Role of p53 in promoting BMP9-induced osteogenic differentiation of mesenchymal stem cells through TGF-beta 1

作者全名："Yao, Xintong; Li, Peipei; Deng, Yixuan; Yang, Yuanyuan; Luo, Honghong; He, Baicheng"

作者地址："[Yao, Xintong; Li, Peipei; Deng, Yixuan; Yang, Yuanyuan; Luo, Honghong; He, Baicheng] Chongqing Med Univ, Coll Pharm, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Yao, Xintong; Li, Peipei; Deng, Yixuan; Yang, Yuanyuan; Luo, Honghong; He, Baicheng] Chongqing Med Univ, Chongqing Key Lab Biochem & Mol Pharmacol, Chongqing 400016, Peoples R China"

通信作者："He, BC (通讯作者)，Chongqing Med Univ, Coll Pharm, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源：EXPERIMENTAL AND THERAPEUTIC MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000984706700001

JCR分区：Q3

影响因子：2.4

年份：2023

卷号：25

期号：6

开始页：　

结束页：　

文献类型：Article

关键词：p53; bone remodeling; mesenchymal stem cells; osteogenic differentiation; TGF-beta 1 signaling

摘要："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)-alpha 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 PPAR. and lipid droplet formation, as measured by western blotting, RT-qPCR and oil red O staining, respectively, whereas PFT-alpha facilitated adipo-differentiation in MSCs. In addition, p53 promoted TGF-beta 1 expression and inhibition of TGF-beta 1 by LY364947 partially attenuated the effects of p53 on promoting BMP9-induced MSC osteo-differentiation and inhibiting adipo-differentiation. The inhibitory effect of PFT-alpha on osteogenic markers and the promoting effect on adipogenic markers can be reversed when combined with TGF-beta 1. TGF-beta 1 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."

基金机构：National Key Research and Development Program of China [2016YFC1000803]; National Natural Science Foundation of China (NSFC) [81572226]

基金资助正文："This work was supported by the National Key Research and Development Program of China (grant no. 2016YFC1000803) and the National Natural Science Foundation of China (NSFC, grant no. 81572226)."