Chondrocytes regulate joint inflammation through endogenous glucocorticoid signalling — ASN Events
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Chondrocytes regulate joint inflammation through endogenous glucocorticoid signalling (#122)

Jinwen Tu 1 2 3 , Shihani Stoner 1 , Phillip D Fromm 4 , Tingyu Wang 5 , Di Chen 6 , Jan Tuckermann 7 , Mark S Cooper 2 3 8 , Markus J Seibel 1 3 8 , Hong Zhou 1 3 8
  1. Bone Research Program, ANZAC Research Institute, Sydney, NSW, Australia
  2. Adrenal Steroid Laboratory, ANZAC Research Institute, Sydney, NSW, Australia
  3. Concord Medical School, The University of Sydney, Sydney, NSW, Australia
  4. Dendritic Cell Research, ANZAC Research Institute, Sydney, NSW, Australia
  5. Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
  6. Tissue Department of Biochemistry, Rush University Medical Center, Chicago, USA
  7. Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
  8. Department of Endocrinology & Metabolism, Concord Hospital, Sydney, Australia

Glucocorticoids (GCs) are widely used in the treatment of rheumatoid arthritis (RA), however, the function of endogenous GCs in the pathogenesis and maintenance of RA is less clear. The current study determined whether disruption of endogenous glucocorticoid signaling in chondrocytes modulates the course and severity of experimental immune arthritis.

Tamoxifen-inducible chondrocyte-targeted glucocorticoid receptor knockout (chGRKO) mice were generated by breeding GRflox/flox mice with tamoxifen-inducible Collagen 2a1 Cre mice (Col2a1-CreERT2). Antigen-induced arthritis (AIA) and K/BxN serum-transfer induced arthritis (STIA) was induced in chGRKO mice and their Cre-negative GRflox/flox littermates (WT) at 8 weeks of age. Arthritis was assessed by daily measurement of the inflamed joint swelling and histological analysis of the inflamed joints harvested at day 14. Neutrophil activity was evaluated in STIA model by flow cytometry analysis of the cells isolated from the spleen, bone marrow and synovial fluid of the mice, as well as the gene expression analysis of the RNA isolated from inflamed ankle joints at days 7 (D7) and 14 (D14). 

The inflammatory response was significantly greater in chGRKO mice compared to WT mice in both arthritis models, as assessed by knee joint width (AIA) and ankle size (STIA). Correspondingly, when compared to WT mice, histological analysis revealed significantly increased inflammatory activity in chGRKO mice. The STIA model was further characterised by local up-regulation of CXCR2/ CXCR2 ligand gene expression in ankle tissues, and a significant and selective expansion of splenic CXCR2+ neutrophils in chGRKO arthritic mice (compared to WT arthritic mice) at D7. While the above chemokine gene expression changes were less pronounced on D14, the expression of MMP-9, an enzyme involved in cartilage degradation, was significantly up-regulated in chGRKO mice. 

Endogenous glucocorticoid signalling in chondrocytes has an important regulatory role in immune-mediated arthritis, possibly through the regulation of neutrophil activity and cartilage degradation.