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A functional autophagy pathway is essential for BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs).

ABSTRACT: Mesenchymal stem cells (MSCs) are capable of differentiating into bone, cartilage and adipose tissues. We identified BMP9 as the most potent osteoinductive BMP although detailed mechanism underlying BMP9-regulated osteogenesis of MSCs is indeterminate. Emerging evidence indicates that autophagy plays a critical role in regulating bone homeostasis. We investigated the possible role of autophagy in osteogenic differentiation induced by BMP9. We showed that BMP9 upregulated the expression of multiple autophagy-related genes in MSCs. Autophagy inhibitor chloroquine (CQ) inhibited the osteogenic activity induced by BMP9 in MSCs. While overexpression of ATG5 or ATG7 did not enhance osteogenic activity induced by BMP9, silencing Atg5 expression in MSCs effectively diminished BMP9 osteogenic signaling activity and blocked the expression of the osteogenic regulator Runx2 and the late marker osteopontin induced by BMP9. Stem cell implantation study revealed that silencing Atg5 in MSCs profoundly inhibited ectopic bone regeneration and bone matrix mineralization induced by BMP9. Collectively, our results strongly suggest a functional autophagy pathway may play an essential role in regulating osteogenic differentiation induced by BMP9 in MSCs. Thus, restoration of dysregulated autophagic activity in MSCs may be exploited to treat fracture healing, bone defects or osteoporosis.

SUBMITTER: Zhao X

PROVIDER: S-EPMC8205769 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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A functional autophagy pathway is essential for BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs).

Zhao Xia X Huang Bo B Wang Hao H Ni Na N He Fang F Liu Qing Q Shi Deyao D Chen Connie C Zhao Piao P Wang Xi X Wagstaff William W Pakvasa Mikhail M Tucker Andrew Blake AB Lee Michael J MJ Wolf Jennifer Moriatis JM Reid Russell R RR Hynes Kelly K Strelzow Jason J Ho Sherwin H SH Yu Tengbo T Yang Jian J Shen Le L He Tong-Chuan TC Zhang Yongtao Y

American journal of translational research 20210515 5

Mesenchymal stem cells (MSCs) are capable of differentiating into bone, cartilage and adipose tissues. We identified BMP9 as the most potent osteoinductive BMP although detailed mechanism underlying BMP9-regulated osteogenesis of MSCs is indeterminate. Emerging evidence indicates that autophagy plays a critical role in regulating bone homeostasis. We investigated the possible role of autophagy in osteogenic differentiation induced by BMP9. We showed that BMP9 upregulated the expression of multip ...[more]

PMID: 34150011

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Project description:Known as a tumour suppressor gene, p53 also plays a key role in controlling the differentiation of mesenchymal stem cells (MSCs). Bone morphogenetic protein 9 (BMP9) has been identified as a potent factor in inducing osteogenic differentiation of MSCs, but its relationship with p53 remains unclear. The present study revealed that TP53 was expressed at higher levels in MSCs from patients with osteoporosis and was associated with the top 10 core central genes found in the current osteoporosis genetic screen. p53 was expressed in C2C12, C3H10T1/2, 3T3-L1, MEFs, and MG-63 cell lines, and could be upregulated by BMP9, as measured by western blotting and reverse-transcription quantitative PCR (RT-qPCR). Furthermore, overexpression of p53 increased the mRNA and protein levels of osteogenic marker Runx2 and osteopontin, as evaluated by western blotting and RT-qPCR in BMP9-induced MSCs, whereas the p53 inhibitor pifithrin (PFT)-α attenuated these effects. The same trend was found in alkaline phosphatase activities and matrix mineralization, as measured by alkaline phosphatase staining and alizarin red S staining. Moreover, p53 overexpression reduced adipo-differentiation markers of PPARγ and lipid droplet formation, as measured by western blotting, RT-qPCR and oil red O staining, respectively, whereas PFT-α facilitated adipo-differentiation in MSCs. In addition, p53 promoted TGF-β1 expression and inhibition of TGF-β1 by LY364947 partially attenuated the effects of p53 on promoting BMP9-induced MSC osteo-differentiation and inhibiting adipo-differentiation. The inhibitory effect of PFT-α on osteogenic markers and the promoting effect on adipogenic markers can be reversed when combined with TGF-β1. TGF-β1 may enhance the promotion of osteo-differentiation of MSCs by p53 through inhibition of adipo-differentiation. Collectively, by promoting BMP9-induced MSCs bone differentiation and inhibiting adipose differentiation, p53 may be a novel therapeutic target for bone-related diseases.

Dataset Information

A functional autophagy pathway is essential for BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs).

Publications

A functional autophagy pathway is essential for BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs).

Similar Datasets

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