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.

炎症导致全身性骨质疏松或局部骨质破坏，然而，其潜在的分子机制仍知之甚少。在这项研究中，我们报告 PRL2 是破骨细胞生成和骨吸收的负调节因子。 PRL2 缺陷的小鼠表现出骨量减少和破骨细胞数量增加。 PRL2通过激活RAC1负向调节RANKL诱导的活性氧产生，因此PRL2缺陷的破骨细胞前体细胞具有增强的破骨细胞分化能力和骨吸收能力。在炎症过程中，氧化的 PRL2 是 HSC70 的选定底物，氧化应激条件会通过 HSC70 介导的内体微自噬和分子伴侣介导的自噬触发 PRL2 的快速降解。在炎症性骨病小鼠模型中消除 PRL2 会导致破骨细胞数量增加和骨损伤加剧。此外，在小鼠关节炎模型和人类类风湿性关节炎中，外周骨髓细胞中PRL2蛋白水平降低与骨破坏高度相关，而自噬抑制剂羟氯喹在体内阻断了炎症诱导的PRL2降解和骨破坏。因此，我们的研究结果将 PRL2 确定为骨免疫的新调节因子，提供了炎症与骨质疏松症之间的联系。因此，PRL2是炎症性骨病的潜在治疗靶点，抑制HSC70介导的PRL2自噬降解可能为炎症性骨病的治疗提供新的治疗工具。