Abstract
BackgroundIL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS). Blocking IL-17A is expected to inhibit bony ankylosis. Here, we investigated the effects of anti IL-17A agents in AS.MethodsTNFα, IL-17A, and IL-12/23 p40 levels in serum and synovial fluid from patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), osteoarthritis (OA), or healthy controls (HC) were measured by ELISA. Bone tissue samples were obtained at surgery from the facet joints of ten patients with AS and ten control (Ct) patients with noninflammatory spinal disease. The functional relevance of IL-17A, biological blockades, Janus kinase 2 (JAK2), and non-receptor tyrosine kinase was assessed in vitro with primary bone-derived cells (BdCs) and serum from patients with AS.ResultsBasal levels of IL-17A and IL-12/23 p40 in body fluids were elevated in patients with AS. JAK2 was also highly expressed in bone tissue and primary BdCs from patients with AS. Furthermore, addition of exogenous IL-17A to primary Ct-BdCs promoted the osteogenic stimulus-induced increase in ALP activity and mineralization. Intriguingly, blocking IL-17A with serum from patients with AS attenuated ALP activity and mineralization in both Ct and AS-BdCs by inhibiting JAK2 phosphorylation and downregulating osteoblast-involved genes. Moreover, JAK2 inhibitors effectively reduced JAK2-driven ALP activity and JAK2-mediated events.ConclusionsOur findings indicate that IL-17A regulates osteoblast activity and differentiation via JAK2/STAT3 signaling. They shed light on AS pathogenesis and suggest new rational therapies for clinical AS ankylosis.
Highlights
IL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS)
Blocking IL-17A postpones osteogenic differentiation of AS-bone-derived cells (BdCs) We found that the levels of IL-17A and IL-12/23 p40 were higher in AS sera; the level of Tumor necrosis factor alpha (TNF-α) tended to be higher, not significantly so
Inhibition of Janus kinase 2 (JAK2) suppresses the increase in Alkaline phosphatase (ALP) activity mediated by AS serum To conclusively demonstrate that JAK2 is the main cytokine responsible for ALP activity, we evaluated the effects of tyrophostin tyrosine kinase inhibitor (AG490), a selective JAK2 inhibitor, in concert with six serum samples from patients with active AS in an ALP promoter assay
Summary
IL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS). A key feature of ankylosing spondylitis (AS) is chronic inflammation of the spine, leading to bony ankylosis. Effective and safe therapeutic approaches to AS remain a substantial clinical challenge, as the suitability of TNF blockade for preventing new bone formation is yet controversial [2,3,4,5,6,7,8] The mechanisms by which blocking IL-17 in inflammation contributes to the regulation of new bone formation are not understood
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