Benzo[a]pyrene injures BMP2-induced osteogenic differentiation of mesenchymal stem cells through AhR reducing BMPRII

• Published in: Ecotoxicology and environmental safety 2020-10, Vol.203, p.110930-110930, Article 110930
• Main Authors: An, Liqin, Shi, Qiong, Fan, Mengtian, Huang, Gaigai, Zhu, Mengying, Zhang, Menghao, Liu, Yan, Weng, Yaguang
• Format: Article
• Language: English
• Subjects: Aryl hydrocarbon receptor; Benzo[a]pyrene; BMPRII; Bone morphogenetic protein 2; Mesenchymal stem cells
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2020.110930

Benzo[a]pyrene(BaP), a polycyclic aromatic hydrocarbons (PAH) of environmental pollutants, is one of the main ingredients in cigarettes and an agonist of the aryl hydrocarbon receptor (AhR). Mesenchymal stem cells (MSCs) including C3H10T1/2 and MEF cells, adult multipotent stem cells, can be differentiated toward osteoblasts during the induction of osteogenic induction factor-bone morphogenetic protein 2(BMP2). Accumulating evidence suggests that BaP decreases bone development in mammals, but the further mechanisms of BaP on BMP2-induced bone formation involved are unknown. Here, we researched the role of BaP on BMP2-induced osteoblast differentiation and bone formation. We showed that BaP significantly suppressed early and late osteogenic differentiation, and downregulated the runt-related transcription factor 2(Runx2), osteocalcin(OCN) and osteopontin (OPN) during the induction of BMP2 in MSCs. Consistent with in vitro results, administration of BaP inhibited BMP2-induced subcutaneous ectopic osteogenesis in vivo. Interestingly, blocking AhR reversed the inhibition of BaP on BMP2-induced osteogenic differentiation, which suggested that AhR played an important role in this process. Moreover, BaP significantly decreased BMP2-induced Smad1/5/8 phosphorylation. Furthermore, BaP significantly reduced bone morphogenetic protein receptor 2(BMPRII) expression and excessively activated Hey1. Thus, our data demonstrate the role of BaP in BMP2-induced bone formation and suggest that impaired BMP/Smad pathways through AhR regulating BMPRII and Hey1 may be an underlying mechanism for BaP inhibiting BMP2-induced osteogenic differentiation. BMP2 binding to BMPR-II to phosphorylate Smads(including Smad1/5/8) and then shuttles in the nucleus to regulate the expression of osteogenic gene. BaP crosses cell membrane and binds to AhR, inhibiting the expression of BMPR-II, thereby inhibiting the activation of Smad1/5/8, and finally inhibiting the expression of Runx2, OCN, and OPN. In addition, BaP excessively activate Hey1. This may eliminate the activation of the BMP signaling pathway through negative feedback, then negatively regulate BMP2-induced osteogenesis. [Display omitted] •BaP inhibits BMP2/Smad signaling pathway via AhR in MSCs.•BaP inhibits BMP2-induced osteogenic differentiation of MSCs by regulating BMPRII and Hey1.•Our research provides a theoretical basis for improving the bone formation of BaP exposed crowd.