Background/Purpose: Spondyloarthritis (SpA) results in significant pain and loss of function due to inflammation and resulting enthesial/periosteal bone formation. Inhibition of the Janus kinase (JAK)/STAT pathway is being evaluated clinically as a therapeutic approach in SpA. We studied JAK inhibition in two preclinical models of SpA: the SKG mouse model, in which the IL-23 pathway has been implicated as playing a key role, and rat collagen-induced arthritis (rCIA), an inflammation driven model of bone erosion and aberrant bone formation. In this model, aberrant bone formation increases significantly over time ⁽¹⁾ and in both models, enthesial/periosteal bone formation is a prominent feature. 

Methods: 9-10 week-old SKG mice were injected IP with curdlan at day 0 to synchronize onset of disease. JAKi was delivered beginning at day 0 twice daily by oral gavage for 30 days. rCIA was induced by IP injection of bovine type II collagen in incomplete Freund’s adjuvant at days 0 and 6. Treatment with JAKi was initiated at peak inflammation (d17) and continued for 25 days. Clinical and histological scores were used to quantitate inflammation and periosteal/entheseal bone formation was quantitated by histology and microCT. In the SKG model, gene expression at enthesial sites was determined using laser capture microscopy from 2 sites: a reproducible site of periosteal bone formation on the tibia, and inflammatory sites around tail vertebrae at which bone formation did not occur. Whole transcriptome analysis was performed using Affymetrix gene array MTA 1.0.

Results: JAKi suppressed inflammation in both models. Clinical and histologic inflammation scores were significantly decreased by JAKi in SKG mice (p<0.05). Paw volume (p<0.001) and pannus scores (p<0.05) were significantly decreased by JAKi in rCIA. In addition, periosteal/entheseal bone formation at peripheral sites was significantly inhibited in both models by greater than 50% (Figure). In SKG mice, global gene expression analysis of inflamed tissue from entheses identified distinct gene expression patterns at sites of bone formation and sites of inflammation without bone formation. Differentially regulated genes included cartilage and bone markers, such as biglycan and collagen type I alpha 1. IPA upstream regulator analysis identified significant enrichment of major skeletal pathway regulators at sites of periosteal bone formation, including TGF-beta, Wnt3A and AhR, the aryl hydrocarbon receptor, implicated in osteoclastogenesis.

Conclusion: Treatment with JAKi suppressed both inflammation and periosteal/entheseal bone formation in two animal models of SpA, accompanied by directed changes in gene expression and activated pathways. These results demonstrate the therapeutic potential of a JAKi in the treatment of SpA, with the possibility of controlling periosteal/enthesial bone formation in these diseases.

1.     Schett G, Arthritis Rheum, 2009;60(9):2644-54.