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.
PY - 2019/1/1
Y1 - 2019/1/1
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
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
SN - 2326-5191
ER -