Macrophage-driven pathological ossification of the posterior longitudinal ligament: mechanistic insights and therapeutic opportunities.

Ossification of the posterior longitudinal ligament (OPLL) is a chronic degenerative spinal condition in which bone gradually forms within the ligament, compressing the spinal cord and causing progressive neurological decline. While genetic predisposition and metabolic disturbances are well-recognized contributors, growing evidence points to macrophages as central players in shaping the tissue environment that drives pathological bone formation. Macrophages are remarkably plastic cells whose phenotypes and functions are continuously molded by cues from their local tissue environment. While pro-inflammatory macrophages sustain chronic low-grade inflammation through cytokine release and matrix remodeling, anti-inflammatory macrophages paradoxically amplify disease progression by driving fibrotic remodeling, excessive matrix accumulation, and aberrant vascularization, collectively fostering a hypoxic, ossification-prone niche within the ligament. Supporting this notion, similar macrophage-mediated mechanisms have been described in heterotopic ossification, though OPLL represents a distinct pathological process. This review synthesizes current evidence on how macrophages shape the OPLL microenvironment, draws mechanistic connections between macrophage activity and disease progression, and explores whether targeting these cells could open new therapeutic avenues.