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

Xia Zhao, Bo Huang, Hao Wang, Na Ni, Fang He, Qing Liu, Deyao Shi, Connie Chen, Piao Zhao, Xi Wang, William Wagstaff, Mikhail Pakvasa, Andrew Blake Tucker, Michael J. Lee, Jennifer Moriatis Wolf, Russell R. Reid, Kelly Hynes, Jason Strelzow, Sherwin H. Ho, Tengbo YuJian Yang, Le Shen, Tong Chuan He, Yongtao Zhang, Tong Chuan He

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Pages (from-to)4233-4250
Number of pages18
JournalAmerican Journal of Translational Research
Volume13
Issue number5
StatePublished - May 30 2021

Keywords

  • autophagy
  • BMP9
  • bone formation
  • lineage-specific differentiation
  • mesenchymal stem cells
  • osteogenic signaling

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