Interleukin-17A Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis

Autor: Lukas Roth, Dominique Baeten, Peter Ingold, Sabina Pfister, Leonie M. van Duivenvoorde, Melissa N van Tok, Ina Kramer, Marleen G H van de Sande, Frank Kolbinger, Joel D. Taurog, Iris C Blijdorp
Přispěvatelé: AII - Inflammatory diseases, Clinical Immunology and Rheumatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Rok vydání: 2018
Předmět:
0301 basic medicine
Cell Culture Techniques
Arthritis
Transgenic
0302 clinical medicine
Osteogenesis
Immunology and Allergy
Medicine
Osteoblasts/metabolism
HLA-B27 Antigen
Spondylarthritis/drug therapy
Interleukin-17
Cell Differentiation
Synoviocytes
Osteogenesis/drug effects
Tumor Necrosis Factor-alpha/pharmacology
Tumor necrosis factor alpha
Interleukin 17
medicine.symptom
Rats
Transgenic
Synoviocytes/drug effects
medicine.drug
musculoskeletal diseases
Immunology
Inflammation
Article
03 medical and health sciences
Rheumatology
In vivo
Spondylarthritis
Animals
Humans
Dexamethasone
030203 arthritis & rheumatology
Interleukin-17/physiology
Osteoblasts
business.industry
Beta-2 microglobulin
Animal
Tumor Necrosis Factor-alpha
X-Ray Microtomography
Ascorbic acid
medicine.disease
HLA-B27 Antigen/metabolism
Rats
Disease Models
Animal
030104 developmental biology
Cell Differentiation/drug effects
Disease Models
Cancer research
business
Zdroj: Arthritis & rheumatology (Hoboken, N.J.), 71(4), 612-625. John Wiley and Sons Ltd
ISSN: 2326-5205
2326-5191
Popis: 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 β2 -microglobulin (hβ2 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/hβ2 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.
Databáze: OpenAIRE
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