Glycolytic reprogramming mediated by the ADAM12/IGF1 axis promotes ossification of the posterior longitudinal...

Ossification of the posterior longitudinal ligament (OPLL) is a debilitating spinal disorder characterized by heterotopic bone formation and severe neurological deficits, yet its underlying pathogenic mechanisms remain poorly understood. Here, we report that glycolytic reprogramming orchestrated by the ADAM12/IGF1 axis is a critical driver of OPLL pathogenesis. Through integrated multi-omics analysis of human OPLL tissues, we uncovered a profound metabolic shift featuring enhanced glycolysis and suppressed oxidative phosphorylation as ligament progenitor cells differentiated into osteoblasts. This glycolytic reprogramming was functionally indispensable for ossification, as its inhibition with 2-deoxy-D-glucose robustly attenuated osteogenic differentiation in vitro and ectopic bone formation in vivo. We identified ADAM12 as a pivotal upstream regulator that is highly upregulated in OPLL. Mechanistically, ADAM12 activates the IGF1 signaling pathway by modulating IGFBP5, which in turn drives glycolytic flux and lactate production to fuel the osteogenic differentiation of ligament cells. Crucially, the pro-ossific effects of ADAM12 were reversed by inhibition of either IGF1R or glycolysis. Taken together, our study establishes the ADAM12-IGF1-glycolysis axis as a central pathogenic mechanism and a promising therapeutic target for OPLL.