Targeting osteoclast-derived DPP4 alleviates inflammation-mediated ectopic bone formation in ankylosing spondylitis

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by ectopic bone formation. The anti-inflammatory function of dipeptidyl peptidase-4 (DPP4) inhibitor has been reported in bone metabolism, but its utility in AS has not previously been investigated. We assessed DPP4 level in serum, synovial fluid, and facet joint tissue of AS patients. Additionally, we investigated the effect of a DPP4 inhibitor in an experimental AS model using curdlan-injected SKG mice. Following curdlan injection, SKG mice were orally administered a DPP4 inhibitor three times per week for 5 weeks and observed clinical arthritis scores, and analyzed by micro-CT. Furthermore, osteoclast precursor cells (OPCs) from curdlan-injected SKG mice were treated with DPP4 inhibitor and evaluated the inhibitory effects of this treatment in vitro. Soluble DPP4 level was elevated in the serum and synovial fluid of patients with AS compared to those in the control group. Expression of DPP4 increased gradually during human osteoclastogenesis and was high in mature osteoclasts. Oral administration of a DPP4 inhibitor resulted in a decrease in thickness of the hind paw, clinical arthritis scores, and enthesitis at the ankle in curdlan-injected SKG mice compared to the vehicle group. Micro-CT data revealed a significant reduction in inflammation-induced low bone density in the DPP4 inhibitor group. Moreover, treatment with a DPP4 inhibitor significantly reduced osteoclast differentiation of OPC in addition to decreasing expression of osteoclast differentiation markers. Our findings suggest that inhibiting DPP4 may have a therapeutic effect on inflammation-mediated ectopic bone formation in AS patients.