Enhanced osteoclastogenesis causes bone fragility, osteoporosis, and an increased risk of fractures. Recent studies have suggested a possible correlation between osteoporosis and the pathological features of Parkinson's disease (PD). To establish a molecular link between these conditions, we focused on the physiological function of the PD-related protein ubiquitin carboxy-terminal hydrolase L1 (UCHL1) in bone remodeling. To this end, we investigated the role of UCHL1 in regulating osteoclast differentiation in Uchl1 spontaneous mutant gad mice. We found that gad-mouse-derived osteoclast progenitors exhibit enhanced osteoclast differentiation. Likewise, CRISPR-mediated Uchl1 knockout in mouse macrophage-derived preosteoclast RAW-D cells increased RANKL-dependent osteoclastogenesis. Supporting this observation, these Uchl1-depleted cells showed elevated expression of osteoclast marker genes. To uncover the molecular mechanisms by which the loss of Uchl1 enhances osteoclast differentiation, we screened for UCHL1-interacting proteins in RAW-D preosteoclast cells and identified AKT1 as a potential UCHL1-regulated protein. UCHL1 depletion in preosteoclasts led to increased Thr308/Ser473 phosphorylation of AKT1. Furthermore, ectopic expression of UCHL1 decreased the K63-linked polyubiquitination of AKT1. These findings suggest that UCHL1 is critical in partially suppressing osteoclastogenesis through modulating AKT signaling.

Keywords: bone; cell differentiation; osteoclasts; osteoporosis; post‐translational modification.

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增强的成骨细胞生成会导致骨骼脆弱、骨质疏松以及骨折风险增加。最近的研究表明，骨质疏松症与帕金森病（PD）的病理特征之间可能存在关联。为了建立这些条件之间的分子联系，我们关注了与帕金森病相关的蛋白质泛素羧基末端水解酶L1 (UCHL1) 在骨骼重塑中的生理功能。为此，我们在Uchl1自发突变型gad小鼠中研究了UCHL1在调节破骨细胞分化中的作用。我们发现，由gad小鼠衍生的破骨细胞祖细胞表现出增强的破骨细胞分化。同样地，在使用CRISPR技术敲除Uchl1的RAW-D小鼠巨噬细胞来源的前破骨细胞中，RANKL依赖性的破骨细胞生成也增加了。支持这一观察结果的是，这些Uchl1耗尽的细胞显示出破骨细胞标记基因表达升高。为了揭示UCHL1缺失增强破骨细胞分化背后的分子机制，我们在RAW-D前破骨细胞中筛选了与UCHL1相互作用的蛋白质，并鉴定出AKT1作为潜在的UCHL1调控蛋白。在前破骨细胞中耗尽UCHL1导致AKT1 Thr308/Ser473 磷酸化水平升高。此外，异位表达UCHL1降低了AKT1的K63连接多泛素化。这些发现表明，UCHL1通过调节AKT信号传导部分抑制破骨细胞生成，在这一过程中起关键作用。

关键词：
骨骼；细胞分化；破骨细胞；骨质疏松症；翻译后修饰。