Wang Shenghong, Tian Cong, Liu Jinmin, Feng Zhiwei, Zhao Dacheng, Yang Ao, Xiang Dejian, Chen Changshun, Xia Yayi, Geng Bin
Department of Orthopaedics, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China; Orthopaedics Clinical Medicine Research Center of Gansu Province, Lanzhou, China; Intelligent Orthopedics Industry Technology Center of Gansu Province, Lanzhou, China.
Orthopaedics Clinical Medicine Research Center of Gansu Province, Lanzhou, China; Intelligent Orthopedics Industry Technology Center of Gansu Province, Lanzhou, China; Department of Orthopaedics, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong, China.
Cell Signal. 2025 Nov;135:112017. doi: 10.1016/j.cellsig.2025.112017. Epub 2025 Jul 21.
Bone marrow-derived mesenchymal stem cells (BMSCs) maintain bone homeostasis by balancing adipogenesis and osteogenesis, with disruption of this balance favoring adipogenesis contributing to osteoporosis. Melatonin, known for regulating bone metabolism, promotes osteogenesis and inhibits adipogenesis, but the mechanisms remain unclear. This study investigates whether melatonin regulates BMSC differentiation by modulating the methylation of the Krüppel-like factor 5 (KLF5) promoter, a transcription factor involved in both adipogenesis and osteogenesis. Using an ovariectomy (OVX)-induced osteoporosis mouse model, we found that melatonin treatment significantly reversed OVX-induced bone loss, increased bone mineral density, and reduced bone marrow adiposity, accompanied by increased KLF5 expression in bone tissue. In vitro, melatonin promoted osteogenic differentiation and suppressed adipogenic differentiation in BMSCs, with decreased methylation of the KLF5 promoter. Knockdown of KLF5 suppressed osteogenesis and enhanced adipogenesis, while KLF5 overexpression promoted osteogenesis and inhibited adipogenesis. Melatonin-induced demethylation of the KLF5 promoter was associated with increased KLF5 expression, which in turn promoted osteogenic differentiation and inhibited adipogenic differentiation. These findings reveal a novel epigenetic mechanism underlying melatonin's bone-protective effects and suggest KLF5 promoter methylation as a potential therapeutic target for osteoporosis and related bone disorders.
骨髓间充质干细胞（BMSCs）通过平衡脂肪生成和成骨作用来维持骨稳态，这种平衡的破坏有利于脂肪生成，从而导致骨质疏松症。褪黑素以调节骨代谢而闻名，它能促进成骨作用并抑制脂肪生成，但其机制尚不清楚。本研究调查褪黑素是否通过调节参与脂肪生成和成骨作用的转录因子Krüppel样因子5（KLF5）启动子的甲基化来调节BMSC分化。使用卵巢切除（OVX）诱导的骨质疏松小鼠模型，我们发现褪黑素治疗显著逆转了OVX诱导的骨质流失，增加了骨矿物质密度，并减少了骨髓脂肪，同时骨组织中KLF5表达增加。在体外，褪黑素促进BMSCs的成骨分化并抑制脂肪生成分化，同时KLF5启动子的甲基化减少。敲低KLF5会抑制成骨作用并增强脂肪生成，而KLF5过表达则促进成骨作用并抑制脂肪生成。褪黑素诱导的KLF5启动子去甲基化与KLF5表达增加有关，进而促进成骨分化并抑制脂肪生成分化。这些发现揭示了褪黑素骨保护作用的一种新的表观遗传机制，并表明KLF5启动子甲基化是骨质疏松症和相关骨疾病的潜在治疗靶点。
