Chaperonin 60 regulation of SOX9 ubiquitination mitigates the development of knee osteoarthritis.
Articular cartilage integrity loss is a prominently deleterious feature of osteoarthritis (OA). The mechanistic underlying the development of OA warrants characterization. Heat shock proteins (HSPs), members of the chaperone family, reportedly orchestrate tissue homeostasis and remodeling in response to detrimental stress. This study was undertaken to characterize the biological role of HSP60 in the pathogenesis of OA knee. Articular specimens from OA knee patients displayed severe articular damage histopathology concomitant with low HSP60 concentrations in cartilage and synovial fluid compared to non-OA patients. In vitro, a gain of HSP60 signaling counteracted the IL-1β-mediated suppression of mitochondrial biogenesis, chondrogenic transcription factor SOX9, and cartilage matrix expression of human chondrocytes cultures. Transgenic mice that overexpressed human HSP60 (TgHSP60) had higher chondrocyte proliferation and thicker articular cartilage than wild-type mice. In collagenase-induced OA knees, analyses of CatWalk, 2-deoxyglucose-probed fluorescence imaging, and μCT revealed that affected knees of TgHSP60 mice showed minor footprint irregularity, joint inflammation, and osteophyte formation. HSP60 overexpression also alleviated the histopathology of cartilage damage, synovial hypervascularization, and macrophage infiltration within joint lesions. Intra-articular administration of exogenous HSP60 ameliorated the pathogenesis of cartilage deterioration, synovitis, and osteophyte accumulation, thereby improving gait profiles of the collagenase-injured knees. HSP60 signaling maintains SOX9 levels by attenuating SOX9 hyper-ubiquitination of affected joints. Taken together, HSP60 deficiency in articular compartments was relevant to OA knee incidence. Sustained HSP60 signaling is favorable to mitigate the progression of OA. This study highlights the joint-anabolic actions of HSP60 and provides perspective on its therapeutic potential for OA.



HSP60 deficiency is relevant to the existence of end-stage knee osteoarthritis. HSP60 overexpression attenuates cartilage matrix loss of inflammatory chondrocytes. HSP60 transgenic mice showed mild articular injury during knee osteoarthritis. HSP60 maintains knee joint homeostasis through reducing SOX9 ubiquitination. Control of cartilage-anabolic regulator HSP60 ameliorates knee osteoarthritis.
Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
Jih-Yang
JY
Ko
Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.|Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao Sung District, Kaohsiung, 833, Taiwan.
Yi-Chih
YC
Sun
Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.|Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao Sung District, Kaohsiung, 833, Taiwan.
Wen-Chin
WC
Li
Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. wangfs@ms33.hinet.net.|Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan. wangfs@ms33.hinet.net.|Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao Sung District, Kaohsiung, 833, Taiwan. wangfs@ms33.hinet.net.
Feng-Sheng
FS
Wang
D000328:Adult; D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002358:Cartilage, Articular / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D018834:Chaperonin 60 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015552:Injections, Intralesional; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D007719:Knee Joint / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D001678:Organelle Biogenesis; D020370:Osteoarthritis, Knee / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D013582:Synovial Fluid; D014057:Tomography, X-Ray Computed; D054875:Ubiquitination
D018834:Chaperonin 60; C060293:HSPD1 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; D024101:Mitochondrial Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human
HSP60; Osteoarthritis; SOX9; Ubiquitination