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Oral citrate supplementation mitigates age-associated pathological 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. Here, we investigate the efficacy of long-term oral K₃Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age-associated disc calcification. K₃Citrate successfully reduced the incidence of disc calcification in LG/J mice without deleterious effects on vertebral bone structure, plasma chemistry, and locomotion. Notably, a positive effect on grip strength was evident in treated mice. Spectroscopic investigation of the persisting calcified nodules indicated K₃Citrate did not alter the mineral composition and revealed that reactivation of an endochondral differentiation program in endplates may drive LG/J disc calcification. Importantly, K₃Citrate reduced calcification incidence without altering the pathological endplate chondrocyte hypertrophy, suggesting mitigation of disc calcification primarily occurred through Ca²⁺ chelation, a conclusion supported by chondrogenic differentiation and Seahorse metabolic assays. Overall, this study underscores the therapeutic potential of K₃Citrate as a systemic intervention strategy for disc calcification.

SUBMITTER: Ottone OK

PROVIDER: S-EPMC11275755 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Oral citrate supplementation mitigates age-associated pathological intervertebral disc calcification in LG/J mice.

Ottone Olivia K OK Mundo Jorge J JJ Kwakye Boahen N BN Slaweski Amber A Collins John A JA Wu Qinglin Q Connelly Margery A MA Niaziorimi Fatemeh F van de Wetering Koen K Risbud Makarand V MV

bioRxiv : the preprint server for biology 20240719

Despite the high prevalence of age-dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. Here, we investigate the efficacy of long-term oral K<sub>3</sub>Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age-associated disc calcification. K<sub>3</sub>Citrate successfully reduced the incidence of disc calcification in LG/J mice without deleterious effects on vertebral bone structure ...[more]

PMID: 39071393

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Project description:Parathyroid hormone-related protein (PTHrP) and hedgehog signaling play an important role in chondrocyte development, (hypertrophic) differentiation, and/or calcification, but their role in intervertebral disc (IVD) degeneration is unknown. Better understanding their involvement may provide therapeutic clues for low back pain due to IVD degeneration. Therefore, this study aimed to explore the role of PTHrP and hedgehog proteins in postnatal canine and human IVDs during the aging/degenerative process. The expression of PTHrP, hedgehog proteins and related receptors was studied during the natural loss of the notochordal cell (NC) phenotype during IVD maturation using tissue samples and de-differentiation in vitro and degeneration by real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. Correlations between their expression and calcification levels (Alizarin Red S staining) were determined. In addition, the effect of PTHrP and hedgehog proteins on canine and human chondrocyte-like cells (CLCs) was determined in vitro focusing on the propensity to induce calcification. The expression of PTHrP, its receptor (PTHR1) and hedgehog receptors decreased during loss of the NC phenotype. N-terminal (active) hedgehog (Indian hedgehog/Sonic hedgehog) protein expression did not change during maturation or degeneration, whereas expression of PTHrP, PTHR1 and hedgehog receptors increased during IVD degeneration. Hedgehog and PTHR1 immunopositivity were increased in nucleus pulposus tissue with abundant vs no/low calcification. In vitro, hedgehog proteins facilitated calcification in CLCs, whereas PTHrP did not affect calcification levels. In conclusion, hedgehog and PTHrP expression is present in healthy and degenerated IVDs. Hedgehog proteins had the propensity to induce calcification in CLCs from degenerated IVDs, indicating that in the future, inhibiting hedgehog signaling could be an approach to inhibit calcification during IVD degeneration.

Dataset Information

Oral citrate supplementation mitigates age-associated pathological intervertebral disc calcification in LG/J mice.

Publications

Oral citrate supplementation mitigates age-associated pathological intervertebral disc calcification in LG/J mice.

Similar Datasets

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