Abstract
Bone morphogenetic protein 2 (BMP2) has been used to induce bone regeneration by promoting osteogenic differentiation of bone marrow-derived mesenchymal stem cells (MSCs). However, its effect is attenuated in osteoporotic conditions by unknown mechanisms. In this study, we investigated the molecular mechanisms of reduced osteogenic effect of BMP2 in osteoporotic conditions. By interrogating the microarray data from osteoporosis patients, we revealed an upregulation of the epigenetic modifying protein lysine (K)-specific demethylase 5A (KDM5A) and decreased Runt-related transcription factor 2 (RUNX2) expression. Further studies were focused on the role of KDM5A in osteoporosis. We first established ovariectomized (OVX) mouse model and found that the BMP2-induced osteogenic differentiation of osteoporotic MSCs was impaired. The elevated level of KDM5A was confirmed in osteoporotic MSCs. Overexpression of KDM5A in normal MSCs inhibited BMP2-induced osteogenesis. Moreover, osteogenic differentiation of osteoporotic MSCs was restored by specific KDM5A short hairpin RNA or inhibitor. Furthermore, by chromatin immunoprecipitation assay we demonstrated that KDM5A functions as endogenous modulator of osteogenic differentiation by decreasing H3K4me3 levels on promoters of Runx2, depend on its histone methylation activity. More importantly, we found an inhibitory role of KDM5A in regulating bone formation in osteoporotic mice, and pretreatment with KDM5A inhibitor partly rescued the bone loss during osteoporosis. Our results show, for the first time, that KDM5A-mediated H3K4me3 modification participated in the etiology of osteoporosis and may provide new strategies to improve the clinical efficacy of BMP2 in osteoporotic conditions.
Highlights
Osteoporosis, characterized by low bone mineral density and destruction of bone structure, is one of the most common and debilitating skeletal disorders, especially in aged population.[1,2] Bone marrow-derived mesenchymal stem cells (MSCs) are common progenitors of osteoblasts and adipocytes in bone
We first examined the transcriptomes of MSCs, from four osteoporotic patients and four age-matched normal people using the gene set enrichment analysis (GSEA) method
Further dissection through cytoscape and GeneMANIA with GO-based weighting revealed a functional interactive network among the upregulated KDM5A and downregulated SMADs in terms of pathways, physical interactions, coexpression and colocalization parameters (Figure 1c). These results indicate that KDM5A may be involved in impaired osteogensis of osteoporotic MSCs
Summary
Osteoporosis, characterized by low bone mineral density and destruction of bone structure, is one of the most common and debilitating skeletal disorders, especially in aged population.[1,2] Bone marrow-derived mesenchymal stem cells (MSCs) are common progenitors of osteoblasts and adipocytes in bone. Bone morphogenetic protein 2 (BMP2) has been used to induce bone regeneration by promoting osteogenic differentiation of MSCs.[5,6] extended clinical use of BMP has revealed its transient and low osteo-inductive efficacy in vivo.[7,8] The molecular mechanism of abnormal endogenous MSCs fate determination remains elusive, which hinders the progress of osteoporosis treatment. Knockdown of Kdm5a restored osteoporotic BMSC cell lineage commitment by increasing H3K4me[3] levels on promoter region of Runt-related transcription factor 2 (Runx2), recovered osteogenic differentiation of osteoporotic MSCs both in vitro and in vivo. We demonstrated that Kdm5a-mediated H3K4me[3] modification participates in the etiology of osteoporosis, which may provide new strategies to improve the clinical efficacy of BMP2 and to enhance bone formation under osteoporotic conditions
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