Dissecting SOX9 dynamics reveals its differential regulation in osteoarthritis

Kannan Govindaraj*, Sakshi Kannan, Rodrigo Coutinho de Almeida, Lucas Jansen Klomp, Marcel Karperien, Ingrid Meulenbelt, Janine N. Post*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The transcription factor SOX9 is integral to tissue homeostasis and is implicated in skeletal malformation, campomelic dysplasia, and osteoarthritis (OA). Despite extensive research, the complete regulatory landscape of SOX9 transcriptional activity, interconnected with signaling pathways (TGFβ, WNT, BMP, IHH, NFκB, and HIF), remains challenging to decipher. This study focuses on elucidating SOX9 signaling in OA pathology using Fluorescence Recovery After Photobleaching (FRAP) to assess SOX9 activity directly in live human primary chondrocytes (hPCs). Single cell FRAP data revealed two distinct subpopulations with differential SOX9 dynamics, showing varied distribution between healthy and OA hPCs. Moreover, inherently elevated SOX9-DNA binding was observed in healthy hPCs compared to preserved and OA counterparts. Anabolic factors (BMP7 and GREM1) and catabolic inhibitors (DKK1 and FRZb) were found to modulate SOX9 transcriptional activity in OA-hPCs. These findings provide valuable insights into the intricate regulation of SOX9 signaling in OA, suggesting potential therapeutic avenues for modulating SOX9 activity in diseased states.

Original languageEnglish
Article numbere31443
JournalJournal of cellular physiology
DOIs
Publication statusE-pub ahead of print/First online - 29 Sept 2024

Keywords

  • UT-Hybrid-D
  • Cellular heterogeneity
  • DNA localization
  • FRAP
  • Protein dynamics
  • Transcription factor dynamics
  • cartilage

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