Aging aggravates intervertebral disc degeneration by regulating transcription factors toward chondrogenesis.
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.
['Silva|Matthew J|MJ|', 'Holguin|Nilsson|N|']
D000375:Aging D000818:Animals D000943:Antigens, Differentiation D019902:Chondrocytes D020219:Chondrogenesis D050659:Core Binding Factor Alpha 1 Subunit D005326:Fetal Proteins D005786:Gene Expression Regulation D055959:Intervertebral Disc Degeneration D051379:Mice D008822:Mice, Transgenic D000076182:Sp7 Transcription Factor D020825:T-Box Domain Proteins
osterix biomechanics Wnt/β-catenin/LRPs genetic animal models