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Project description:Skeletal aging is a complex process, characterized by a decrease in bone formation, an increase in marrow fat, and stem cell exhaustion. Loss of H3K9me3, a heterochromatin mark, has been proposed to be associated with aging. Here, we report that loss of KDM4B in mesenchymal stromal cells (MSCs) exacerbated skeletal aging and osteoporosis by reducing bone formation and increasing marrow adiposity via increasing H3K9me3. KDM4B epigenetically coordinated β-catenin/Smad1-mediated transcription by removing repressive H3K9me3. Importantly, KDM4B ablation impaired MSC self-renewal and promoted MSC exhaustion by inducing senescence-associated heterochromatin foci formation, providing a mechanistic explanation for stem cell exhaustion with aging. Moreover, while KDM4B was required for parathyroid hormone-mediated bone anabolism, KDM4B depletion accelerated bone loss and marrow adiposity induced by a high-fat diet. Our results suggest that the epigenetic rejuvenation and reversing bone-fat imbalance might be new strategies for preventing and treating skeletal aging and osteoporosis by activating KDM4B in MSCs.
| S-EPMC8178178 | biostudies-literature
Project description:Primary mMSCs were cultured in control medium (Con), containing DMEM and 15% FBS, or were subjeucted to osteogenic induction (OI) for 2 days. RNA was isolated using RNeasy Mini Kit (Qiagen, Cat#74104) from three biological replicates of primary MSCs from Prx1Cre;Kdm4bf/f mice and control mice. Total RNA was then purified with Dynabeads™ mRNA Purification Kit (Invitrogen, Cat#61006). RNA-seq libraries were constructed using Stranded RNA-Seq Library Preparation Kit (Kapa Biosystems, Cat#KK8400), and sequenced using an illumina HiSeq 3000 sequencer at the Technology Center for Genomics & Bioinformatics (TCGB) core at UCLA.
2021-02-10 | GSE104258 | GEO
Project description:Mesenchymal stem/stromal cells (MSCs) are multipotent progenitor cells with multilineage differentiation potentials. We previously reported histone demethylases KDM4B promoted osteogenesis and inhibited adipogenesis of human MSCs. To identify genome-wide enrichments of KDM4B and the changes in H3K9me3 marks when loss of KDM4B, Primary MSCs were isolated from Prx1Cre; Kdm4bf/f mice and control mice. ChIP-seq assay was performed using KDM4B, H3K9me3 and H3 antibody, respectively.
2021-02-10 | GSE104257 | GEO
Project description:Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging
| PRJNA412178 | ENA
Project description:Loss of KDM4B Exacerbates Bone-Fat Imbalance and Mesenchymal Stem Cell Exhaustion in Skeletal Aging [ChIP-seq]
| PRJNA412202 | ENA
Project description:Loss of KDM4B Exacerbates Bone-Fat Imbalance and Mesenchymal Stem Cell Exhaustion in Skeletal Aging [RNA-seq]
| PRJNA412206 | ENA
Project description:BackgroundSkeletal aging is characterized by a decrease in bone mass and an increase in marrowfat content. Advanced oxidation protein products (AOPPs) accumulate easily with aging and disrupt redox homeostasis. We examined whether AOPPs accumulation contributes to the bone-fat imbalance during skeletal aging.MethodsBoth young and aged mice were employed to assess the changes of AOPPs levels and its contribution to bone-fat imbalance during skeletal aging. Primary bone marrow mesenchymal stromal cells (MSCs) were used to examine the potential role of AOPPs in age-related switch between osteogenic and adipogenic differentiation. Aged mice were also gavaged by non-selective antioxidant N-acetyl-L-cysteine (NAC), followed by close monitoring of the changes in AOPPs levels and bone-fat metabolism. Furthermore, young mice were chronically exposed to AOPPs and then evaluated for the changes of bone mass and marrow adiposity.ResultsThe levels of AOPPs in serum and bone marrow were markedly higher in aged mice than that in young mice. Age-related accumulation of AOPPs was accompanied by reduced bone formation, increased marrow adiposity and deterioration of bone microstructure. Reduced AOPPs accumulation by antioxidant NAC leaded to improvement of the bone-fat imbalance in aged mice. Similarly, the bone-fat imbalance was induced by chronic AOPPs loading in young mice. Compared with MSCs from young mice, MSCs from aged mice tended to differentiate into adipocytes rather than osteoblasts and displayed cellular senescence. Exposure of primary MSCs to AOPPs resulted in the switch from osteogenic to adipogenic lineage and cellular senescence. AOPPs challenge also increased intracellular ROS generation by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria. The antioxidant NAC, after scavenging ROS, ameliorated the AOPPs-induced lineage switch and senescence in MSCs by inhibiting the PI3K/AKT/mTOR pathway.ConclusionOur findings revealed the involvement of AOPPs in age-related switch between osteogenic and adipogenic differentiation, and illuminated a novel potential mechanism underlying bone-fat imbalance during skeletal aging.The translational potential of this articleReducing AOPPs accumulation and its cascading effects on MSCs might be an attractive strategy for delaying skeletal aging.
| S-EPMC11788738 | biostudies-literature
Project description:Mesenchymal stem/stromal cells (MSCs) are the predominant source of bone and adipose tissue in adult bone marrow and play a critical role in skeletal homeostasis. Age-induced changes in bone marrow favor adipogenesis over osteogenesis leading to skeletal involution and increased marrow adiposity so pathways that prevent MSC aging are potential therapeutic targets for treating age-related bone diseases. Here, we show that inositol hexakisphosphate kinase 1 (Ip6k1) deletion in mice increases MSC yields from marrow and enhances cell growth and survival ex vivo. In response to the appropriate stimuli, Ip6k1-/- versus Ip6k1+/+ MSCs also exhibit enhanced osteogenesis and hematopoiesis-supporting activity and reduced adipogenic differentiation. Mechanistic-based studies revealed that Ip6k1-/- MSCs express higher MDM2 and lower p53 protein levels resulting in lower intrinsic mitochondrial reactive oxygen species (ROS) levels as compared to Ip6k1+/+ MSCs, but both populations upregulate mitochondrial ROS to similar extents in response to oxygen-induced stress. Finally, we show that mice fed a high fat diet exhibit reduced trabecular bone volume, and that pharmacological inhibition of IP6K1 using a pan-IP6K inhibitor largely reversed this phenotype while increasing MSC yields from bone marrow. Together, these findings reveal an important role for IP6K1 in regulating MSC fitness and differentiation fate. Unlike therapeutic interventions that target peroxisome proliferator-activated receptor gamma and leptin receptor activity, which yield detrimental side effects including increased fracture risk and altered feeding behavior, respectively, inhibition of IP6K1 maintains insulin sensitivity and prevents obesity while preserving bone integrity. Therefore, IP6K1 inhibitors may represent more effective insulin sensitizers due to their bone sparing properties. Stem Cells 2017;35:1973-1983.
| S-EPMC5533188 | biostudies-literature
Project description:Aging of craniofacial skeleton significantly impairs the repair and regeneration of trauma-induced bony defects, and complicates dental treatment outcomes. Age-related alveolar bone loss could be attributed to decreased progenitor pool through senescence, imbalance in bone metabolism and bone-fat ratio. Mesenchymal stem cells isolated from oral bones (OMSCs) have distinct lineage propensities and characteristics compared to MSCs from long bones, and are more suited for craniofacial regeneration. However, the effect of epigenetic modifications regulating OMSC differentiation and senescence in aging has not yet been investigated. In this study, we found that the histone demethylase KDM4B plays an essential role in regulating the osteogenesis of OMSCs and oral bone aging. Loss of KDM4B in OMSCs leads to inhibition of osteogenesis. Moreover, KDM4B loss promoted adipogenesis and OMSC senescence which further impairs bone-fat balance in the mandible. Together, our data suggest that KDM4B may underpin the molecular mechanisms of OMSC fate determination and alveolar bone homeostasis in skeletal aging, and present as a promising therapeutic target for addressing craniofacial skeletal defects associated with age-related deteriorations.
| S-EPMC9079076 | biostudies-literature
Project description:Impairment of glucose (Glu) uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions. The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis. Our results showed that conditional deletion of hnRNP A1 in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet (HFD). Conditional knockout mice fed a HFD showed exacerbated obesity, insulin resistance, and hepatic steatosis. In vitro interference of hnRNP A1 in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake, whereas hnRNP A1 overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin. The expression and stability of glycogen synthase (gys1) mRNA were also decreased in the absence of hnRNP A1. Mechanistically, hnRNP A1 interacted with gys1 and stabilized its mRNA, thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue. Taken together, our findings are the first to show that reduced expression of hnRNP A1 in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.
| S-EPMC7232127 | biostudies-literature