Objective: It remains unclear if and how inflammation and new bone formation in spondyloarthritis (SpA) are coupled. We undertook this study to assess the hypothesis that interleukin-17A (IL-17A) is a pivotal driver of both processes. Methods: The effect of tumor necrosis factor (TNF) and IL-17A on osteogenesis was tested in an osteoblastic differentiation assay using SpA fibroblast-like synoviocytes (FLS) differentiated with dexamethasone, β-glycophosphatase, and ascorbic acid. IL-17A blockade was performed in HLA–B27/human β 2 -microglobulin (hβ 2 m)–transgenic rats, which served as a model for SpA in both prophylactic and therapeutic settings. Inflammation and new bone formation were evaluated by micro–computed tomography imaging, histologic analysis, and gene expression profiling. Results: TNF and IL-17A significantly increased in vitro osteoblastic differentiation. In vivo, prophylactic blockade of IL-17A significantly delayed spondylitis and arthritis development and decreased arthritis severity. Anti–IL-17A treatment was also associated with prevention of bone loss and periosteal new bone formation. Therapeutic targeting of IL-17A after the initial inflammatory insult also significantly reduced axial and peripheral joint inflammation. This treatment was again associated with a marked reduction in spinal and peripheral structural damage, including new bone formation. RNA sequencing of target tissue confirmed that IL-17A is a key driver of the molecular signature of disease in this model and that therapeutic anti–IL-17A treatment reversed the inflammatory signature and the selected gene expression related to bone damage. Conclusion: Both prophylactic and therapeutic inhibition of IL-17A diminished inflammation and new bone formation in HLA-B27/hβ 2 m–transgenic rats. Taken together with the ability of IL-17A to promote osteoblastic differentiation of human SpA FLS, these data suggest a direct link between IL-17A–driven inflammation and pathologic new bone formation in SpA.
ASJC Scopus subject areas
- Immunology and Allergy