Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Intensive articular cartilage deterioration and synovial fibrosis in joints are prominently pathogenic features of osteoarthritic (OA) knees. Epigenetic reactions in joint microenvironments are linked to the incidence of OA knees. Histone lysine demethylase KDM6A is an emerging epigenetic regulator cntributing to tissue development and remodeling. This study was undertaken to investigate the biological roles of KDM6A in joint integrity of OA knees and decipher the epigenetic actions of KDM6A on methylation statuses of master cartilage regulator SOX9 promoter and histone 3 lysine 27 (H3K27) and metabolism of cartilage and synovial matrices in OA knee joints.
Methods: Mice with collagenase-induced OA knees were weekly administered with KDM6A inhibitor GSK-J4 or vehicle for 12 weeks. Gait profiles, fluorescence probe 2-deoxyglucose uptake by inflammatory tissues, and subchondral bone microstructures were analyzed using Catwalk, near infrared fluorescence in vivo imaging and μCT. Quantitative RT-PCR, immunoblotting, methylation-specific PCR, and chromatin immunoprecipitation were performed to quantify mRNA, protein expression, methylation statuses and enrichments of SOX9 promoter and H3K27.
Results: Articular cartilage damage and synovial fibrosis were in conjunction with increased expression of KDM6A, KDM6B and decreased levels of SOX9 and methylated H3K27 in OA knee joints. Administration with KDM6A inhibitor GSK-J4 alleviated the deleterious effects of OA on gait characteristics (maximum contact intensity, area and print area of paws) and joint inflammation. It also improved subchondral bone microarchitecture (trabecular volume, thickness, number and cortical porosity) and bone mineral density of affected joints. Inhibition of KDM6A attenuated the adverse effects of OA on chondrogenic matrix expression, morphology and OARSI scores of articular cartilage, as well as mitigated nucleated cell infiltration, hypervascularization and fibrotic matrix accumulation in synovial compartments. Loss of KDM6A signaling restored methylation of CpG islands in SOX9 promoter and alleviated the OA-mediated inhibition of SOX9 mRNA transcription and protein levels. Treatment with KDM6A inhibitor also increased H3K27 methylation that reduced the enrichment of H3K27 to proximal promoter region of fibrogenic transcription factor AP-1 and profibrotic gene expression in injured joint tissues.
Conclusion: KDM6A induces SOX9 promoter and H3K27 hypomethylation that deregulates SOX9 and AP-1 actions on articular cartilage integrity and synovium homeostasis in the pathogenesis of OA knees. Inhibition of KDM6A ameliorates the OA-mediated epigenetic dysfucntion in cartilage and synovium, thereby protects aganist excessive joint remodeling. This study sheds emerging lights on epigenetic modulation of joint integrity in OA knees and highlights that pharmaceutical modulation of KDM6A actions has therapeutic potentials for preventing against OA-induced joint damage.
Disclosure:
F. S. Wang,
None;
P. C. Chuang,
None;
Y. C. Sun,
None;
Y. S. Chen,
None;
J. Y. Ko,
None.
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/histone-lysine-demethylase-kdm6a-mediates-joint-destruction-in-osteoarthritic-knees-by-epigenetic-disturbance-of-sox9-promoter-and-histone-h3k27/