Background/Purpose: RORγt is a nuclear hormone receptor expressed in Th₁₇ cells and distinct subsets of lymphoid cells, including innate lymphoid cells (ILC), and γδ T-cells. RORγt is required for Th₁₇ cell and innate lymphocyte differentiation and regulates the transcription of the effector cytokines genes including IL17A and IL22. Ankylosing spondylitis (AS) is characterized by a peripheral oligoarthritis and enthesitis.  A key feature of AS is the imbalance between bone resorption and formation leading to aberrant bone formation and ankylosis. The contribution of IL23/IL17 axis to the pathogenesis of AS is supported by several lines of evidence. The protective IL23R variant (R381Q) is associated with decreased expression of Th₁₇ genes. Elevated levels of serum IL23 and IL17 and increased numbers of circulating Th₁₇ cells have been reported in AS patients.  Finally, anti IL17A antibody (Secukinumab) therapy has been demonstrated to be efficacious in AS. Overexpression of IL23 using minicircle DNA technology is characterized by a rapid and pronounced skin and rheumatic phenotype characterized by synovitis, enthesitis, and aberrant bone formation in the B10RIII mouse (Sherlock et al.). Furthermore, significant expression of IL23 pathway associated genes including IL17A and IL22 was observed in the entheses tissue.  The potent and selective RORγt antagonist (Compound A), was utilized to test the hypothesis that antagonism of RORγt can inhibit the IL23 pathway in the context of synovial and entheseal inflammation and subsequent bone remodeling.

Methods: Adult B10RIII female mice were administered 1.5 mg/mL (3 mg dose) of IL23 minicircle DNA via hydrodynamic injection on day 1. Starting on day 2, mice received a 10 mg/kg dose of Compound A, p.o. bidfor 28 days. Mice were monitored daily for signs of arthritis. Arthritis severity was graded using a 0-4 score per paw for a maximum score of 16. Upon sacrifice (Day 28) serum was collected for cytokine analysis.  Enthesis tissue was collected for biomarker analysis and paws were collected for histologic assessment (Bolder Biopath, Boulder, CO).  Medullary trabecular and cortical bone were assessed for erosion.  Presence of osteoclasts was also incorporated in the bone erosion score.  The distribution and widths of periosteal bone proliferation were used to assess aberrant bone formation.

Results: Administration of 10 mg/kg Compound A, p.o. bid for 28 days resulted in significant inhibition (49 ± 7%) of arthritic score (AUC).  Entheses tissue biomarkers including IL-17A, IL-22, S100a8 and S100a9 were significantly inhibited (>80%) at the 10 mg/kg dose.  In addition, biomarkers of bone erosion including RANKL and MMP9 were inhibited 99 ± 1% and 94 ± 3% respectively at day 28.  Histological analysis demonstrated a significant inhibition of both synovitis and enthesitis.  Finally, bone erosion and aberrant bone formation were inhibited 95 ± 4% and 98 ± 2% respectively at day 28.    

Conclusion: These data support the hypothesis that antagonism of RORγt can attenuate IL23-dependent inflammation in entheseal tissue and attenuates both bone erosion and aberrant bone formation in the joint in vivo.  Correlations between entheseal tissue biomarker responses and bone endpoints are being established.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/rorc-antagonism-inhibits-il-23-dependent-aberrant-bone-formation-in-vivo/