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Interleukin‐17A Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis
Author(s) -
Tok Melissa N.,
Duivenvoorde Leonie M.,
Kramer Ina,
Ingold Peter,
Pfister Sabina,
Roth Lukas,
Blijdorp Iris C.,
Sande Marleen G. H.,
Taurog Joel D.,
Kolbinger Frank,
Baeten Dominique L.
Publication year - 2019
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40770
Subject(s) - medicine , inflammation , interleukin 17 , tumor necrosis factor alpha , ankylosing spondylitis , arthritis , interleukin 23 , immunology , pathology
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.