title: 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 (Ca2+) impair CEP homeostasis. Indeed, our results demonstrated that the Ca2+ content was consistently higher in human CEP tissue with grade of disc degeneration. Increasing the levels of Ca2+ resulted in decreases in the secretion and accumulation of collagens type I, II and proteoglycan in cultured human CEP cells. Ca2+ 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 Ca2+ directly enhanced the activity of aggrecanases. Finally, supplementing Ca2+ 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 Ca2+ may be impaired, as the increased metabolic demand of IVD cells would be compromised by decreases in the permeability of the CEP.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis - Jewish General Hospital, 3755 Chemin Cote Ste Catherine, Montréal, H3T1E2, Canada.fmwale@jgh.mcgill.ca.
authors.forename: M P
authors.initials: MP
authors.lastname: Grant
authors.forename: L M
authors.initials: LM
authors.lastname: Epure
authors.forename: R
authors.initials: R
authors.lastname: Bokhari
authors.forename: P
authors.initials: P
authors.lastname: Roughley
authors.forename: J
authors.initials: J
authors.lastname: Antoniou
authors.forename: F
authors.initials: F
authors.lastname: Mwale
mesh_terms: D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D002114:Calcinosis / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002356:Cartilage / Q000378:metabolism* / Q000473:pathology*; D002417:Cattle; D019902:Chondrocytes / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004058:Diffusion; D005109:Extracellular Matrix / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007403:Intervertebral Disc / Q000378:metabolism* / Q000473:pathology*; D055959:Intervertebral Disc Degeneration / Q000378:metabolism / Q000473:pathology*; D009924:Organ Culture Techniques; D011509:Proteoglycans / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*
chemical_list: D053674:Aggrecans; D011509:Proteoglycans; D034741:RNA, Small Interfering; D044169:Receptors, Calcium-Sensing; D003094:Collagen; D005947:Glucose; D002118:Calcium