TY - JOUR
T1 - Dissecting SOX9 dynamics reveals its differential regulation in osteoarthritis
AU - Govindaraj, Kannan
AU - Kannan, Sakshi
AU - Coutinho de Almeida, Rodrigo
AU - Jansen Klomp, Lucas
AU - Karperien, Marcel
AU - Meulenbelt, Ingrid
AU - Post, Janine N.
N1 - Publisher Copyright:
© 2024 The Author(s). Journal of Cellular Physiology published by Wiley Periodicals LLC.
PY - 2024/9/29
Y1 - 2024/9/29
N2 - 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.
AB - 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.
KW - UT-Hybrid-D
KW - Cellular heterogeneity
KW - DNA localization
KW - FRAP
KW - Protein dynamics
KW - Transcription factor dynamics
KW - cartilage
UR - http://www.scopus.com/inward/record.url?scp=85205305240&partnerID=8YFLogxK
U2 - 10.1002/jcp.31443
DO - 10.1002/jcp.31443
M3 - Article
AN - SCOPUS:85205305240
SN - 0021-9541
JO - Journal of cellular physiology
JF - Journal of cellular physiology
M1 - e31443
ER -