Deletion of the chondrocyte glucocorticoid receptor attenuates cartilage degradation through suppression of early synovial activation in murine posttraumatic osteoarthritis.

Autor: Macfarlane E; Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia. Electronic address: eugenie.macfarlane@anzac.edu.au., Cavanagh L; Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia. Electronic address: lauryn.cavanagh@sydney.edu.au., Fong-Yee C; Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia. Electronic address: colette.fong-yee@sydney.edu.au., Tuckermann J; Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Baden-Württemberg, Germany. Electronic address: jan.tuckermann@uni-ulm.de., Chen D; Research Center for Human Tissues and Organs Degeneration, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China. Electronic address: di.chen@siat.ac.cn., Little CB; Raymond Purves Laboratories, Kolling Institute and Institute of Bone and Joint Research, University of Sydney, and Royal North Shore Hospital, St. Leonards, NSW, Australia. Electronic address: christopher.little@sydney.edu.au., Seibel MJ; Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia; Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Sydney, NSW, Australia. Electronic address: markus.seibel@sydney.edu.au., Zhou H; Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia. Electronic address: h.zhou@sydney.edu.au.
Jazyk: angličtina
Zdroj: Osteoarthritis and cartilage [Osteoarthritis Cartilage] 2023 Sep; Vol. 31 (9), pp. 1189-1201. Date of Electronic Publication: 2023 Apr 25.
DOI: 10.1016/j.joca.2023.04.009
Abstrakt: Objective: Disruption of endogenous glucocorticoid signalling in bone cells attenuates osteoarthritis (OA) in aged mice, however, the role of endogenous glucocorticoids in chondrocytes is unknown. Here, we investigated whether deletion of the glucocorticoid receptor, specifically in chondrocytes, also alters OA progression.
Design: Knee OA was induced by surgical destabilisation of the medial meniscus (DMM) in male 22-week-old tamoxifen-inducible glucocorticoid receptor knockout (chGRKO) mice and their wild-type (WT) littermates (n = 7-9/group). Mice were harvested 2, 4, 8 and 16 weeks after surgery to examine the spatiotemporal changes in molecular, cellular, and histological characteristics.
Results: At all time points following DMM, cartilage damage was significantly attenuated in chGRKO compared to WT mice. Two weeks after DMM, WT mice exhibited increased chondrocyte and synoviocyte hypoxia inducible factor (HIF)-2α expression resulting in extensive synovial activation characterised by synovial thickening and increased interleukin-1 beta expression. At 2 and 4 weeks after DMM, WT mice displayed pronounced chondrocyte senescence and elevated catabolic signalling (reduced Yes-associated protein 1 (YAP1) and increased matrix metalloprotease [MMP]-13 expression). Contrastingly, at 2 weeks after DMM, HIF-2α expression and synovial activation were much less pronounced in chGRKO than in WT mice. Furthermore, chondrocyte YAP1 and MMP-13 expression, as well as chondrocyte senescence were similar in chGRKO-DMM mice and sham-operated controls.
Conclusion: Endogenous glucocorticoid signalling in chondrocytes promotes synovial activation, chondrocyte senescence and cartilage degradation by upregulation of catabolic signalling through HIF-2α in murine posttraumatic OA. These findings indicate that inhibition of glucocorticoid signalling early after injury may present a promising way to slow osteoarthritic cartilage degeneration.
(Copyright © 2023. Published by Elsevier Ltd.)
Databáze: MEDLINE
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