Oral Citrate Supplementation Mitigates Age‐Associated Pathologic Intervertebral Disc Calcification in LG/J Mice

ABSTRACT Despite the high prevalence of age‐dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. We investigated the efficacy of long‐term oral K 3 Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age‐associated disc calcification. K 3 Citrate reduced the incidence of disc calcification without affecting the vertebral bone structure, knee calcification, plasma chemistry, or locomotion in LG/J mice. Notably, a positive effect on grip strength was evident in treated mice. FTIR spectroscopy of the persisting calcified nodules indicated K 3 Citrate did not alter the mineral composition. Mechanistically, activation of an endochondral differentiation in the cartilaginous endplates and nucleus pulposus (NP) compartment contributed to LG/J disc calcification. Importantly, K 3 Citrate reduced calcification incidence by Ca 2+ chelation throughout the disc while exhibiting a differential effect on NP and endplate cell differentiation. In the NP compartment, K 3 Citrate reduced the NP cell acquisition of a hypertrophic chondrocytic fate, but the pathologic endochondral program was unimpacted in the endplates. Overall, this study for the first time shows the therapeutic potential of oral K 3 Citrate as a systemic intervention strategy to ameliorate disc calcification.