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.
A. T. Shaw,
E. M. Gravallese,
Eli Lilly and Company,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-17a-deficiency-promotes-periosteal-bone-formation-in-a-model-of-inflammatory-arthritis/