Aging aggravates intervertebral disc degeneration by regulating transcription factors toward chondrogenesis. Issue 2 (24th December 2019)

• Record Type: Journal Article
• Authors: Silva, Matthew J.; Holguin, Nilsson
• Is Part Of: FASEB journal. Volume 34:Issue 2(2020)
• Page Start: 1970
• Page End: 1982
• Publication Date: 2019-12-24
• Subjects: biomechanics -- genetic animal models -- osterix -- Wnt/β‐catenin/LRPs; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201902109R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: 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.