TY - JOUR
T1 - Interleukin-17A Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis
AU - van Tok, Melissa N.
AU - van Duivenvoorde, Leonie M.
AU - Kramer, Ina
AU - Ingold, Peter
AU - Pfister, Sabina
AU - Roth, Lukas
AU - Blijdorp, Iris C.
AU - van de Sande, Marleen G.H.
AU - Taurog, Joel D.
AU - Kolbinger, Frank
AU - Baeten, Dominique L.
N1 - Funding Information:
Mr. 阀ngold and Drs. Kramer, Pfister, and Roth own stock or stock options in Novartis Pharma. Dr. van de Sande has received consulting fees from AbbVie, Eli Lilly, Janssen, and Novartis (less than $10,000 each) and research grants from those companies. Dr. Taurog holds license agreements with AbbVie, AnGes, Celgene, and Novartis and has received research support from AbbVie. Dr. Baeten owns stock or stock options in UCB. No other disclosures relevant to this article were reported.
Funding Information:
Dr. Baeten’s work was supported by the Netherlands Scientific Organization (NWO Vici grant) and the European Research Council (ERC Consolidator grant).
Publisher Copyright:
© 2019, American College of Rheumatology
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/4
Y1 - 2019/4
N2 - 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.
AB - 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.
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U2 - 10.1002/art.40770
DO - 10.1002/art.40770
M3 - Article
C2 - 30390386
AN - SCOPUS:85061774988
VL - 71
SP - 612
EP - 625
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
SN - 2326-5191
IS - 4
ER -