Work

A novel HDAC1-specific inhibitor prevents estrogen deficiency-induced osteoporosis in mice by inhibiting osteoclast function

Year: 2025

Type: article

Abstract: Postmenopausal osteoporosis (PMOP) features reduced bone mass and deteriorated bone microstructure, increasing fracture risk. Estrogen deficiency-induced osteoclast overactivation is a primary driver. OCP-001, a novel highly selective HDAC1 inhibitor, was investigated. TRAP staining showed dose-dependent inhibition of osteoclast differentiation by OCP-001. qPCR revealed concomitant downregulation of RANKL-induced osteoclast marker genes (Trap, DC-Stamp, NFATc1, ATP60) and key regulatory proteins (c-Fos, NFATc1, Blimp-1, IRF-8). In an ovariectomized (OVX)-induced PMOP mouse model, body weight monitoring showed no toxicity from OCP-001 treatment. Micro-CT analysis confirmed that it effectively prevented femoral bone mass loss and microstructural deterioration. Histological analysis further verified its inhibition of OVX-induced osteoclastogenesis. Furthermore, OCP-001 normalized OVX-altered serum bone turnover markers (PINP, β-CTx). Mechanistically, OCP-001 suppressed osteoclast differentiation partly via inhibiting the Blimp-1/IRF-8 pathway. Thus, the selective HDAC1 inhibitor OCP-001 alleviates OVX-induced bone loss and deterioration by potently inhibiting osteoclastogenesis and function, supporting its potential as a PMOP therapeutic.

Source: Archives of Gerontology and Geriatrics

DOI: 10.1016/j.archger.2025.106020

Authors: Hang Yuan, Yizhong Bao, Li Li, Yepeng Luan, Fangcai Li

Institutions: Zhejiang Hospital, Second Affiliated Hospital of Zhejiang University, Zhejiang University, Qingdao University

Language: English

Topic: Bone Metabolism and Diseases

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,750