Govindaraj Kannan, Kannan Sakshi, Coutinho de Almeida Rodrigo, Jansen Klomp Lucas, Karperien Marcel, Meulenbelt Ingrid, Post Janine N
Department of Developmental Bioengineering, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede, The Netherlands.
Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
J Cell Physiol. 2024 Dec;239(12):e31443. doi: 10.1002/jcp.31443. Epub 2024 Sep 29.
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.
转录因子SOX9对于组织内稳态至关重要，并且与骨骼畸形、弯肢侏儒症和骨关节炎（OA）有关。尽管进行了广泛研究，但与信号通路（转化生长因子β、WNT、骨形态发生蛋白、印度刺猬因子、核因子κB和低氧诱导因子）相互关联的SOX9转录活性的完整调控格局，仍难以破译。本研究聚焦于利用光漂白后荧光恢复（FRAP）来评估OA病理学中的SOX9信号传导，以直接在原代人软骨细胞（hPC）中评估SOX9活性。单细胞FRAP数据揭示了具有不同SOX9动态变化的两个不同亚群，显示出健康和OA的hPC之间分布各异。此外，与保存的hPC和OA的hPC相比，在健康的hPC中观察到固有升高的SOX9 - DNA结合。发现合成代谢因子（骨形态发生蛋白7和GREM1）和分解代谢抑制剂（DKK1和FRZb）可调节OA - hPC中的SOX9转录活性。这些发现为OA中SOX9信号传导的复杂调控提供了有价值的见解，提示了在疾病状态下调节SOX9活性的潜在治疗途径。
