Li Zhuoran, Zhang Junyan, Xu Tingting, Hao Zhiying, Li Yadong
School of Medicine, University of Nottingham, Nottingham, NG7 2NR, UK.
Department of Affiliated Cancer Hospital, Shanxi Medical University, Taiyuan, 030001, China.
Mol Med. 2025 Feb 19;31(1):65. doi: 10.1186/s10020-025-01098-5.
Osteoporosis represents a salient metabolic bone disorder. Histone demethylase plays a vital role in bone development and homeostasis. This study explored the mechanism of histone demethylase KDM5A affecting osteoporotic fracture healing via the miR-495/SKP2/Runx2 axis.
The murine model of osteoporotic fracture was established. The bone mineral density, maximum elastic stress, and maximum load were tested. The relative trabecular bone volume, bone trabecular thickness, and trabecular number at the proximal end of tibia were detected. The histopathological changes of femur tissues and bone microstructure were observed. Expressions of KDM5A and osteogenic factors were detected. The cell proliferation, alkaline phosphatase activity, and calcified nodules were measured. The binding relationships between KDM5A and miR-495 promoter, and miR-495 and SKP2 were verified. The interaction between SKP2 and Runx2 was detected. The ubiquitination level of Runx2 and the stability of Runx2 protein were detected.
KDM5A was highly expressed in the murine model of osteoporotic fracture. Interference of KDM5A expression facilitated fracture healing in osteoporotic mice. KDM5A downregulated miR-495 expression by promoting the H3K4me3 methylation of the miR-495 promoter. Inhibition of miR-495 reversed the effect of KDM5A silencing on osteoblast proliferation, differentiation, and mineralization. miR-495 facilitated osteoblast proliferation, differentiation, and mineralization by targeting SKP2. SKP2 suppressed Runx2 expression through ubiquitination degradation. Inhibition of Runx2 reversed the promoting effect of SKP2 silencing on osteogenic differentiation.
KDM5A attenuated the inhibition of miR-495 on SKP2 and promoted the ubiquitination degradation of Runx2 protein by SKP2, thereby repressing osteoblast differentiation and retarding osteoporotic fracture healing.
骨质疏松症是一种显著的代谢性骨疾病。组蛋白去甲基化酶在骨骼发育和稳态中起着至关重要的作用。本研究探讨了组蛋白去甲基化酶KDM5A通过miR-495/SKP2/Runx2轴影响骨质疏松性骨折愈合的机制。
建立骨质疏松性骨折小鼠模型。检测骨密度、最大弹性应力和最大负荷。检测胫骨近端相对骨小梁体积、骨小梁厚度和骨小梁数量。观察股骨组织的组织病理学变化和骨微观结构。检测KDM5A和成骨因子的表达。测量细胞增殖、碱性磷酸酶活性和钙化结节。验证KDM5A与miR-495启动子、miR-495与SKP2之间的结合关系。检测SKP2与Runx2之间的相互作用。检测Runx2的泛素化水平和Runx2蛋白的稳定性。
KDM5A在骨质疏松性骨折小鼠模型中高表达。干扰KDM5A表达促进了骨质疏松小鼠的骨折愈合。KDM5A通过促进miR-495启动子的H3K4me3甲基化下调miR-495表达。抑制miR-495可逆转KDM5A沉默对成骨细胞增殖、分化和矿化的影响。miR-495通过靶向SKP2促进成骨细胞增殖、分化和矿化。SKP2通过泛素化降解抑制Runx2表达。抑制Runx2可逆转SKP2沉默对成骨分化的促进作用。
KDM5A减弱了miR-495对SKP2的抑制作用，并促进了SKP2对Runx2蛋白的泛素化降解，从而抑制成骨细胞分化并延缓骨质疏松性骨折愈合。
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