MicroRNA-29a Mitigates Osteoblast Senescence and Counteracts Bone Loss through Oxidation Resistance-1 Control of FoxO3 Methylation

Abstract

Senescent osteoblast overburden accelerates bone mass loss. Little is understood about microRNA control of oxidative stress and osteoblast senescence in osteoporosis. We revealed an association between microRNA-29a (miR-29a) loss, oxidative stress marker 8-hydroxydeoxyguanosine (8-OHdG), DNA hypermethylation marker 5-methylcystosine (5mC), and osteoblast senescence in human osteoporosis. miR-29a knockout mice showed low bone mass, sparse trabecular microstructure, and osteoblast senescence. miR-29a deletion exacerbated bone loss in old mice. Old miR-29a transgenic mice showed fewer osteoporosis signs, less 5mC, and less 8-OHdG formation than age-matched wild-type mice. miR-29a overexpression reversed age-induced senescence and osteogenesis loss in bone-marrow stromal cells. miR-29a promoted transcriptomic landscapes of redox reaction and forkhead box O (FoxO) pathways, preserving oxidation resistance protein-1 (Oxr1) and FoxO3 in old mice. In vitro, miR-29a interrupted DNA methyltransferase 3b (Dnmt3b)-mediated FoxO3 promoter methylation and senescence-associated β-galactosidase activity in aged osteoblasts. Dnmt3b inhibitor 5′-azacytosine, antioxidant N-acetylcysteine, or Oxr1 recombinant protein attenuated loss in miR-29a and FoxO3 to mitigate oxidative stress, senescence, and mineralization matrix underproduction. Taken together, miR-29a promotes Oxr1, compromising oxidative stress and FoxO3 loss to delay osteoblast aging and bone loss. This study sheds light on a new antioxidation mechanism by which miR-29a protects against osteoblast aging and highlights the remedial effects of miR-29a on osteoporosis.

Age Related Osteoporosis: Targeting Cellular Senescence

“…Mechanisms underlying senescent induced changes in MSCs have since then been addressed in multiple studies, identifying important mediators of MSC senescence [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. For instance, several miRNAs have been identified that are involved in regulating senescence and the balance between osteoblastic and adipocytic differentiation of BMSCs [ 52 , 55 , 60 , 61 ]. Lian et al investigated an involvement of miR-29a in age-related bone loss [ 61 ].…”

“…For instance, several miRNAs have been identified that are involved in regulating senescence and the balance between osteoblastic and adipocytic differentiation of BMSCs [ 52 , 55 , 60 , 61 ]. Lian et al investigated an involvement of miR-29a in age-related bone loss [ 61 ]. Knockout and overexpression of miR-29a was associated with exacerbated and reduced bone loss, respectively, in old mice.…”

“…Knockout and overexpression of miR-29a was associated with exacerbated and reduced bone loss, respectively, in old mice. Oxidation resistance protein-1 ( Oxr1 ) and forkehead box O3 ( FoxO3 ) were identified as target genes, suggesting an antioxidative effect of miR-29a associated with reduced osteoblast senescence [ 61 ]. A miRNA thought to be involved in regulating the shift between osteogenic and adipogenic differentiation is miR-499 [ 60 ].…”

MicroRNA-29a in Osteoblasts Represses High-Fat Diet-Mediated Osteoporosis and Body Adiposis through Targeting Leptin

“…Serum or exosomal miR-29a involves the development of obesity or HFD-induced diabetes [53,54]. Other groups and we have revealed that low serum miR-29-3p or miR-29a levels are present in aged patients with osteoporosis [55] or postmenopausal women with osteoporotic spine fracture [56]. The limitations of this study, we should acknowledge, are that we do not exclude miR-29a signaling in osteoblasts that may directly or indirectly influence adipose tissue metabolism.…”

MicroRNA Regulation of Bone Marrow Mesenchymal Stem Cells in the Development of Osteoporosis in Obesity

“…In an animal model of obesity, the levels of miR-211, miR-130b, miR-188, and miR-128 were increased [45][46][47][48] (Table 1, Ref. [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63]). Several microRNAs are known to induce BMSC adipogenesis by inhibiting the activity of the transcription factor RUNX2, which is involved in osteoblastogenesis.…”