Abstract
In normal healthy individuals, mineral formation is restricted to specialized tissues which form the skeleton and the dentition. Within these tissues, mineral formation is tightly controlled both in growth and development and in normal adult life. The mechanism of calcification in skeletal and dental tissues has been under investigation for a considerable period. One feature common to almost all of these normal mineralization mechanisms is the elaboration of matrix vesicles, small (20–200 nm) membrane particles, which bud off from the plasma membrane of mineralizing cells and are released into the pre-mineralized organic matrix. The first crystals which form on this organic matrix are seen in and around matrix vesicles. Pathologic ectopic mineralization is seen in a number of human genetic and acquired diseases, including calcification of joint cartilage resulting in osteoarthritis and mineralization of the cardiovasculature resulting in exacerbation of atherosclerosis and blockage of blood vessels. Surprisingly, increasing evidence supports the contention that the mechanisms of soft tissue calcification are similar to those seen in normal skeletal development. In particular, matrix vesicle-like membranes are observed in a number of ectopic calcifications. The purpose of this review is to describe how matrix vesicles function in normal mineral formation and review the evidence for their participation in pathologic calcification.
Similar content being viewed by others
References
Anderson HC (1967) Electron microscopic studies of induced cartilage development and calcification. J Cell Biol 35:81–101
Bonucci E (1967) Fine structure of early cartilage calcification. J Ultrastruct Res 20:33–50
Landis WJ, Paine M, Glimcher MJ (1977) Electron microscopic observations of bone tissue prepared anhydrously in organic solvents. J Utrastruct Res 59:1–30
Majeska RJ, Wuthier RE (1975) Studies on matrix vesicles isolated from chick epiphyseal cartilage. Association of pyrophosphatase and ATPase activities with alkaline phosphatase. Biochim Biophys Acta 391:51–60
Ali SY (1976) Analysis of matrix vesicles and their role in the calcification of epiphyseal cartilage. Fed Proc 35:135–142
Howell DS, Pita JC, Alvarez J (1976) Possible role of extracellular matrix vesicles in initial calcification of healing rachitic cartilage. Fed Proc 35:122–126
Wuthier RE (1982) A review of the primary mechanism of endochondral calcification wilh special emphasis on the role of cells, mitochondria and matrix vesicles. Clin Orthop Relat Res 169:219–242
Anderson HC (1984) Mineralization by matrix vesicles. Scan Electron Microsc 2:953–964
Hayashi Y (1985) Ultrastructural characterization of extracellular matrix vesicles in the mineralizing fronts of apical cementum in cats. Arch Oral Biol 30:445–449
Landis WJ, Paine MC, Hodgens KJ, Glimcher MJ (1986) Matrix vesicles in embryonic chick bone: considerations of their identification, number, distribution, and possible effects on calcification of extracellular matrices. J Ultrastruct Mol Struct Res 95:142–163
Anderson HC, Stechschulte DJ Jr, Collins DE, Jacobs DH, Morris DC, Hsu HH, Redford PA, Zeiger S (1990) Matrix vesicle biogenesis in vitro by rachitic and normal rat chondrocytes. Am J Pathol 136:391–398
Iannotti JP, Naidu S, Noguchi Y, Hunt RM, Brighton CT (1994) Growth plate matrix vesicle biogenesis. The role of intracellular calcium. Clin Orthop Relat Res 306:222–229
Rabinovitch AL, Anderson HC (1976) Biogenesis of matrix vesicles in cartilage growth plates. Fed Proc 35:112–116
Ali SY (1992) Constitutive enzymes of matrix vesicles. Bone Miner 17:168–171
Balcerzak M, Malinowska A, Thouverey C, Sekrecka A, Dadlez M, Buchet R, Pikula S (2008) Proteome analysis of matrix vesicles isolated from femurs of chicken embryo. Proteomics 8:192–205
Dean DD, Schwartz Z, Muniz OE, Gomez R, Swain LD, Howell DS, Boyan BD (1992) Matrix vesicles are enriched in metalloproteinases that degrade proteoglycans. Calcif Tissue Int 50:342–349
Majeska RJ, Holwerda DL, Wuthier RE (1979) Localization of phosphatidylserine in isolated chick epiphyseal cartilage matrix vesicles with trinitrobenzenesulfonate. Calcif Tissue Int 27:41–46
Wuthier RE (1975) Lipid composition of isolated epiphyseal cartilage cells, membranes and matrix vesicles. Biochim Biophys Acta 409:128–143
Houston B, Stewart AJ, Farquharson C (2004) PHOSPHO1—a novel phosphatase specifically expressed at sites of mineralisation in bone and cartilage. Bone 34:629–637
Roberts SJ, Stewart AJ, Sadler PJ, Farquharson C (2004) Human PHOSPHO1 exhibits high specific phosphoethanolamine and phosphocholine phosphatase activities. Biochem J 382:59–65
Nielsen LB, Pedersen FS, Pedersen L (2001) Expression of type III sodium-dependent phosphate transporters/retroviral receptors mRNAs during osteoblast differentiation. Bone 28:160–166
Anderson HC, Harmey D, Camacho NP, Garimella R, Sipe JB, Tague S, Bi X, Johnson K, Terkeltaub R, Millan JL (2005) Sustained osteomalacia of long bones despite major improvement in other hypophosphatasia-related mineral deficits in tissue nonspecific alkaline phosphatase/nucleotide pyrophosphatase phosphodiesterase 1 double-deficient mice. Am J Pathol 166:1711–1720
Damek-Poprawa M, Golub E, Otis L, Harrison G, Phillips C, Boesze-Battaglia K (2006) Chondrocytes utilize a cholesterol-dependent lipid translocator to externalize phosphatidylserine. Biochemistry 45:3325–3336
Shapiro IM, Burke A, Schattschneider S, Golub EE (1981) Proceedings of the third international conference on matrix vesicles. Wichtig Editore, Milan
Termine JD (1972) Mineral chemistry and skeletal biology. Clin Orthop Relat Res 85:207–239
Trautz OR (1955) X-ray diffraction of biological and synthetic apatites. Ann NY Acad Sci 60:696–712
Simmer JP, Papagerakis P, Smith CE, Fisher DC, Rountrey AN, Zheng L, Hu JCC (2010) Regulation of dental enamel shape and hardness. J Dent Res 89:1024–1038
Bei M (2009) Molecular genetics of ameloblast cell lineage. J Exp Zool 312B:437–444
Sosnoski DM, Gay CV (2008) NCX3 is a major functional isoform of the sodium–calcium exchanger in osteoblasts. J Cell Biochem 103:1101–1110
Palmer G, Manen D, Bonjour JP, Caverzasio J (2001) Species-specific mechanisms control the activity of the Pit1/PIT1 phosphate transporter gene promoter in mouse and human. Gene 279:49–62
Boskey A, Maresca M, Appel J (1989) The effects of noncollagenous matrix proteins on hydroxyapatite formation and proliferation in a collagen gel system. Connect Tissue Res 21:171–176
Gordon JA, Tye CE, Sampaio AV, Underhill TM, Hunter GK, Goldberg HA (2007) Bone sialoprotein expression enhances osteoblast differentiation and matrix mineralization in vitro. Bone 41:462–473
Hao J, Zou B, Narayanan K, George A (2004) Differential expression patterns of the dentin matrix proteins during mineralized tissue formation. Bone 34:921–932
He G, George A (2004) Dentin matrix protein 1 immobilized on type I collagen fibrils facilitates apatite deposition in vitro. J Biol Chem 279:11649–11656
Ito S, Saito T, Amano K (2004) In vitro apatite induction by osteopontin: interfacial energy for hydroxyapatite nucleation on osteopontin. J Biomed Mater Res A 69:11–16
Mckee MD, Farach-Carson MC, Butler WT, Hauschka PV, Nanci A (1993) Ultrastructural immunolocalization of noncollagenous (osteopontin and osteocalcin) and plasma (albumin and alpha 2HS-glycoprotein) proteins in rat bone. J Bone Miner Res 8:485–496
Mckee MD, Zalzal S, Nanci A (1996) Extracellular matrix in tooth cementum and mantle dentin: localization of osteopontin and other noncollagenous proteins, plasma proteins, and glycoconjugates by electron microscopy. Anat Rec 245:293–312
Murshed M, Mckee MD (2010) Molecular determinants of extracellular matrix mineralization in bone and blood vessels. Curr Opin Nephrol Hypertens 19:359–365
Young MF, Kerr JM, Ibaraki K, Heegaard AM, Robey PG (1992) Structure, expression, and regulation of the major noncollagenous matrix proteins of bone. Clin Orthop Relat Res 281:275–294
Hessle L, Johnson KA, Anderson HC, Narisawa S, Sali A, Goding JW, Terkeltaub R, Millan JL (2002) Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci U S A 99:9445–9449
Bronner F, Stein WD (1995) Calcium homeostasis—an old problem revisited. J Nutr 125:1987S–1995S
Talmage DW, Talmage RV (2007) Calcium homeostasis: how bone solubility relates to all aspects of bone physiology. J Musculoskelet Neuronal Interact 7:108–112
Talmage RV, Talmage DW (2006) Calcium homeostasis: solving the solubility problem. J Musculoskelet Neuronal Interact 6:402–407
Gurley KA, Reimer RJ, Kingsley DM (2006) Biochemical and genetic analysis of ANK in arthritis and bone disease. Am J Hum Genet 79:1017–1029
Ho AM, Johnson MD, Kingsley DM (2000) Role of the mouse ank gene in control of tissue calcification and arthritis. Science 289:265–270
Kim HJ, Minashima T, McCarthy EF, Winkles JA, Kirsch T (2010) Progressive ankylosis protein (ANK) in osteoblasts and osteoclasts controls bone formation and bone remodeling. J Bone Miner Res 25:1771–1783
Terkeltaub RA (2001) Inorganic pyrophosphate generation and disposition in pathophysiology. Am J Physiol Cell Physiol 281:C1–C11
Harmey D, Hessle L, Narisawa S, Johnson KA, Terkeltaub R, Millan JL (2004) Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp 1, and ank: an integrated model of the pathogenesis of mineralization disorders. Am J Pathol 164:1199–1209
Alini M, Carey D, Hirata S, Grynpas MD, Pidoux I, Poole AR (1994) Cellular and matrix changes before and at the time of calcification in the growth plate studied in vitro: arrest of type X collagen synthesis and net loss of collagen when calcification is initiated. J Bone Miner Res 9:1077–1087
Aubin JE, Liu F, Malaval L, Gupta AK (1995) Osteoblast and chondroblast differentiation. Bone 17:77S–83S
Collin P, Nefussi JR, Wetterwald A, Nicolas V, Boy-Lefevre ML, Fleisch H, Forest N (1992) Expression of collagen, osteocalcin, and bone alkaline phosphatase in a mineralizing rat osteoblastic cell culture. Calcif Tissue Int 50:175–183
Golub EE, Boesze-Battaglia K (2007) The role of alkaline phosphatase in mineralization. Curr Opin Orthop 18:444–448
Weiss MJ, Cole DE, Ray K, Whyte MP, Lafferty MA, Mulivor R, Harris H (1989) First identification of a gene defect for hypophosphatasia: evidence that alkaline phosphatase acts in skeletal mineralization. Connect Tissue Res 21:99–104
Whyte MP (1994) Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. [Review]. Endocr Rev 15:439–461
Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, Waymire K, Narisawa S, Millan JL, Macgregor GR, Whyte MP (1999) Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. J Bone Miner Res 14:2015–2026
Johnson K, Pritzker K, Goding J, Terkeltaub R (2001) The nucleoside triphosphate pyrophosphohydrolase isozyme PC-1 directly promotes cartilage calcification through chondrocyte apoptosis and increased calcium precipitation by mineralizing vesicles. J Rheumatol 28:2681–2691
Katz EP, Wachtel E, Yamauchi M, Mechanic GL (1989) The structure of mineralized collagen fibrils. Connect Tissue Res 21:149–158
Landis WJ (1999) An overview of vertebrate mineralization with emphasis on collagen–mineral interaction. Gravit Space Biol Bull 12:15–26
Landis WJ (1995) Tomographic imaging of collagen–mineral interaction: implications for osteogenesis imperfecta. Connect Tissue Res 31:287–290
Fratzl P, Groschner M, Vogl G, Plenk H Jr, Eschberger J, Fratzl-Zelman N, Koller K, Klaushofer K (1992) Mineral crystals in calcified tissues: a comparative study by SAXS. J Bone Miner Res 7:329–334
Tesch W, Vandenbos T, Roschgr P, Fratzl-Zelman N, Klaushofer K, Beertsen W, Fratzl P (2003) Orientation of mineral crystallites and mineral density during skeletal development in mice deficient in tissue nonspecific alkaline phosphatase. J Bone Miner Res 18:117–125
Tong W, Glimcher MJ, Katz JL, Kuhn L, Eppell SJ (2003) Size and shape of mineralites in young bovine bone measured by atomic force microscopy. Calcif Tissue Int 72:592–598
Yamauchi M, Katz EP (1993) The post-translational chemistry and molecular packing of mineralizing tendon collagens. Connect Tissue Res 29:81–98
Glimcher MJ, Krane SM (1968) The organization and structure of bone and the mechanism of calcification. In: Ramachandran GN, Gould BS (eds) Treatise on collagen, vol 7B. Academic, New York, pp 68–251
Glimcher MJ (1987) The nature of the mineral component of bone and the mechanism of calcification. Instr Course Lect 36:49–69
Moradian-Oldak J, Frolow F, Addadi L, Weiner S (1992) Interactions between acidic matrix macromolecules and calcium phosphate ester crystals: relevance to carbonate apatite formation in biomineralization. Proc Biol Sci 247:47–55
Posner AS, Blumenthal NC, Boskey AL (1973) Calcified tissue. Facta Publications, Vienna
Raggio CL, Boyan BD, Boskey AL (1986) In vivo hydroxyapatite formation induced by lipids. J Bone Miner Res 1:409–415
Wuthier RE (1993) Involvement of cellular metabolism of calcium and phosphate in calcification of avian growth plate cartilage. J Nutr 123:301–309
Glimcher MJ (1981) The chemistry and biology of mineralized connective tissues. Elsevier, New York
Boskey AL (1992) Mineral–matrix interactions in bone and cartilage. Clin Orthop Relat Res 281:244–274
Boyan BD, Schwartz Z, Swain LD (1990) Matrix vesicles as a marker of endochondral ossification. Connect Tissue Res 24:67–75
Wuthier RE (1989) Mechanism of de novo mineral formation by matrix vesicles. Connect Tissue Res 22:27–33
Kirsch T, Nah HD, Demuth DR, Harrison G, Golub EE, Adams SL, Pacifici M (1997) Annexin V-mediated calcium flux across membranes is dependent on the lipid composition: implications for cartilage mineralization. Biochemistry 36:3359–3367
Anderson HC, Garimella R, Tague SE (2005) The role of matrix vesicles in growth plate development and biomineralization. Front Biosci 10:822–837
Wu LN, Yoshimori T, Genge BR, Sauer GR, Kirsch T, Ishikawa Y, Wuthier RE (1993) Characterization of the nucleational core complex responsible for mineral induction by growth plate cartilage matrix vesicles. J Biol Chem 268:25084–25094
Wu LN, Genge BR, Dunkelberger DG, LeGeros RZ, Concannon B, Wuthier RE (1997) Physicochemical characterization of the nucleational core of matrix vesicles. J Biol Chem 272:4404–4411
Wuthier RE, Wu LN, Sauer GR, Genge BR, Yoshimori T, Ishikawa Y (1992) Mechanism of matrix vesicle calcification: characterization of ion channels and the nucleational core of growth plate vesicles. Bone Miner 17:290–295
Wiesmann HP, Meyer U, Plate U, Hohling HJ (2005) Aspects of collagen mineralization in hard tissue formation. Int Rev Cytol 242:121–156
Tenenbaum HC (1987) Levamisole and inorganic pyrophosphate inhibit beta-glycerophosphate induced mineralization of bone formed in vitro. Bone Miner 3:13–26
Nancollas GH, Zawacki SJ (1989) Calcium phosphate mineralization. Connect Tissue Res 21:239–244
Neuman WF, Neuman MW, Diamond AG, Menanteau J, Gibbons WS (1982) Blood:bone disequilibrium. VI. Studies of the solubility characteristics of brushite: apatite mixtures and their stabilization by noncollagenous proteins of bone. Calcif Tissue Int 34:149–157
Boyan BD, Boskey AL (1984) Co-isolation of proteolipids and calcium–phospholipid–phosphate complexes. Calcif Tissue Int 36:214–218
He G, Dahl T, Veis A, George A (2003) Nucleation of apatite crystals in vitro by self-assembled dentin matrix protein 1. Nat Mater 2:552–558
McEwen BF, Song MJ, Landis WJ (1991) Quantitative determination of the mineral distribution in different collagen zones of calcifying tendon using high voltage electron microscopic tomography. J Comput Assist Microsc 3:201–210
Gajjeraman S, He G, Narayanan K, George A (2008) Biological assemblies provide novel templates for the synthesis of hierarchical structures and facilitate cell adhesion. Adv Funct Mater 18:3972–3980
He G, Ramachandran A, Dahl T, George S, Schultz D, Cookson D, Veis A, George A (2005) Phosphorylation of phosphophoryn is crucial for its function as a mediator of biomineralization. J Biol Chem 280:33109–33114
Boskey AL, Posner AS (1977) The role of synthetic and bone extracted calcium–phospholipid–phosphate complexes in hydroxyapatite formation. Calcif Tissue Res 23:251–258
Boskey AL, Dickson IR (1988) Influence of vitamin D status on the content of complexed acidic phospholipids in chick diaphyseal bone. Bone Miner 4:365–371
Boyan BD, Schwartz Z, Swain LD, Khare A (1989) Role of lipids in calcification of cartilage. Anat Rec 224:211–219
Genge BR, Wu LN, Wuthier RE (1989) Identification of phospholipid-dependent calcium-binding proteins as constituents of matrix vesicles. J Biol Chem 264:10917–10921
Wuthier RE (1976) Lipids of matrix vesicles. Fed Proc 35:117–121
Demer LL, Tintut Y (2008) Vascular calcification: pathobiology of a multifaceted disease. Circulation 117:2938–2948
Ali SY, Wisby A (1978) Apatite crystal nodules in arthritic cartilage. Eur J Rheumatol Inflamm 1:115–119
Kirsch T (2006) Determinants of pathological mineralization. Curr Opin Rheumatol 18:174–180
Tanimura A, McGregor DH, Anderson HC (1983) Matrix vesicles in atherosclerotic calcification. Proc Soc Exp Biol Med 172:173–177
Reynolds JL, Joannides AJ, Skepper JN, McNair R, Schurgers LJ, Proudfoot D, Jahnen-Dechent W, Weissberg PL, Shanahan CM (2004) Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 15:2857–2867
Fukuda T, Kohda M, Kanomata K, Nojima J, Nakamura A, Kamizono J, Noguchi Y, Iwakiri K, Kondo T, Kurose J, Endo K, Awakura T, Fukushi J, Nakashima Y, Chiyonobu T, Kawara A, Nishida Y, Wada I, Akita M, Komori T, Nakayama K, Nanba A, Maruki Y, Yoda T, Tomoda H, Yu PB, Shore EM, Kaplan FS, Miyazono K, Matsuoka M, Ikebuchi K, Ohtake A, Oda H, Jimi E, Owan I, Okazaki Y, Katagiri T (2009) Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva. J Biol Chem 284:7149–7156
Shore EM, Kaplan FS (2010) Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 6:518–527
Koos R, Krueger T, Westenfeld R, Kuhl HP, Brandenburg V, Mahnken AH, Stanzel S, Vermeer C, Cranenburg EC, Floege J, Kelm M, Schurgers LJ (2009) Relation of circulating matrix Gla-protein and anticoagulation status in patients with aortic valve calcification. Thromb Haemost 101:706–713
Krueger T, Westenfeld R, Schurgers L, Brandenburg V (2009) Coagulation meets calcification: the vitamin K system. Int J Artif Organs 32:67–74
Munroe PB, Olgunturk RO, Fryns JP, Van Maldergem L, Ziereisen F, Yuksel B, Gardiner RM, Chung E (1999) Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet 21:142–144
Sage AP, Tintut Y, Demer LL (2010) Regulatory mechanisms in vascular calcification. Nat Rev Cardiol 7:528–536
Einhorn TA, Gordon SL, Siegel SA, Hummel CF, Avitable MJ, Carty RP (1985) Matrix vesicle enzymes in human osteoarthritis. J Orthop Res 3:160–169
Kirsch T, Swoboda B, Nah H (2000) Activation of annexin II and V expression, terminal differentiation, mineralization and apoptosis in human osteoarthritic cartilage. Osteoarthritis Cartilage 8:294–302
Jubeck B, Gohr C, Fahey M, Muth E, Matthews M, Mattson E, Hirschmugl C, Rosenthal AK (2008) Promotion of articular cartilage matrix vesicle mineralization by type I collagen. Arthritis Rheum 58:2809–2817
Karpouzas GA, Terkeltaub RA (1999) New developments in the pathogenesis of articular cartilage calcification. Curr Rheumatol Rep 1:121–127
Blanco FJ, Guitian R, Vazquez-Martul E, de Toro FJ, Galdo F (1998) Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology. Arthritis Rheum 41:284–289
Gibson G (1998) Active role of chondrocyte apoptosis in endochondral ossification. Microsc Res Tech 43:191–204
Golub EE, Schattschneider SC, Berthold P, Burke A, Shapiro IM (1983) Induction of chondrocyte vesiculation in vitro. J Biol Chem 258:616–621
Kirsch T, Wang W, Pfander D (2003) Functional differences between growth plate apoptotic bodies and matrix vesicles. J Bone Miner Res 18:1872–1881
Schlieper G, Aretz A, Verberckmoes SC, Kruger T, Behets GJ, Ghadimi R, Weirich TE, Rohrmann D, Langer S, Tordoir JH, Amann K, Westenfeld R, Brandenburg VM, D'Haese PC, Mayer J, Ketteler M, Mckee MD, Floege J (2010) Ultrastructural analysis of vascular calcifications in uremia. J Am Soc Nephrol 21:689–696
Shao JS, Cai J, Towler DA (2006) Molecular mechanisms of vascular calcification: lessons learned from the aorta. Arterioscler Thromb Vasc Biol 26:1423–1430
Chen NX, OΓÇÖNeill KD, Chen X, Moe SM (2008) Annexin-mediated matrix vesicle calcification in vascular smooth muscle cells. J Bone Miner Res 23:1798–1805
Narisawa S, Harmey D, Yadav MC, O'Neill WC, Hoylaerts MF, Millan JL (2007) Novel inhibitors of alkaline phosphatase suppress vascular smooth muscle cell calcification. J Bone Miner Res 22:1700–1710
Acknowledgement
This work was supported by a grant from the National Institute for Dental and Craniofacial Research, NIH, DE017323.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Golub, E.E. Biomineralization and matrix vesicles in biology and pathology. Semin Immunopathol 33, 409–417 (2011). https://doi.org/10.1007/s00281-010-0230-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-010-0230-z