| Summary: | 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 (<i>miR-29a</i>) loss, oxidative stress marker 8-hydroxydeoxyguanosine (8-OHdG), DNA hypermethylation marker 5-methylcystosine (5mC), and osteoblast senescence in human osteoporosis. <i>miR-29a</i> knockout mice showed low bone mass, sparse trabecular microstructure, and osteoblast senescence. <i>miR-29a</i> deletion exacerbated bone loss in old mice. Old <i>miR-29a</i> transgenic mice showed fewer osteoporosis signs, less 5mC, and less 8-OHdG formation than age-matched wild-type mice. <i>miR-29a</i> overexpression reversed age-induced senescence and osteogenesis loss in bone-marrow stromal cells. <i>miR-29a</i> promoted transcriptomic landscapes of redox reaction and forkhead box O (FoxO) pathways, preserving oxidation resistance protein-1 (<i>Oxr1</i>) and <i>FoxO3</i> in old mice. In vitro, <i>miR-29a</i> interrupted DNA methyltransferase 3b (Dnmt3b)-mediated <i>FoxO3</i> 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 <i>miR-29a</i> and <i>FoxO3</i> to mitigate oxidative stress, senescence, and mineralization matrix underproduction. Taken together, <i>miR-29a</i> 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 <i>miR-29a</i> protects against osteoblast aging and highlights the remedial effects of <i>miR-29a</i> on osteoporosis.
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