Genetic, epigenetic, and biomechanical updates on the pathogenesis of ossification of the posterior longitudinal ligament

Ossification of posterior longitudinal ligament (OPLL) is a complex multifactorial spinal disorder characterized by ectopic bone formation within the ligament, leading to progressive spinal canal stenosis and neurological deficits. While its epidemiological and clinical profiles are well-established, the precise molecular pathogenesis remains incompletely understood. This review systematically synthesizes recent advances in understanding the mechanistic underpinnings of OPLL, highlighting the interplay of genetic predisposition, epigenetic regulation, metabolic disorders, and biomechanical stress. Pathological manifestations, anatomical features, and the dual-origin hypothesis of OPLL are elaborated, alongside its phenotypic overlaps with ankylosing spondylitis and the contribution of inflammatory signaling cascades. Susceptibility loci identified via genome-wide association studies and their functional relevance to key regulatory pathways are summarized. Epigenetic regulation, encompassing pre and posttranscriptional modifications, is highlighted with particular attention to the roles of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs). Metabolic mechanisms implicated in OPLL, including diabetes, lipoprotein receptor-related protein 5 signaling, and lipid metabolism dysregulation, are discussed, as is the critical role of biomechanical stress in disease progression. By integrating insights across multiple disciplines, this review establishes a comprehensive pathophysiological framework for OPLL, with the goal of bridging basic science and clinical practice and identifying promising avenues for the development of targeted therapeutic strategies.