Osteoclast-derived DEL1 promotes pathological bone formation in ankylosing spondylitis by regulating RUNX2 expression in osteoblasts

Abstract

Background: Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by ectopic bone formation. We investigated in vitro and in vivo the role of developmental endothelial locus-1 (DEL1) on new bone formation and determined the association between DEL1 and spinal progression in AS. Methods: DEL1 levels were measured in plasma and facet joint tissues from patients with AS, and in osteoclast-derived medium. Human osteoblast precursor cells were treated with recombinant DEL1 protein and cilengitide trifluoroacetate, an alpha v beta 3 integrin inhibitor, to evaluate their effects on osteoblast differentiation markers. A curdlan-injected SKG mouse model was used to mimic AS pathogenesis. Three weeks after curdlan injection, recombinant DEL1 protein or cilengitide was administered, and the mice's ankle thickness was assessed. The mice were sacrificed after six weeks, and micro-CT and histological analyses were performed. Results: DEL1 expression significantly increased during osteoclast differentiation, peaked at the terminal stage, and correlated with disease progression in AS mice. Systemic plasma DEL1 levels were not different between patients with AS and the control group, but were positively correlated with structural damage (mSASSS; R = 0.3433, p = 0.0195). DEL1 pro-osteogenic effects were neutralized by cilengitide, which attenuated DEL1-induced RUNX2 expression and matrix mineralization. Conclusion: Our findings establish DEL1 as a key osteoclast-derived coupling factor that drives new bone formation in AS. DEL1 promotes pathological bone formation and osteoblast differentiation by signaling through the integrin alpha V beta 3-RUNX2 axis; targeting this pathway may offer a novel approach to prevent structural damage in patients with AS.