bone resorptive capacity. During inflammation, oxidized PRL2 is a selected substrate of HSC70 and conditions of oxidative stress trigger rapid degradation of PRL2 by HSC70 mediated endosomal microautophagy and chaperone-mediated autophagy. Ablation of PRL2 in mouse models of inflammatory bone disease leads to an increase in the number of osteoclasts and exacerbation of bone damage. Moreover, reduced PRL2 protein levels in peripheral myeloid cells are highly correlated with bone destruction in a mouse arthritis model and in human rheumatoid arthritis, while the autophagy inhibitor hydroxychloroquine blocked inflammation-induced PRL2 degradation and bone destruction in vivo. Therefore, our findings identify PRL2 as a new regulator in osteoimmunity, providing a link between inflammation and osteoporosis. As such, PRL2 is a potential therapeutic target for inflammatory bone disease and inhibition of HSC70 mediated autophagic degradation of PRL2 may offer new therapeutic tools for the treatment of inflammatory bone disease.
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We are grateful to Dr. Qing Zhong for providing reagents including Torin1 (Selleck Chemicals, USA), and rabbit anti-LC3B antibody. We thank Dr. Qian Zhao for providing the pLVX-KFERQ-PA-mCherryN1 plasmid. We would like to thank Dr. Fubin Li for providing K/B mice. We would like to thank Dr. Huabing Li for providing RAW 264.7 cells expressing Cas9. Last, we would like to thank Dr. Helena Helmby for editing the manuscript.
This work was supported by the National Natural Science Foundation of China (81971486), the Natural Science Foundation of Shanghai (19ZR1428500), and Innovative research team of high-level local universities in Shanghai, the Fifth Round of Three-Year Public Health Action Plan of Shanghai (No. GWV-10.1-XK13).
The authors declare no competing interests.
Human subject research was approved by the Ethics Committee of Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Project number 2021-K-46), and all subjects provided signed informed consent. This study has been registered at chictr.org.cn (ChiCTR2100046850). All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Shanghai Jiao Tong University School of Medicine (Project number A-2019-053, A-2019-069).
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Li, Q., Yue, T., Du, X. et al. HSC70 mediated autophagic degradation of oxidized PRL2 is responsible for osteoclastogenesis and inflammatory bone destruction. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01068-y