Human cartilaginous endplate degeneration is induced by calcium and the extracellular calcium-sensing receptor in the intervertebral disc

Abstract

The cartilaginous endplates (CEPs) are thin layers of hyaline cartilage found adjacent to intervertebral discs (IVDs). In addition to providing structural support, CEPs regulate nutrient and metabolic exchange in the disc. In IVD pathogenesis, CEP undergoes degeneration and calcification, compromising nutrient availability and disc cell metabolism. The mechanism(s) underlying the biochemical changes of CEP in disc degeneration are currently unknown. Since calcification is often observed in later stages of IVD degeneration, we hypothesised that elevations in free calcium (Ca 2+) impair CEP homeostasis. Indeed, our results demonstrated that the Ca 2+ content was consistently higher in human CEP tissue with grade of disc degeneration. Increasing the levels of Ca 2+ resulted in decreases in the secretion and accumulation of collagens type I, II and proteoglycan in cultured human CEP cells. Ca 2+ exerted its effects on CEP matrix protein synthesis through activation of the extracellular calcium-sensing receptor (CaSR); however, aggrecan content was also affected independent of CaSR activation as increases in Ca 2+ directly enhanced the activity of aggrecanases. Finally, supplementing Ca 2+ in our IVD organ cultures was sufficient to induce degeneration and increase the mineralisation of CEP, and decrease the diffusion of glucose into the disc. Thus, any attempt to induce anabolic repair of the disc without addressing Ca 2+ may be impaired, as the increased metabolic demand of IVD cells would be compromised by decreases in the permeability of the CEP.

Mechanotransduction and cell biomechanics of the intervertebral disc

“…Aging, or a lifetime of spinal motion and loading, is often associated with vertebral body changes that can include EP calcification, EP thinning, or evidence of bony microdamage. Factors that drive osteoblast and osteoclast remodeling in the vertebral body, and the formation of osteophytes where relevant, would be important to determine. The mechanism(s) underlying the biochemical changes of the cartilage EP in disc degeneration are currently unknown, though some recent studies are beginning to address these questions. Further investigations are needed to assess related mechanism and to unveil effect of cartilage EP changes on cell mechanobiology, mediated through the cytoskeleton and other pathways.…”

TRPC6 in simulated microgravity of intervertebral disc cells

“…The molecular mechanisms leading to IVD degeneration and ageing are not yet completely understood. However, high levels of free calcium in the cartilaginous endplates are associated with IVD degeneration [21]. Furthermore, free calcium seems to contribute to IVD degeneration through the calcium-sensing receptor (CaSR) [22].…”

Mesenchymal stem cell therapies for intervertebral disc degeneration: Consideration of the degenerate niche

“…This hydrogel system provides a potential approach for there generation of the degenerate disc, however the successful translation is dependent on understanding the cell behaviour within the degenerate niche. Thus, here, we investigated the viability and differentiation of hMSCs within the L‐pNIPAM‐co‐DMAc hydrogel (NPgel) within a hostile catabolic microenvironment associated with degeneration, a 4 week timepoint was selected as this has been shown previously to be sufficient to support MSC differentiation within NPgel toward NP like cells . These studies aimed to determine, whether combination therapies to inhibit the degenerate niche would be necessary to improve the likelihood of success for MSC applications.…”