USP18 is downregulated in an osteoporosis model and alleviates osteoblast inflammation and apoptosis by deubiquitinating TAK1 to inhibit the MAPK pathway.

Abstract

Osteoporosis (OP) is a systemic metabolic disease associated with inflammation and apoptosis of osteoblasts. Ubiquitin-specific protease 18 (USP18) has been shown to participate in the progression of bone metabolic disorders; however, its role in osteoblast injury remains unclear. A rat OP model was established via bilateral ovariectomy (OVX). Pathological changes were observed using H&E and Masson staining, and Western blotting was used to detect the expression of related proteins. In vitro, an inflammatory injury model was constructed by inducing MC3T3-E1 mouse osteoblasts with 1 µg/mL LPS. CCK-8, EdU, flow cytometry, and Co-IP were utilized to validate the role of USP18 in osteoblast injury. OVX-treated rat femoral tissue samples exhibited severe inflammatory cell infiltration and bone damage. USP18 expression was significantly downregulated in OP rats and in LPS-stimulated osteoblasts. Overexpression of USP18 significantly increased cell viability and proliferation; upregulated the expression of osteogenesis-related protein markers (Runx2, ALP, and OCN); and reduced the levels of inflammatory factors (TNF-α and IL-6) and apoptotic proteins (Bax and cleaved caspase-3), thereby ameliorating LPS-induced osteoblast injury. Mechanistic studies revealed that USP18 binds to TAK1, removes K63-linked ubiquitination modifications on TAK1, and inhibits the activation of the p38/JNK-MAPK pathway. Notably, the MAPK activator anisomycin or TAK1 overexpression weakened the protective effects of USP18 on osteoblasts. USP18 inhibits MAPK pathway activation by deubiquitinating TAK1 and alleviates LPS-induced inflammation and apoptosis in osteoblasts. Furthermore, USP18 overexpression mitigates OP progression.

Supplementary information: The online version contains supplementary material available at https://doi.org/10.1007/s10616-026-01068-7.