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

Abstract

AbstractBackground: 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.Methods: 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 mouse model induced by intraperitoneal injection with 3 mg curdlan. Following curdlan injection, SKG mice were orally administered a DPP4 inhibitor three times per week for 5 weeks, and ankles of mice were scored for thickness and given clinical arthritis scores. At the end of 5 weeks, mice were sacrificed, and micro-CT and histological analyses were performed. Furthermore, osteoclast precursor cells (OPCs) from curdlan-injected SKG mice were treated with DPP4 inhibitor, and the effects of this treatment on osteoclastogenesis and differentiation markers were evaluated.Results: 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. Histological analysis revealed that 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 control group. Micro-CT data showed a significant reduction in inflammation-induced low bone density and ectopic bone formation in the DPP4 inhibitor group compared to those in the control group. Intriguingly, DPP4 co-expressed in TRAP-positive osteoclasts was detected in ectopic bone in the tibia of curdlan-injected SKG mice as well as spinal bone tissue of AS patients. Moreover, treatment with a DPP4 inhibitor significantly reduced osteoclastogenesis in the bone marrow of curdlan-injected SKG mice in addition to decreasing expression of osteoclast differentiation markers.Conclusion: Our findings suggest that inhibiting DPP4 may have a therapeutic effect on excessive bone formation in AS patients.