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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.

SUBMITTER: Lian WS

PROVIDER: S-EPMC8389244 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Thymic senescence contributes to increased incidence of infection, cancer and autoimmunity at senior ages. This process manifests as adipose involution. As with other adipose tissues, thymic adipose involution is also controlled by PPARgamma. This is supported by observations reporting that systemic PPARgamma activation accelerates thymic adipose involution. Therefore, we hypothesized that decreased PPARgamma activity could prevent thymic adipose involution, although it may trigger metabolic adverse effects. We have confirmed that both human and murine thymic sections show marked staining for PPARgamma at senior ages. We have also tested the thymic lobes of PPARgamma haplo-insufficient and null mice. Supporting our working hypothesis both adult PPARgamma haplo-insufficient and null mice show delayed thymic senescence by thymus histology, thymocyte mouse T-cell recombination excision circle qPCR and peripheral blood naive T-cell ratio by flow-cytometry. Delayed senescence showed dose-response with respect to PPARgamma deficiency. Functional immune parameters were also evaluated at senior ages in PPARgamma haplo-insufficient mice (null mice do not reach senior ages due to metabolic adverse affects). As expected, sustained and elevated T-cell production conferred oral tolerance and enhanced vaccination efficiency in senior PPARgamma haplo-insufficient, but not in senior wild-type littermates according to ELISA IgG measurements. Of note, humans also show increased oral intolerance issues and decreased protection by vaccines at senior ages. Moreover, PPARgamma haplo-insufficiency also exists in human known as a rare disease (FPLD3) causing metabolic adverse effects, similar to the mouse. When compared to age- and metabolic disorder-matched other patient samples (FPLD2 not affecting PPARgamma activity), FPLD3 patients showed increased human Trec (hTrec) values by qPCR (within healthy human range) suggesting delayed thymic senescence, in accordance with mouse results and supporting our working hypothesis. In summary, our experiments prove that systemic decrease of PPARgamma activity prevents thymic senescence, albeit with metabolic drawbacks. However, thymic tissue-specific PPARgamma antagonism would likely solve the issue.

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

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