Loss of UCHL1 Leads to Enhanced Mouse Osteoclast Formation

ABSTRACT 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.