Matrix vesicles: structure, composition, formation and function in calcification

Abstract

Matrix vesicles (MVs) induce calcification during endochondral bone formation. Experimental methods for structural, compositional, and functional analysis of MVs are reviewed. MV proteins, enzymes, receptors, transporters, regulators, lipids and electrolytes are detailed. MV formation is considered from both structural and biochemical perspectives. Confocal imaging of Ca(2+) and H(+) were used to depict how living chondrocytes form MVs. Biochemical studies revealed that coordinated mitochondrial Ca(2+) and Pi metabolism produce MVs containing a nucleational complex (NC) of amorphous calcium phosphate, phosphatidylserine and annexin A5--all critical to the mechanism of mineral nucleation. Reconstitution of the NC and modeling with unilamellar vesicles reveal how the NC transforms into octacalcium phosphate, regulated by Mg(2+), Zn(2+) and annexin A5. Extravasation of intravesicular mineral is mediated by phospholipases and tissue-nonspecific alkaline phosphatase (TNAP). In the extravesicular matrix, hydroxyapatite crystal propagation is enhanced by cartilage collagens and TNAP, which destroys inhibitory PPi, and by metalloproteases that degrade proteoglycans. Other proteins also modulate mineral formation. Recent findings from single and multiple gene knockouts of TNAP, NPP1, ANK, PHOSPHO1, and Annexin A5 are reviewed.

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…In addition to the intracellular role of phospholipids, membrane-derived extracellular vesicles (for example, apoptotic bodies, microparticles, exosomes, matrix vesicles), healthy and dying/dead cells, as well as enveloped pathogens can also display a distinct pattern of phospholipids extracellularly to regulate processes including skeletal development, immunity and coagulation. [1][2][3] Interestingly, pathogens have also evolved to express a variety of molecules that can either interact with or modify their host's phospholipids intracellularly and extracellularly to aid the infection process. Similarly, host organisms are also armed innately with numerous phospholipid-recognition proteins that can interact with pathogens and protect the host from microbial assault.…”

Biophysical aspects of biomineralization

“…Curiously, VSMCderived MVs appear to be devoid of AnxA5, in contrast to cartilage MVs. These studies suggest that AnxA6, and possibly AnxA2, may be important for MV binding to type I collagen in smooth muscle calcification (Wuthier and Lipscomb 2011) and that AnxA5 may be important for MV binding to type II collagen in cartilage calcification .…”

“…Experimental evidence shows that these trimers may be involved in the formation of the nucleational core (NC) within MVs and that they contribute to the ability of MVs to induce mineral formation. More than any other protein so far studied, AnxA5 greatly accelerates the nucleational activity of the acidic phospholipid-Ca 2+ -P i complexes present in the NC that triggers de novo calcium phosphate mineral formation in MVs (Genge et al 2007;Wuthier and Lipscomb 2011).…”

“…Various experiments have revealed the presence of HA crystals both inside and outside collagen fibrils in the ECM (McNally et al 2012) and also within the lumen of matrix vesicles (MVs) (Ali et al 1970;Anderson 1969;Bonucci 1970). MVs are extracellular vesicles with a diameter ranging from approximately 100 to 300 nm (Anderson 2003;Anderson et al 2010;Cui et al 2016;Golub 2009;Wuthier and Lipscomb 2011) which harbor the biochemical machinery needed to establish the appropriate inorganic pyrophosphate (PP i ) to inorganic phosphate (P i ) ratio (Ciancaglini et al 2006Harmey et al 2004;Hessle et al 2002;Johnson et al 2000;Roberts et al 2007;Yadav et al 2011;Zhou et al 2012) required to initiate the synthesis of apatitic mineral (Bechkoff et al 2008;Thouverey et al 2009;Wu et al 1997), which will subsequently be propagated onto the collagenous ECM. These vesicles are released from the hypertrophic chondrocytes and mature osteoblasts, the cells responsible for endochondral and membranous ossification.…”

“…Phosphate transporter 1 (PiT-1) helps to incorporate the P i generated in the perivesicular space into the MVs. MVs isolated from growth plate cartilage have a higher content of cholesterol (Chol), SM and phosphatidylserine (PS) (Thouverey et al 2009(Thouverey et al , 2011Wuthier and Lipscomb 2011) than do the plasma membranes, as well as longer fatty acids (Abdallah et al 2014). It is significant that MVs are enriched in SM as SM, via the enzymatic action of SMPD3, is converted to the PC to be used by PHOSPHO1 to produce P i intravesicularly.…”