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

Melissa N van Tok; Leonie M van Duivenvoorde; Ina Kramer; Peter Ingold; Sabina Pfister; Lukas Roth; Iris C Blijdorp; Marleen G H van de Sande; Joel D Taurog; Frank Kolbinger; Dominique L Baeten

doi:https://doi.org/10.1002/art.40770

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

Melissa N van Tok, Leonie M van Duivenvoorde, Ina Kramer, Peter Ingold, Sabina Pfister, Lukas Roth, Iris C Blijdorp, Marleen G H van de Sande, Joel D Taurog, Frank Kolbinger, Dominique L Baeten

Research output: Contribution to journal › Article › Academic › peer-review

80 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	612-625
Number of pages	14
Journal	Arthritis & rheumatology (Hoboken, N.J.)
Volume	71
Issue number	4
DOIs	https://doi.org/10.1002/art.40770
Publication status	Published - Apr 2019

Keywords

Animals
Cell Culture Techniques
Cell Differentiation/drug effects
Disease Models, Animal
HLA-B27 Antigen/metabolism
Humans
Inflammation
Interleukin-17/physiology
Osteoblasts/metabolism
Osteogenesis/drug effects
Rats
Rats, Transgenic
Spondylarthritis/drug therapy
Synoviocytes/drug effects
Tumor Necrosis Factor-alpha/pharmacology
X-Ray Microtomography

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https://doi.org/10.1002/art.40770

Cite this

van Tok, M. N., van Duivenvoorde, L. M., Kramer, I., Ingold, P., Pfister, S., Roth, L., Blijdorp, I. C., van de Sande, M. G. H., Taurog, J. D., Kolbinger, F., & Baeten, D. L. (2019). Interleukin-17A Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis. Arthritis & rheumatology (Hoboken, N.J.), 71(4), 612-625. https://doi.org/10.1002/art.40770

@article{6847f86c42c74b35ba9097956bc4b14c,

title = "Interleukin-17A Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis",

abstract = "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.",

keywords = "Animals, Cell Culture Techniques, Cell Differentiation/drug effects, Disease Models, Animal, HLA-B27 Antigen/metabolism, Humans, Inflammation, Interleukin-17/physiology, Osteoblasts/metabolism, Osteogenesis/drug effects, Rats, Rats, Transgenic, Spondylarthritis/drug therapy, Synoviocytes/drug effects, Tumor Necrosis Factor-alpha/pharmacology, X-Ray Microtomography",

author = "{van Tok}, {Melissa N} and {van Duivenvoorde}, {Leonie M} and Ina Kramer and Peter Ingold and Sabina Pfister and Lukas Roth and Blijdorp, {Iris C} and {van de Sande}, {Marleen G H} and Taurog, {Joel D} and Frank Kolbinger and Baeten, {Dominique L}",

note = "{\textcopyright} 2019, American College of Rheumatology.",

year = "2019",

month = apr,

doi = "https://doi.org/10.1002/art.40770",

language = "English",

volume = "71",

pages = "612--625",

journal = "Arthritis & rheumatology (Hoboken, N.J.)",

issn = "2326-5191",

publisher = "John Wiley and Sons Ltd",

number = "4",

}

van Tok, MN, van Duivenvoorde, LM, Kramer, I, Ingold, P, Pfister, S, Roth, L, Blijdorp, IC, van de Sande, MGH, Taurog, JD, Kolbinger, F & Baeten, DL 2019, 'Interleukin-17A Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis', Arthritis & rheumatology (Hoboken, N.J.), vol. 71, no. 4, pp. 612-625. https://doi.org/10.1002/art.40770

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 - 2019/4

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 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.

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 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.

KW - Animals

KW - Cell Culture Techniques

KW - Cell Differentiation/drug effects

KW - Disease Models, Animal

KW - HLA-B27 Antigen/metabolism

KW - Humans

KW - Inflammation

KW - Interleukin-17/physiology

KW - Osteoblasts/metabolism

KW - Osteogenesis/drug effects

KW - Rats

KW - Rats, Transgenic

KW - Spondylarthritis/drug therapy

KW - Synoviocytes/drug effects

KW - Tumor Necrosis Factor-alpha/pharmacology

KW - X-Ray Microtomography

U2 - https://doi.org/10.1002/art.40770

DO - https://doi.org/10.1002/art.40770

M3 - Article

C2 - 30390386

SN - 2326-5191

VL - 71

SP - 612

EP - 625

JO - Arthritis & rheumatology (Hoboken, N.J.)

JF - Arthritis & rheumatology (Hoboken, N.J.)

IS - 4

ER -