Aging aggravates intervertebral disc degeneration by regulating transcription factors toward chondrogenesis

FASEB J. 2020 Feb;34(2):1970-1982. doi: 10.1096/fj.201902109R. Epub 2019 Dec 24.


Osterix is a critical transcription factor of mesenchymal stem cell fate, where its loss or loss of Wnt signaling diverts differentiation to a chondrocytic lineage. Intervertebral disc (IVD) degeneration activates the differentiation of prehypertrophic chondrocyte-like cells and inactivates Wnt signaling, but its interactive role with osterix is unclear. First, compared to young-adult (5 mo), mechanical compression of old (18 mo) IVD induced greater IVD degeneration. Aging (5 vs 12 mo) and/or compression reduced the transcription of osterix and notochordal marker T by 40-75%. Compression elevated the transcription of hypertrophic chondrocyte marker MMP13 and pre-osterix transcription factor RUNX2, but less so in 12 mo IVD. Next, using an Ai9/td reporter and immunohistochemical staining, annulus fibrosus and nucleus pulposus cells of young-adult IVD expressed osterix, but aging and compression reduced its expression. Lastly, in vivo LRP5-deficiency in osterix-expressing cells inactivated Wnt signaling in the nucleus pulposus by 95%, degenerated the IVD to levels similar to aging and compression, reduced the biomechanical properties by 45-70%, and reduced the transcription of osterix, notochordal markers and chondrocytic markers by 60-80%. Overall, these data indicate that age-related inactivation of Wnt signaling in osterix-expressing cells may limit regeneration by depleting the progenitors and attenuating the expansion of chondrocyte-like cells.

Keywords: Wnt/β-catenin/LRPs; biomechanics; genetic animal models; osterix.

Publication types

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

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Aging / pathology
  • Animals
  • Antigens, Differentiation / biosynthesis
  • Antigens, Differentiation / genetics
  • Chondrocytes / metabolism*
  • Chondrocytes / pathology
  • Chondrogenesis*
  • Core Binding Factor Alpha 1 Subunit / biosynthesis*
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Fetal Proteins / biosynthesis*
  • Fetal Proteins / genetics
  • Gene Expression Regulation
  • Intervertebral Disc Degeneration / genetics
  • Intervertebral Disc Degeneration / metabolism*
  • Intervertebral Disc Degeneration / pathology
  • Mice
  • Mice, Transgenic
  • Sp7 Transcription Factor / biosynthesis*
  • Sp7 Transcription Factor / genetics
  • T-Box Domain Proteins / biosynthesis*
  • T-Box Domain Proteins / genetics


  • Antigens, Differentiation
  • Core Binding Factor Alpha 1 Subunit
  • Fetal Proteins
  • Runx2 protein, mouse
  • Sp7 Transcription Factor
  • Sp7 protein, mouse
  • T-Box Domain Proteins
  • Brachyury protein