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Mechanism of histone demethylase KDM5A in osteoporotic fracture healing through epigenetic regulation of the miR-495/SKP2/Runx2 axis.

Zhuoran Li·Junyan Zhang·Tingting Xu·Zhiying Hao·Yadong Li
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Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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AnimalsMicroRNAsCore Binding Factor Alpha 1 SubunitEpigenesis, GeneticMiceFracture HealingOsteoporotic FracturesDisease Models, AnimalRetinoblastoma-Binding Protein 2HumansOsteogenesisMaleOsteoblastsPromoter Regions, GeneticOsteoporosisMice, Inbred C57BLEpigeneticsFracture healingHistone demethylaseKDM5ARunx2SKP2miR-495Journal ArticleResearch Support, Non-U.S. Gov't

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Zhuoran Li, Junyan Zhang, Tingting Xu, Zhiying Hao, Yadong Li. 2025-02-19. Mechanism of histone demethylase KDM5A in osteoporotic fracture healing through epigenetic regulation of the miR-495/SKP2/Runx2 axis.. https://doi.org/10.1186/s10020-025-01098-5

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