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Abstract Number: 1914

IL-17A Deficiency Promotes Periosteal Bone Formation in a Model of Inflammatory Arthritis

Anita T. Shaw1, Yukiko Maeda1, Catherine Manning1 and Ellen M. Gravallese1,2, 1Department of Medicine, Division of Rheumatology, University of Massachusetts Medical School, Worcester, MA, 2Department of Medicine, Division of Rheumatology, UMass Memorial Medical Center, Worcester, MA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Bone, osteoblasts and spondylarthropathy, WNT Signaling

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Session Information

Title: Spondyloarthropathies and Psoriatic Arthritis - Pathogenesis, Etiology: From Genes to Cytokines

Session Type: Abstract Submissions (ACR)

Background/Purpose: Enthesial and periosteal bone formation in spondyloarthropathies (SpAs) are important sequelae of disease that contribute to patient morbidity. Anti-TNF therapies do not significantly alter progression of this debilitating process; therefore, new agents that inhibit both inflammation and bone formation are being sought. IL-17A contributes to inflammation in many diseases, including SpAs, and is a potential therapeutic target. IL-17A promotes osteoclastogenesis through induction of RANKL in synovial fibroblasts and by inducing expression of the proinflammatory cytokines TNF, IL-1 and IL-6.  However, the effects of IL-17A on bone-forming osteoblasts (OB) have not been fully elucidated and data are conflicting as to whether it promotes or protects from bone formation. We investigated the impact of IL-17A on OB differentiation in vitro and determined its role on bone formation in an in vivo murine model of arthritis.

Methods:  The effect of IL-17A on the Wingless (Wnt) signaling pathway, a critical pathway for OB differentiation, was determined using calvarial OBs from TOPGAL mice containing a reporter construct for Wnt signaling. Cells were cultured in the presence of IL-17A throughout differentiation and Wnt activity was determined. Calvarial OBs were also treated with IL-17A at early, mid and late stages of differentiation and qPCR analysis of Wnt signaling antagonist expression was performed. Periosteal bone formation is a prominent feature in the K/BxN serum transfer arthritis (STA) model. To determine the effects of IL-17A on OB function in vivo, STA was induced in IL-17A null and wild type mice. Periosteal bone formation was quantitated and ankle joints were also analyzed for erosion severity.

Results:  Long-term culture of TOPGAL calvarial OBs with IL-17A suppressed Wnt signaling, as reflected by a reduction in Wnt reporter activity. In addition, preliminary staining with von Kossa demonstrated inhibition of matrix mineralization in these cells cultured with IL-17A. Expression of the Wnt antagonists dickkopf (DKK)1, DKK2, DKK3, secreted frizzled related protein (sFRP)2 and sFRP4 mRNA expression in calvarial OBs was reduced to one-fifth of baseline levels by treatment with IL-17A at an early stage of differentiation (day 7). However, inhibition was reversed by day 21 of differentiation. IL-17A null and wild type mice displayed similar clinical and histologic inflammation scores, as well as similar articular bone erosion scores. Importantly however, IL-17A null mice formed significantly more periosteal bone than wild type mice (p < 0.05).  

Conclusion:  IL-17A may promote OB differentiation in early stages by suppressing expression of antagonists of Wnt signaling. However, the net effect of long-term treatment of OBs with IL-17A is inhibition of differentiation. These in vitro findings are borne out in vivo, as mice lacking IL-17A develop a significantly greater amount of periosteal bone than wild type mice.  However, deficiency of IL-17A did not affect inflammation or the degree of bone erosion in this model. These findings have potential clinical significance, as blocking IL-17A in patients with SpAs may further exacerbate the extent of periosteal bone formation.


Disclosure:

A. T. Shaw,
None;

Y. Maeda,
None;

C. Manning,
None;

E. M. Gravallese,

AbbVie,

2,

Eli Lilly and Company,

2.

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