Lipid Availability Determines Fate of Skeletal Progenitor Cells via SOX9

Nature. 2020 Mar;579(7797):111-117. doi: 10.1038/s41586-020-2050-1. Epub 2020 Feb 26.

Abstract

The avascular nature of cartilage makes it a unique tissue1-4, but whether and how the absence of nutrient supply regulates chondrogenesis remain unknown. Here we show that obstruction of vascular invasion during bone healing favours chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate forkhead box O (FOXO) transcription factors, which bind to the Sox9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. Our results define lipid scarcity as an important determinant of chondrogenic commitment, reveal a role for FOXO transcription factors during lipid starvation, and identify SOX9 as a critical metabolic mediator. These data highlight the importance of the nutritional microenvironment in the specification of skeletal cell fate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone and Bones / blood supply
  • Bone and Bones / cytology*
  • Cellular Microenvironment*
  • Chondrocytes / cytology
  • Chondrocytes / metabolism
  • Chondrogenesis*
  • Fatty Acids / metabolism
  • Female
  • Food Deprivation
  • Forkhead Transcription Factors / metabolism
  • Lipid Metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Osteogenesis
  • Oxidation-Reduction
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism*
  • Signal Transduction
  • Stem Cells / cytology*
  • Stem Cells / metabolism*
  • Wound Healing

Substances

  • Fatty Acids
  • Forkhead Transcription Factors
  • SOX9 Transcription Factor
  • Sox9 protein, mouse