Lactate metabolic coupling between the endplates and nucleus pulposus via MCT1 is essential for intervertebral disc health

During skeletal growth, there is an increased secretion of lactate by glycolytic nucleus pulposus (NP) cells of the intervertebral disc. To investigate the role of this anion, we generated annulus fibrosus (AF) and endplate (EP) specificMct1^cKO(Slc16a1^Col2CreERT2) mice. Histological and spatial transcriptomic studies indicated significant disc degeneration inMct1^cKO, characterized by NP cell loss and delayed EP maturation. Metabolic assays showed that while AF and EP cells were glycolytic, EP chondrocytes readily metabolized lactate. In EP cells, lactate promoted protein, and H3K18 lactylation, implying epigenetic programming. These findings suggest that NP-derived lactate promotes EP cartilage transdifferentiation into the subchondral bone, and in its absence, continued glucose consumption by the persistent EP cartilage reduces glucose availability to the NP and AF likely contributing to tissue degeneration. This study provides the firstin vivoevidence that metabolic coupling between NP and EP cells is essential for disc growth and health.