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Mapk7 regulates bone-fat balance by targeting Lrp6/β-catenin axis

ABSTRACT: The lineage commitment and differentiation of mesenchymal stem cells (MSCs) play a crucial role in the maintenance of bone stability. MAPK7 (Mitogen-activated protein kinase 7), a member of the MAPK family, controls cell proliferation, differentiation, and survival. However, the specific role of Mapk7 in regulating the osteogenic and adipogenic differentiation of MSCs remains to be determined. In this study, depletion of Mapk7 in MSCs (Prx1-Cre) resulted in severe low bone mass and accumulation of bone marrow fat in mice exhibiting osteoporosis. In vitro, overexpression of Mapk7 in MSCs induced an enhancement of osteogenesis in MSCs, while adipogenesis was attenuated. Mechanistically, MAPK7 availed to influence the activity of WNT/β-catenin signaling by modulating the phosphorylation of LRP6 ser1490, which ultimately impacted the osteogenic-adipogenic differentiation fate of MSCs for the first time. This is of great clinical and scientific significance for understanding the biological function of Mapk7 gene and developing new therapeutic targets for OP. Our study for the first time demonstrates that Mapk7/Lrp6/β-catenin signal axis plays a critical role in regulating the osteogenic and adipogenic differentiation of MSCs. It also suggests that modulating the function of Mapk7 may benefit the treatment of MSCs differentiation inbalance related bone diseases such as osteoporosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE255596 | GEO | 2024/02/15

REPOSITORIES: GEO

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Project description:Gene Expression analysis of a differentiation timeseries of human Mesenchymal Stem Cells (hMSCs) in the presence of adipogenic/osteogenic factors. hMSCs differentiate into fat cells when treated with dexamethasone (10^-6 M), insulin (10 ug/ml), rosiglitazone (10^-7 M) and IBMX (250 uM). TGFbeta (5 ng/ml) inhibits this process and redirects these cells to differentiate into bone cells. Introduction: Patients suffering from osteoporosis show an increased number of adipocytes in their bone marrow, concomitant with a reduction in the pool of human mesenchymal stem cells (hMSCs) that are able to differentiate into osteoblasts, thus leading to suppressed osteogenesis. Methods: In order be able to interfere with this process, we have investigated in vitro culture conditions whereby adipogenic differentiation of hMSCs is impaired and osteogenic differentiation is promoted. By means of gene expression microarray analysis, we have investigated genes which are potential targets for prevention of fat cell differentiation. Results: Our data show that BMP2 promotes both adipogenic and osteogenic differentiation of hMSCs, while TGFÎ² inhibits differentiation into both lineages. However, when cells are cultured under adipogenic differentiation conditions, which contains cAMP-enhancing agents such as IBMX of PGE2, TGFÎ² promotes osteogenic differentiation, while at the same time inhibiting adipogenic differentiation. Gene expression and immunoblot analysis indicated that cAMP-induced suppression of HDAC5 levels plays an important role in the inhibitory effect of TGFÎ² on osteogenic differentiation. By means of gene expression microarray analysis, we have investigated genes which are downregulated by TGFÎ² under adipogenic differentiation conditions and may therefore be potential targets for prevention of fat cell differentiation. We thus identified 9 genes for which FDA-approved drugs are available. Our results show that drugs directed against the nuclear hormone receptor PPARG, the metalloproteinase ADAMTS5 and the aldo-keto reductase AKR1B10 inhibit adipogenic differentiation in a dose-dependent manner, although in contrast to TGFÎ² they do not appear to promote osteogenic differentiation. Conclusions: The approach chosen in this study has resulted in the identification of new targets for inhibition of fat cell differentiation, which may not only be relevant for prevention of osteoporosis, but also of obesity. hMSCs were induced to differentiate in the presence dexamethasone, insulin and rosiglitazone, to which was added either 50 ng/ml BMP2; BMP2 + TGFbeta; BMP2 + IBMX; BMP2 + TGFbeta + IBMX.

Project description:Gene Expression analysis of a differentiation timeseries of human Mesenchymal Stem Cells (hMSCs) in the presence of adipogenic/osteogenic factors. hMSCs differentiate into fat cells when treated with dexamethasone (10^-6 M), insulin (10 ug/ml), rosiglitazone (10^-7 M) and IBMX (250 uM). TGFbeta (5 ng/ml) inhibits this process and redirects these cells to differentiate into bone cells. Introduction: Patients suffering from osteoporosis show an increased number of adipocytes in their bone marrow, concomitant with a reduction in the pool of human mesenchymal stem cells (hMSCs) that are able to differentiate into osteoblasts, thus leading to suppressed osteogenesis. Methods: In order be able to interfere with this process, we have investigated in vitro culture conditions whereby adipogenic differentiation of hMSCs is impaired and osteogenic differentiation is promoted. By means of gene expression microarray analysis, we have investigated genes which are potential targets for prevention of fat cell differentiation. Results: Our data show that BMP2 promotes both adipogenic and osteogenic differentiation of hMSCs, while TGFβ inhibits differentiation into both lineages. However, when cells are cultured under adipogenic differentiation conditions, which contains cAMP-enhancing agents such as IBMX of PGE2, TGFβ promotes osteogenic differentiation, while at the same time inhibiting adipogenic differentiation. Gene expression and immunoblot analysis indicated that cAMP-induced suppression of HDAC5 levels plays an important role in the inhibitory effect of TGFβ on osteogenic differentiation. By means of gene expression microarray analysis, we have investigated genes which are downregulated by TGFβ under adipogenic differentiation conditions and may therefore be potential targets for prevention of fat cell differentiation. We thus identified 9 genes for which FDA-approved drugs are available. Our results show that drugs directed against the nuclear hormone receptor PPARG, the metalloproteinase ADAMTS5 and the aldo-keto reductase AKR1B10 inhibit adipogenic differentiation in a dose-dependent manner, although in contrast to TGFβ they do not appear to promote osteogenic differentiation. Conclusions: The approach chosen in this study has resulted in the identification of new targets for inhibition of fat cell differentiation, which may not only be relevant for prevention of osteoporosis, but also of obesity.

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Mapk7 regulates bone-fat balance by targeting Lrp6/β-catenin axis

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