STAT3 promotes a youthful epigenetic state in articular chondrocytes
Abstract
Epigenetic mechanisms guiding articular cartilage regeneration and age‐related disease such as osteoarthritis (OA) are poorly understood. STAT3 is a critical age‐patterned transcription factor highly active in fetal and OA chondrocytes, but the context‐specific role of STAT3 in regulating the epigenome of cartilage cells remain elusive. In this study, DNA methylation profiling was performed across human chondrocyte ontogeny to build an epigenetic clock and establish an association between CpG methylation and human chondrocyte age. Exposure of adult chondrocytes to a small molecule STAT3 agonist decreased DNA methylation, while genetic ablation of STAT3 in fetal chondrocytes induced global hypermethylation. CUT&RUN assay and subsequent transcriptional validation revealed DNA methyltransferase 3 beta (DNMT3B) as one of the putative STAT3 targets in chondrocyte development and OA. Functional assessment of human OA chondrocytes showed the acquisition of progenitor‐like immature phenotype by a significant subset of cells. Finally, conditional deletion of Stat3 in cartilage cells increased DNMT3B expression in articular chondrocytes in the knee joint in vivo and resulted in a more prominent OA progression in a post‐traumatic OA (PTOA) mouse model induced by destabilization of the medial meniscus (DMM). Taken together these data reveal a novel role for STAT3 in regulating DNA methylation in cartilage development and disease. Our findings also suggest that elevated levels of active STAT3 in OA chondrocytes may indicate an intrinsic attempt of the tissue to regenerate by promoting a progenitor‐like phenotype. However, it is likely that chronic activation of this pathway, induced by IL‐6 cytokines, is detrimental and leads to tissue degeneration.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 13, 2023
- Source ID
- 10.1111/acel.13773
Entities
People
- Arijita Sarkar
- Denis Evseenko
- Fangzhou Bian
- Hanhan Tang
- Jade Tassey
- Jason Ernst
- Jenny Magallanes
- Jinxiu Lu
- Karen Lyons
- Litao Tao
- Nancy Q. Liu
- Neil Segil
- Ruzanna Shkhyan
- Siyoung Lee
- Steve Horvath
- Youngjoo Lee
- Yuxin Ouyang
Organizations
- California Institute for Regenerative Medicine
- Creighton University
- Foundation for the National Institutes of Health
- United States Department of Defense
- University of California
- University of California, Los Angeles
- University of Southern California