Oral Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023

Deletion of the chondrocyte glucocorticoid receptor attenuates cartilage degradation through suppression of early synovial activation in murine posttraumatic osteoarthritis (#43)

Eugenie Macfarlane 1 , Lauryn Cavanagh 1 , Colette Fong-Yee 1 , Jan Tuckermann 2 , Di Chen 3 , Christopher B Little 4 , Markus J Seibel 1 5 , Hong Zhou 1
  1. Bone Research Program, ANZAC Research Institute, The University of Sydney, Concord, NSW, Australia
  2. Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
  3. Research Center for Human Tissues and Organs Degeneration, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
  4. Raymond Purves Laboratories, Kolling Institute and Institute of Bone and Joint Research, University of Sydney, and Royal North Shore Hospital, St Leonards, NSW, Australia
  5. Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Concord, NSW, Australia

Objective: We have previously shown that disruption of endogenous glucocorticoid signaling in bone cells attenuates osteoarthritis 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 osteoarthritis progression.

Design: Knee osteoarthritis was induced by surgical destabilization of the medial meniscus (DMM) in male 22-week-old chondrocyte (Col2a1-CreERT2) glucocorticoid receptor knockout (chGRKO) mice and their wild-type (WT) littermates (n=7-9/group). Mice were harvested at 2, 4, 8 and 16 weeks after DMM-surgery to examine spatiotemporal histological and molecular joint changes.

Results: Cartilage damage was attenuated in chGRKO compared to WT mice at all timepoints following DMM (Fig.1A-B). At 2 weeks post-DMM, WT mice exhibited extensive synovial activation characterized by synovial thickening and increased IL-1β expression that subsided over time. Intriguingly in chGRKO mice, synovial thickening and IL-1β expression were significantly less pronounced at 2 weeks post-DMM compared to WT mice (Fig.1A,C-D). To determine how GRKO in chondrocytes reduced synoviocyte activation, we analysed expression of Hypoxia Inducible Factor (HIF)-2α, a protein known to regulate chondrocyte crosstalk with synoviocytes during osteoarthritis. Immunohistochemistry revealed that chondrocyte HIF-2α expression was significantly reduced in chGRKO compared to WT mice at 2 weeks post-DMM, suggesting a mechanism by which chondrocyte glucocorticoid signaling induces synoviocyte activation through HIF-2α (Fig.1E). Consequently, downstream catabolic signaling was reduced in chGRKO compared to WT mice, characterized by high YAP1 and decreased MMP-13 expression, at 2 and 4 weeks post-DMM. Notably, chondrocyte senescence was also reduced in chGRKO compared to WT mice (Fig.1F-H).

Conclusion: Glucocorticoid signaling in chondrocytes promotes synovial activation, chondrocyte senescence and cartilage degradation by upregulation of catabolic signaling through HIF-2α in murine posttraumatic osteoarthritis. These findings indicate that inhibition of glucocorticoid signaling early after injury may present a promising way to slow osteoarthritic cartilage degeneration.649a2484061fa-ANZBMS+Abstract+Fig+1.jpg