A Lox/CHOP-10 crosstalk governs osteogenic and adipogenic cell fate by MSCs

J Cell Mol Med. 2018 Oct;22(10):5097-5108. doi: 10.1111/jcmm.13798. Epub 2018 Jul 25.

Abstract

Accelerated marrow adipogenesis has been associated with ageing and osteoporosis and is thought to be because of an imbalance between adipogenic and osteogenic differentiation of mesenchymal stem cell (MSCs). We have previously found that lysyl oxidase (Lox) inhibition disrupts BMP4-induced adipocytic lineage commitment and differentiation of MSCs. In this study, we found that lox inhibition dramatically up-regulates BMP4-induced expression of CCAAT/enhancer binding protein (C/EBP) homologous protein 10 (CHOP-10), which then promotes BMP4-induced osteogenesis of MSCs both in vitro and in vivo. Specifically, Lox inhibition or CHOP-10 up-regulation activated Wnt/β-catenin signalling to enhance BMP4-induced osteogenesis, with pro-adipogenic p38 MAPK and Smad signalling suppressed. Together, we demonstrate that Lox/CHOP-10 crosstalk regulates BMP4-induced osteogenic and adipogenic fate determination of MSCs, presenting a promising therapeutic target for osteoporosis and other bone diseases.

Keywords: BAPN; BMP4; CHOP-10; Lox; obesity; osteoporosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipogenesis / genetics
  • Animals
  • Bone Morphogenetic Protein 4 / genetics*
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Gene Expression Regulation, Developmental / genetics
  • Humans
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Osteogenesis / genetics*
  • Osteoporosis / genetics
  • Osteoporosis / pathology
  • Osteoporosis / therapy
  • Protein-Lysine 6-Oxidase / genetics*
  • Transcription Factor CHOP / genetics*
  • Wnt Signaling Pathway / genetics
  • p38 Mitogen-Activated Protein Kinases / genetics

Substances

  • Bone Morphogenetic Protein 4
  • Ddit3 protein, mouse
  • Transcription Factor CHOP
  • Protein-Lysine 6-Oxidase
  • p38 Mitogen-Activated Protein Kinases