Seminars in Immunopathology

, Volume 33, Issue 5, pp 409–417 | Cite as

Biomineralization and matrix vesicles in biology and pathology

  • Ellis E. GolubEmail author


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.


Vascular Calcification Matrix Vesicle Chondrocyte Apoptosis Hypophosphatasia Soft Tissue Calcification 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by a grant from the National Institute for Dental and Craniofacial Research, NIH, DE017323.


  1. 1.
    Anderson HC (1967) Electron microscopic studies of induced cartilage development and calcification. J Cell Biol 35:81–101PubMedGoogle Scholar
  2. 2.
    Bonucci E (1967) Fine structure of early cartilage calcification. J Ultrastruct Res 20:33–50PubMedGoogle Scholar
  3. 3.
    Landis WJ, Paine M, Glimcher MJ (1977) Electron microscopic observations of bone tissue prepared anhydrously in organic solvents. J Utrastruct Res 59:1–30Google Scholar
  4. 4.
    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 391:51–60PubMedGoogle Scholar
  5. 5.
    Ali SY (1976) Analysis of matrix vesicles and their role in the calcification of epiphyseal cartilage. Fed Proc 35:135–142PubMedGoogle Scholar
  6. 6.
    Howell DS, Pita JC, Alvarez J (1976) Possible role of extracellular matrix vesicles in initial calcification of healing rachitic cartilage. Fed Proc 35:122–126PubMedGoogle Scholar
  7. 7.
    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 169:219–242PubMedGoogle Scholar
  8. 8.
    Anderson HC (1984) Mineralization by matrix vesicles. Scan Electron Microsc 2:953–964Google Scholar
  9. 9.
    Hayashi Y (1985) Ultrastructural characterization of extracellular matrix vesicles in the mineralizing fronts of apical cementum in cats. Arch Oral Biol 30:445–449PubMedGoogle Scholar
  10. 10.
    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 95:142–163PubMedGoogle Scholar
  11. 11.
    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 136:391–398PubMedGoogle Scholar
  12. 12.
    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 306:222–229PubMedGoogle Scholar
  13. 13.
    Rabinovitch AL, Anderson HC (1976) Biogenesis of matrix vesicles in cartilage growth plates. Fed Proc 35:112–116PubMedGoogle Scholar
  14. 14.
    Ali SY (1992) Constitutive enzymes of matrix vesicles. Bone Miner 17:168–171PubMedGoogle Scholar
  15. 15.
    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 8:192–205PubMedGoogle Scholar
  16. 16.
    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 50:342–349PubMedGoogle Scholar
  17. 17.
    Majeska RJ, Holwerda DL, Wuthier RE (1979) Localization of phosphatidylserine in isolated chick epiphyseal cartilage matrix vesicles with trinitrobenzenesulfonate. Calcif Tissue Int 27:41–46PubMedGoogle Scholar
  18. 18.
    Wuthier RE (1975) Lipid composition of isolated epiphyseal cartilage cells, membranes and matrix vesicles. Biochim Biophys Acta 409:128–143PubMedGoogle Scholar
  19. 19.
    Houston B, Stewart AJ, Farquharson C (2004) PHOSPHO1—a novel phosphatase specifically expressed at sites of mineralisation in bone and cartilage. Bone 34:629–637PubMedGoogle Scholar
  20. 20.
    Roberts SJ, Stewart AJ, Sadler PJ, Farquharson C (2004) Human PHOSPHO1 exhibits high specific phosphoethanolamine and phosphocholine phosphatase activities. Biochem J 382:59–65PubMedGoogle Scholar
  21. 21.
    Nielsen LB, Pedersen FS, Pedersen L (2001) Expression of type III sodium-dependent phosphate transporters/retroviral receptors mRNAs during osteoblast differentiation. Bone 28:160–166PubMedGoogle Scholar
  22. 22.
    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 166:1711–1720PubMedGoogle Scholar
  23. 23.
    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 45:3325–3336PubMedGoogle Scholar
  24. 24.
    Shapiro IM, Burke A, Schattschneider S, Golub EE (1981) Proceedings of the third international conference on matrix vesicles. Wichtig Editore, MilanGoogle Scholar
  25. 25.
    Termine JD (1972) Mineral chemistry and skeletal biology. Clin Orthop Relat Res 85:207–239PubMedGoogle Scholar
  26. 26.
    Trautz OR (1955) X-ray diffraction of biological and synthetic apatites. Ann NY Acad Sci 60:696–712PubMedGoogle Scholar
  27. 27.
    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 89:1024–1038PubMedGoogle Scholar
  28. 28.
    Bei M (2009) Molecular genetics of ameloblast cell lineage. J Exp Zool 312B:437–444Google Scholar
  29. 29.
    Sosnoski DM, Gay CV (2008) NCX3 is a major functional isoform of the sodium–calcium exchanger in osteoblasts. J Cell Biochem 103:1101–1110PubMedGoogle Scholar
  30. 30.
    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 279:49–62PubMedGoogle Scholar
  31. 31.
    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 21:171–176PubMedGoogle Scholar
  32. 32.
    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 41:462–473PubMedGoogle Scholar
  33. 33.
    Hao J, Zou B, Narayanan K, George A (2004) Differential expression patterns of the dentin matrix proteins during mineralized tissue formation. Bone 34:921–932PubMedGoogle Scholar
  34. 34.
    He G, George A (2004) Dentin matrix protein 1 immobilized on type I collagen fibrils facilitates apatite deposition in vitro. J Biol Chem 279:11649–11656PubMedGoogle Scholar
  35. 35.
    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 69:11–16PubMedGoogle Scholar
  36. 36.
    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 8:485–496PubMedGoogle Scholar
  37. 37.
    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 245:293–312PubMedGoogle Scholar
  38. 38.
    Murshed M, Mckee MD (2010) Molecular determinants of extracellular matrix mineralization in bone and blood vessels. Curr Opin Nephrol Hypertens 19:359–365PubMedGoogle Scholar
  39. 39.
    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 281:275–294PubMedGoogle Scholar
  40. 40.
    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 99:9445–9449PubMedGoogle Scholar
  41. 41.
    Bronner F, Stein WD (1995) Calcium homeostasis—an old problem revisited. J Nutr 125:1987S–1995SPubMedGoogle Scholar
  42. 42.
    Talmage DW, Talmage RV (2007) Calcium homeostasis: how bone solubility relates to all aspects of bone physiology. J Musculoskelet Neuronal Interact 7:108–112PubMedGoogle Scholar
  43. 43.
    Talmage RV, Talmage DW (2006) Calcium homeostasis: solving the solubility problem. J Musculoskelet Neuronal Interact 6:402–407PubMedGoogle Scholar
  44. 44.
    Gurley KA, Reimer RJ, Kingsley DM (2006) Biochemical and genetic analysis of ANK in arthritis and bone disease. Am J Hum Genet 79:1017–1029PubMedGoogle Scholar
  45. 45.
    Ho AM, Johnson MD, Kingsley DM (2000) Role of the mouse ank gene in control of tissue calcification and arthritis. Science 289:265–270PubMedGoogle Scholar
  46. 46.
    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 25:1771–1783PubMedGoogle Scholar
  47. 47.
    Terkeltaub RA (2001) Inorganic pyrophosphate generation and disposition in pathophysiology. Am J Physiol Cell Physiol 281:C1–C11PubMedGoogle Scholar
  48. 48.
    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 164:1199–1209PubMedGoogle Scholar
  49. 49.
    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 9:1077–1087PubMedGoogle Scholar
  50. 50.
    Aubin JE, Liu F, Malaval L, Gupta AK (1995) Osteoblast and chondroblast differentiation. Bone 17:77S–83SPubMedGoogle Scholar
  51. 51.
    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 50:175–183PubMedGoogle Scholar
  52. 52.
    Golub EE, Boesze-Battaglia K (2007) The role of alkaline phosphatase in mineralization. Curr Opin Orthop 18:444–448Google Scholar
  53. 53.
    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 21:99–104PubMedGoogle Scholar
  54. 54.
    Whyte MP (1994) Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. [Review]. Endocr Rev 15:439–461PubMedGoogle Scholar
  55. 55.
    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 14:2015–2026PubMedGoogle Scholar
  56. 56.
    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 28:2681–2691PubMedGoogle Scholar
  57. 57.
    Katz EP, Wachtel E, Yamauchi M, Mechanic GL (1989) The structure of mineralized collagen fibrils. Connect Tissue Res 21:149–158PubMedGoogle Scholar
  58. 58.
    Landis WJ (1999) An overview of vertebrate mineralization with emphasis on collagen–mineral interaction. Gravit Space Biol Bull 12:15–26PubMedGoogle Scholar
  59. 59.
    Landis WJ (1995) Tomographic imaging of collagen–mineral interaction: implications for osteogenesis imperfecta. Connect Tissue Res 31:287–290PubMedGoogle Scholar
  60. 60.
    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 7:329–334PubMedGoogle Scholar
  61. 61.
    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 18:117–125PubMedGoogle Scholar
  62. 62.
    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 72:592–598PubMedGoogle Scholar
  63. 63.
    Yamauchi M, Katz EP (1993) The post-translational chemistry and molecular packing of mineralizing tendon collagens. Connect Tissue Res 29:81–98PubMedGoogle Scholar
  64. 64.
    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 68–251Google Scholar
  65. 65.
    Glimcher MJ (1987) The nature of the mineral component of bone and the mechanism of calcification. Instr Course Lect 36:49–69PubMedGoogle Scholar
  66. 66.
    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 247:47–55PubMedGoogle Scholar
  67. 67.
    Posner AS, Blumenthal NC, Boskey AL (1973) Calcified tissue. Facta Publications, ViennaGoogle Scholar
  68. 68.
    Raggio CL, Boyan BD, Boskey AL (1986) In vivo hydroxyapatite formation induced by lipids. J Bone Miner Res 1:409–415PubMedGoogle Scholar
  69. 69.
    Wuthier RE (1993) Involvement of cellular metabolism of calcium and phosphate in calcification of avian growth plate cartilage. J Nutr 123:301–309PubMedGoogle Scholar
  70. 70.
    Glimcher MJ (1981) The chemistry and biology of mineralized connective tissues. Elsevier, New YorkGoogle Scholar
  71. 71.
    Boskey AL (1992) Mineral–matrix interactions in bone and cartilage. Clin Orthop Relat Res 281:244–274PubMedGoogle Scholar
  72. 72.
    Boyan BD, Schwartz Z, Swain LD (1990) Matrix vesicles as a marker of endochondral ossification. Connect Tissue Res 24:67–75PubMedGoogle Scholar
  73. 73.
    Wuthier RE (1989) Mechanism of de novo mineral formation by matrix vesicles. Connect Tissue Res 22:27–33PubMedGoogle Scholar
  74. 74.
    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 36:3359–3367PubMedGoogle Scholar
  75. 75.
    Anderson HC, Garimella R, Tague SE (2005) The role of matrix vesicles in growth plate development and biomineralization. Front Biosci 10:822–837PubMedGoogle Scholar
  76. 76.
    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 268:25084–25094PubMedGoogle Scholar
  77. 77.
    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 272:4404–4411PubMedGoogle Scholar
  78. 78.
    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 17:290–295PubMedGoogle Scholar
  79. 79.
    Wiesmann HP, Meyer U, Plate U, Hohling HJ (2005) Aspects of collagen mineralization in hard tissue formation. Int Rev Cytol 242:121–156PubMedGoogle Scholar
  80. 80.
    Tenenbaum HC (1987) Levamisole and inorganic pyrophosphate inhibit beta-glycerophosphate induced mineralization of bone formed in vitro. Bone Miner 3:13–26PubMedGoogle Scholar
  81. 81.
    Nancollas GH, Zawacki SJ (1989) Calcium phosphate mineralization. Connect Tissue Res 21:239–244PubMedGoogle Scholar
  82. 82.
    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 34:149–157PubMedGoogle Scholar
  83. 83.
    Boyan BD, Boskey AL (1984) Co-isolation of proteolipids and calcium–phospholipid–phosphate complexes. Calcif Tissue Int 36:214–218PubMedGoogle Scholar
  84. 84.
    He G, Dahl T, Veis A, George A (2003) Nucleation of apatite crystals in vitro by self-assembled dentin matrix protein 1. Nat Mater 2:552–558PubMedGoogle Scholar
  85. 85.
    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 3:201–210PubMedGoogle Scholar
  86. 86.
    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 18:3972–3980PubMedGoogle Scholar
  87. 87.
    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 280:33109–33114PubMedGoogle Scholar
  88. 88.
    Boskey AL, Posner AS (1977) The role of synthetic and bone extracted calcium–phospholipid–phosphate complexes in hydroxyapatite formation. Calcif Tissue Res 23:251–258PubMedGoogle Scholar
  89. 89.
    Boskey AL, Dickson IR (1988) Influence of vitamin D status on the content of complexed acidic phospholipids in chick diaphyseal bone. Bone Miner 4:365–371PubMedGoogle Scholar
  90. 90.
    Boyan BD, Schwartz Z, Swain LD, Khare A (1989) Role of lipids in calcification of cartilage. Anat Rec 224:211–219PubMedGoogle Scholar
  91. 91.
    Genge BR, Wu LN, Wuthier RE (1989) Identification of phospholipid-dependent calcium-binding proteins as constituents of matrix vesicles. J Biol Chem 264:10917–10921PubMedGoogle Scholar
  92. 92.
    Wuthier RE (1976) Lipids of matrix vesicles. Fed Proc 35:117–121PubMedGoogle Scholar
  93. 93.
    Demer LL, Tintut Y (2008) Vascular calcification: pathobiology of a multifaceted disease. Circulation 117:2938–2948PubMedGoogle Scholar
  94. 94.
    Ali SY, Wisby A (1978) Apatite crystal nodules in arthritic cartilage. Eur J Rheumatol Inflamm 1:115–119Google Scholar
  95. 95.
    Kirsch T (2006) Determinants of pathological mineralization. Curr Opin Rheumatol 18:174–180PubMedGoogle Scholar
  96. 96.
    Tanimura A, McGregor DH, Anderson HC (1983) Matrix vesicles in atherosclerotic calcification. Proc Soc Exp Biol Med 172:173–177PubMedGoogle Scholar
  97. 97.
    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 15:2857–2867PubMedGoogle Scholar
  98. 98.
    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 284:7149–7156PubMedGoogle Scholar
  99. 99.
    Shore EM, Kaplan FS (2010) Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 6:518–527PubMedGoogle Scholar
  100. 100.
    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 101:706–713PubMedGoogle Scholar
  101. 101.
    Krueger T, Westenfeld R, Schurgers L, Brandenburg V (2009) Coagulation meets calcification: the vitamin K system. Int J Artif Organs 32:67–74PubMedGoogle Scholar
  102. 102.
    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 21:142–144PubMedGoogle Scholar
  103. 103.
    Sage AP, Tintut Y, Demer LL (2010) Regulatory mechanisms in vascular calcification. Nat Rev Cardiol 7:528–536PubMedGoogle Scholar
  104. 104.
    Einhorn TA, Gordon SL, Siegel SA, Hummel CF, Avitable MJ, Carty RP (1985) Matrix vesicle enzymes in human osteoarthritis. J Orthop Res 3:160–169PubMedGoogle Scholar
  105. 105.
    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 8:294–302PubMedGoogle Scholar
  106. 106.
    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 58:2809–2817PubMedGoogle Scholar
  107. 107.
    Karpouzas GA, Terkeltaub RA (1999) New developments in the pathogenesis of articular cartilage calcification. Curr Rheumatol Rep 1:121–127PubMedGoogle Scholar
  108. 108.
    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 41:284–289PubMedGoogle Scholar
  109. 109.
    Gibson G (1998) Active role of chondrocyte apoptosis in endochondral ossification. Microsc Res Tech 43:191–204PubMedGoogle Scholar
  110. 110.
    Golub EE, Schattschneider SC, Berthold P, Burke A, Shapiro IM (1983) Induction of chondrocyte vesiculation in vitro. J Biol Chem 258:616–621PubMedGoogle Scholar
  111. 111.
    Kirsch T, Wang W, Pfander D (2003) Functional differences between growth plate apoptotic bodies and matrix vesicles. J Bone Miner Res 18:1872–1881PubMedGoogle Scholar
  112. 112.
    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 21:689–696PubMedGoogle Scholar
  113. 113.
    Shao JS, Cai J, Towler DA (2006) Molecular mechanisms of vascular calcification: lessons learned from the aorta. Arterioscler Thromb Vasc Biol 26:1423–1430PubMedGoogle Scholar
  114. 114.
    Chen NX, OΓÇÖNeill KD, Chen X, Moe SM (2008) Annexin-mediated matrix vesicle calcification in vascular smooth muscle cells. J Bone Miner Res 23:1798–1805PubMedGoogle Scholar
  115. 115.
    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 22:1700–1710PubMedGoogle Scholar

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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Biochemistry DepartmentUniversity of Pennsylvania School of Dental MedicinePhiladelphiaUSA

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