Pref-1 regulates mesenchymal cell commitment and differentiation through Sox9

Cell Metab. 2009 Mar;9(3):287-302. doi: 10.1016/j.cmet.2009.01.013.


Pref-1 is an EGF repeat-containing transmembrane protein that produces a biologically active soluble form by TACE-mediated cleavage. Although Pref-1 inhibition of adipogenesis has been well established, the specific target(s) of Pref-1 or the Pref-1 function in mesenchymal cell commitment/differentiation are not known. Here, we show that Sox9 downregulation is required for adipocyte differentiation and that Pref-1 inhibits adipocyte differentiation through upregulating Sox9 expression. Sox9 directly binds to the promoter regions of C/EBPbeta and C/EBPdelta to suppress their promoter activity, preventing adipocyte differentiation. Furthermore, we also show that, by inducing Sox9, Pref-1 promotes chondrogenic induction of mesenchymal cells but prevents chondrocyte maturation as well as osteoblast differentiation, with supporting in vivo evidence in Pref-1 null and Pref-1 transgenic mice. Thus, Sox9 is a Pref-1 target, and Pref-1 directs multipotent mesenchymal cells to the chondrogenic lineage but inhibits differentiation into adipocytes as well as osteoblasts and chondrocytes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / physiology
  • Animals
  • Bone Marrow Cells / physiology
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Calcium-Binding Proteins
  • Cell Differentiation / physiology*
  • Cell Line
  • Cell Lineage
  • Chondrocytes / cytology
  • Chondrocytes / physiology
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Lentivirus / genetics
  • Lentivirus / metabolism
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / physiology*
  • Mice
  • Mice, Knockout
  • Osteoblasts / cytology
  • Osteoblasts / physiology
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Promoter Regions, Genetic
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism*
  • Stromal Cells / physiology


  • CCAAT-Enhancer-Binding Proteins
  • Calcium-Binding Proteins
  • Dlk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • PPAR gamma
  • RNA, Small Interfering
  • SOX9 Transcription Factor
  • Sox9 protein, mouse