Removal of aggregated proteinslarger macromolecular complexes to the lysosome for degradation

Some results suggest that matrix calcification could be initiated through passive calcium phosphate deposition and that it could be the formation of calcium phosphate nanocrystals that triggers the osteogenic changes that are associated with the accumulation of extracellular, crystalline structures, whereas other studies show that calcification could be initiated by the release of matrix vesicles and/or apoptotic bodies from VSMC that act as nucleation points for forming crystals. Some studies focused on characterising the anatomical, chemical and crystalline structure of the calcium phosphate deposits in patients or animal models with CKD, but the results remain heterogeneous. A study in uraemic patients revealed hydroxyapatite in non-visceral and arterial calcification, whereas visceral calcification was identified as an amorphous or microcrystalline compound composed of calcium, magnesium and phosphorus. Another study assessed mineral deposits in the aortic wall in calcitriol- and non-calcitriol-treated rodent models of uraemia-induced VC. Here, they were composed of amorphous calcium phosphate precipitate, apatite and also whitlockite in animals treated with calcitriol. In contrast, an other investigation reported a colocalization of hydroxyapatite and whitlockite in three out of six tissue samples taken from iliac arteries of uraemic patients, whereas another recent study on tissue specimens from non-CKD and CKD stage 2-4 patients undergoing carotid endarterectomy for severe atherosclerosis showed that in microcalcifications most of the calcium phosphate was amorphous rather than mature apatite. Moreover, it revealed that the relative contributions of whitlockite and calcium phosphate to microcalcification differed between patients with normal and mildly impaired renal function: Whereas in the samples of patients with normal renal function, whitlockite and calcium phosphate contribute to the mineral phase to an almost identical extent, approximately two-thirds of the mineral consists of calcium phosphate in the patients with impaired renal function. In the course of VC vascular smooth muscle cells that compose the medial layer of the vascular wall are playing a key role. Recently, the effect of magnesium on VSMC transformation and calcification was assessed in vitro as well in as in the aortas of rodents. Here, magnesium was able to inhibit the calcification process and attenuated osteogenic differentiation of cells as reflected through an increased expression of anti-calcification proteins such as matrix gla protein, osteopontin and bone morphogenetic protein 7. These findings were confirmed by Salem et al., who described correlations between magnesium, inhibition of VC in calcification-induced aortic rings of rats and clinical biomarkers. To date, three studies directly addressed the effect of magnesium on VC of VSMC in vitro. Here, magnesium significantly reduced induced calcification both in U0126 bovine as well as human primary VSMC, downregulated known pro-calcification and upregulated anti-calcification markers towards restoring more physiological expression levels seen in uncalcified controls. Moreover, an active, cellular, inhibitory role was attributed to magnesium as it was only able to exert its protective effect on living cells. These findings do not exclude a potential passive role for Mg2+ ions in the onset of calcification, because in the presence of Mg2+ cumulating evidence shows that magnesium can have an inhibitory effect on hydroxyapatite formation and precipitation. Earlier in vitro work shows that magnesium is able to stabilize amorphous calcium phosphate and inhibits the formation of hydroxyapatite as well as calcium pyrophosphate dehydrate and calcium-acidic phospholipid-phosphate complexes. In the literature, biological calcium phosphate crystals are often referred as hydroxyapatite leading this term to designate many complex compounds. Indeed, calcium phosphate hydroxyapatite is considered as a model compound for biological mineralization although its ideal formula has not actually been found in vivo. The composition of calcium phosphate apatite crystals has been shown to vary over a wide range due to the possibilities of anionic and cationic substitutions and the existence of different type of ion vacancies.