Targeting macrophage-mediated TGF-β/BMP signaling in ankylosing spondylitis: from inflammation to pathological bone formation.

Ankylosing spondylitis (AS) is a chronic, immune-mediated disease characterized by inflammatory arthritis and pathological new bone formation, ultimately leading to spinal fusion and functional impairment. Despite effective suppression of inflammation by biologic agents targeting cytokines such as TNF-α and IL-17A, radiographic progression often continues, highlighting a critical dissociation between inflammatory activity and structural damage. The literature suggests that macrophage polarization and the TGF-β/BMP signaling axis collectively constitute a critical nexus linking inflammation to aberrant osteogenesis in AS. Moreover, it details how the unique entheseal microenvironment-shaped by biomechanical stress, hypoxia, and a distinct cytokine milieu-drives macrophages toward a spectrum of pro-osteogenic phenotypes through a mechano-inflammatory feedback loop. After that, polarized macrophages, in turn, serve as pivotal cellular engineers that locally activate and sustain TGF-β/BMP signals through proteolytic cleavage and acidic remodeling of the ECM. This self-amplifying loop directly orchestrates endochondral ossification at ligamentous insertion sites, culminating in syndesmophyte formation and spinal ankylosis. Therapeutically, this mechanistic understanding highlights promising avenues for disease modification beyond conventional anti-inflammatory strategies. Targeting macrophage polarization states or disrupting the TGF-β/BMP activation cascade may offer dual benefits-suppressing both inflammation and structural progression-and pave the way for genuine disease-modifying therapies in AS.