IL-17 Blockade Attenuates Osteoblastic Activity and Differentiation in Ankylosing Spondylitis

Abstract

Background/Purpose:

Ankylosing spondylitis (AS) is a chronic inflammatory bone disease mediated by proinflammatory cytokine secreted by specialized T cells population. The mechanism by which the development of and function of Th17 cells and emerging IL-23/IL-17 axis may be involved in the pathogenesis of AS. However, the effect of IL-17 and IL-23 in osteoblast remain to be elucidated.

Methods:

AS patients satisfying the modified New York criteria were recruited for the study. Healthy donor, rheumatoid arthritis patients and osteoarthritis patients were included as controls. TNFa, IL-17, and IL-23 level were quantized by ELISA in the serum and synovial fluid. Bone tissues were obtained at surgery from facet joints of 10 patient with AS and 26 patients with noninflammatory spinal disease from traffic trauma or spinal compression disease, who served as controls. Immunohistochemistry and RNA level of bone tissue and isolated primary osteoprogenitor cells were performed to identify dominant JAK2 expression. IL-17 cytokine or patient serum with AS stimulated primary osteoprogenitor cells was analyzed by intercellular alkaline phosphatase (ALP) activity, mineralization, real-time PCR, and immunoblotting.

Results:

IL-17 and IL-23 basal level were significantly elevated in serum and synovial fluid of AS patients compared to those of the controls. Expression of JAK2 was enriched in bone tissues and isolated primary osteoprogenitor cells of AS patient. An addition of IL-17 cytokine in osteogenic differentiation exhibited an increase in ALP activity and calcium deposit in cellular level and sustained phos-JAK2 and phos-STAT3, and C/EBPβ in molecular level. Furthermore, adding IL-17A blockade in presence of patient serum with AS upon differentiation exhibited reduced intercellular ALP activity, mineralization, and phos-JAK2 expression in both control and AS osteoprogenitor cells. Intriguing, AG490, a JAK2 specific inhibitor, suppressed ALP activity despite the presence of patient serum with AS.

Conclusion:

This study supports a role of IL-17A in the pathogenesis of AS and attempts to provide a link between proinflammatory cytokine and osteoblast activity in an unexplored cellular system. Blocking of IL-17 could attenuate bony ankyloses in AS.