Skip to main content

Advertisement

Log in

Bone matrix proteins: their function, regulation, and relationship to osteoporosis

  • Review Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Bone is a unique tissue composed of numerous cell types entombed within a mineralized matrix each with its own unique functions. While the majority of the matrix is composed of inorganic materials, study of the organic components has yielded most of the insights into the roles and regulation of cell and tissue specific functions. The goal of this review will be to describe some of the major known organic components of the bone matrix and discuss their functions as currently perceived. The potential usefulness of bone matrix protein assays for diagnosing the status of bone diseases and our current understanding of how these proteins could be related to diseases such as osteoporosis will also be reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Woitge HW, Seibel MJ. Biochemical markers to survey bone turnover. Rheum Dis Clin North Am 2001;27:49–80.

    Google Scholar 

  2. Gundberg CM. Biochemical markers of bone formation. Clin Lab Med 2000;20:489–501.

    Google Scholar 

  3. Knott L, Bailey AJ. Collagen cross-links in mineralizing tissues: a review of their chemistry, function, and clinical relevance. Bone 1998;22:181–7.

    Google Scholar 

  4. Myllyharju J, Kivirikko KI. Collagens and collagen-related diseases. Ann Med 2001;33:7–21.

    Google Scholar 

  5. Pace JM, Chitayat D, Atkinson M, Wilcox WR, Schwarze U, Byers PH. A single amino acid substitution (D1441Y) in the carboxyl-terminal propeptide of the proalpha1(I) chain of type I collagen results in a lethal variant of osteogenesis imperfecta with features of dense bone diseases. J Med Genet 2002;39:23–9.

    Google Scholar 

  6. Primorac D, Rowe DW, Mottes M, Barisic I, Anticevic D, Mirandola S, et al. Osteogenesis imperfecta at the beginning of bone and joint decade. Croat Med J 2001;42:393–415.

    Google Scholar 

  7. Landis WJ, Hodgens KJ, Song MJ, Arena J, Kiyonaga S, Marko M, et al. Mineralization of collagen may occur on fibril surfaces: evidence from conventional and high-voltage electron microscopy and three-dimensional imaging. J Struct Biol 1996;117:24–35.

    Google Scholar 

  8. Landis WJ. An overview of vertebrate mineralization with emphasis on collagen-mineral interaction. Gravit Space Biol Bull 1999;12:15–26.

    Google Scholar 

  9. Prockop DJ, Kivirikko KI. Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem 1995;64:403–34.

    Google Scholar 

  10. Eyre DR, Paz MA, Gallop PM. Cross-linking in collagen and elastin. Annu Rev Biochem 1984;3:717–48.

    Google Scholar 

  11. Bailey AJ, Knott L. Molecular changes in bone collagen in osteoporosis and osteoarthritis in the elderly. Exp Gerontol 1999;34:337–51.

    Google Scholar 

  12. Thompson JB, Kindt JH, Drake B, Hansma HG, Morse DE, Hansma PK. Bone indentation recovery time correlates with bond reforming time. Nature 2001;414:773–76.

    Google Scholar 

  13. Looker AC, Bauer DC, Chesnut CH 3rd, Gundberg CM, Hochberg, MC, Klee G, et al. Clinical use of biochemical markers of bone remodeling: current status and future directions. Osteoporos Int 2000;11:467–80.

    Google Scholar 

  14. Giannobile WV. C-telopeptide pyridinoline cross-links. Sensitive indicators of periodontal tissue destruction. Ann N Y Acad Sci 1999;878:404–12.

    Google Scholar 

  15. Antoniou J, Huk O, Zukor D, Eyre D, Alini M. Collagen crosslinked N-telopeptides as markers for evaluating particulate osteolysis: a preliminary study. J Orthop Res 2000;18:64–7.

    Google Scholar 

  16. Costa L, Demers LM, Gouveia-Oliveira A, Schaller J, Costa EB, de Moura MC, et al. Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol 2002;20:850–6.

    Google Scholar 

  17. Kim JH, Skates SJ, Uede T, Wong KK, Schorge JO, Feltmate CM, et al. Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA 2002;287:1671–9.

    Google Scholar 

  18. Stewart TL, Ralston SH. Role of genetic factors in the pathogenesis of osteoporosis. J Endocrinol 2000;166:235–45.

    Google Scholar 

  19. Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH. Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet 1996;14:203–5.

    Google Scholar 

  20. Mann V, Hobson EE, Li B, Stewart TL, Grant SF, Robins SP, et al. A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest 2001;107:899–907.

    Google Scholar 

  21. McGuigan FE, Armbrecht G, Smith R, Felsenberg D, Reid DM, Ralston SH. Prediction of osteoporotic fractures by bone densitometry and COLIA1 genotyping: a prospective, population-based study in men and women. Osteoporos Int 2001;12:91–6.

    Google Scholar 

  22. Zhao W, Byrne MH, Wang Y, Krane SM. Osteocyte and osteoblast apoptosis and excessive bone deposition accompany failure of collagenase cleavage of collagen. J Clin Invest 2000;106:941–9.

    Google Scholar 

  23. Green J, Schotland S, Stauber DJ, Kleeman CR, Clemens TL. Cell-matrix interaction in bone: type I collagen modulates signal transduction in osteoblast-like cells. Am J Physiol 1995;268:C1090–1103.

    Google Scholar 

  24. Lynch MP, Stein JL, Stein GS, Lian JB. The influence of type I collagen on the development and maintenance of the osteoblast phenotype in primary and passaged rat calvarial osteoblasts: modification of expression of genes supporting cell growth, adhesion, and extracellular matrix mineralization. Exp Cell Res 1995;216:35–45.

    Google Scholar 

  25. Suzawa M, Tamura Y, Fukumoto S, Miyazono K, Fujita T, Kato S, et al. Stimulation of Smad1 transcriptional activity by Ras-extracellular signal-regulated kinase pathway: a possible mechanism for collagen-dependent osteoblastic differentiation. J Bone Miner Res 2002;17:240–8.

    Google Scholar 

  26. Termine JD, Kleinman HK, Whitson SW, Conn KM, McGarvey ML, Martin GR. Osteonectin, a bone-specific protein linking mineral to collagen. Cell 1981;26:99–105.

    Google Scholar 

  27. Gokhale JA, Robey PG, Boskey AL. The biochemistry of bone. San Diego: Academic Press, 2001:107–88.

  28. Gorski JP. Is all bone the same? Distinctive distributions and properties of non-collagenous matrix proteins in lamellar vs woven bone imply the existence of different underlying osteogenic mechanisms. Crit Rev Oral Biol Med 1998;9:201–23.

    Google Scholar 

  29. Jia L, Young MF, Powell J, Yang L, Ho NC, Hotchkiss R, et al. Gene expression profile of human bone marrow stromal cells: high-throughput expressed sequence tag sequencing analysis. Genomics 2002;79:7–17.

    Google Scholar 

  30. Robey PG, Termine JD. Human bone cells in vitro. Calcif Tissue Int 1985;37:453–60.

    Google Scholar 

  31. Moursi AM, Damsky CH, Lull J, Zimmerman D, Doty SB, Aota S, et al. Fibronectin regulates calvarial osteoblast differentiation. J Cell Sci 1996;109:1369-80.

    Google Scholar 

  32. Moursi AM, Globus RK, Damsky CH. Interactions between integrin receptors and fibronectin are required for calvarial osteoblast differentiation in vitro. J Cell Sci 1997;110:2187–96.

    Google Scholar 

  33. Globus RK, Doty SB, Lull JC, Holmuhamedov E, Humphries MJ, Damsky CH. Fibronectin is a survival factor for differentiated osteoblasts. J Cell Sci 1998;111:1385–93.

    Google Scholar 

  34. Couchourel D, Escoffier C, Rohanizadeh R, Bohic S, Daculsi G, Fortun Y, et al. Effects of fibronectin on hydroxyapatite formation. J Inorg Biochem 1999;73:129–36.

    Google Scholar 

  35. Daculsi G, Pilet P, Cottrel M, Guicheux G. Role of fibronectin during biological apatite crystal nucleation: ultrastructural characterization. J Biomed Mater Res 1999;47:228–33.

    Google Scholar 

  36. Dallas SL, Keene DR, Bruder SP, Saharinen J, Sakai LY, Mundy GR, et al. Role of the latent transforming growth factor beta binding protein 1 in fibrillin-containing microfibrils in bone cells in vitro and in vivo. J Bone Miner Res 2000;15:68–81.

    Google Scholar 

  37. Merle B, Durussel L, Delmas PD, Clezardin P. Decorin inhibits cell migration through a process requiring its glycosaminoglycan side chain. J Cell Biochem 1999;75:538–46.

    Google Scholar 

  38. Saad S, Gottlieb DJ, Bradstock KF, Overall CM, Bendall LJ. Cancer cell-associated fibronectin induces release of matrix metalloproteinase-2 from normal fibroblasts. Cancer Res 2002;62:283–9.

    Google Scholar 

  39. George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 1993;119:1079–91.

    Google Scholar 

  40. Oegema TR Jr, Johnson SL, Aguiar DJ, Ogilvie JW. Fibronectin and its fragments increase with degeneration in the human intervertebral disc. Spine 2000;25:2742–7.

    Google Scholar 

  41. Young MF, Ibaraki K, Kerr JM, Heegaard A-M. Molecular and cellular biology of the major noncollagenous proteins in bone. Orlando: Academic Press, 1993:191–234.

  42. Sun BH, Mitnick M, Eielson C, Yao GQ, Paliwal I, Insogna K. Parathyroid hormone increases circulating levels of fibronectin in vivo: modulating effect of ovariectomy. Endocrinology 1997;138:3918–24.

    Google Scholar 

  43. Kaiser E, Sato M, Onyia JE, Chandrasekhar S. Parathyroid hormone (1–34) regulates integrin expression in vivo in rat osteoblasts. J Cell Biochem 2001;83:617–30.

    Google Scholar 

  44. Schwarzbauer JE, Spencer CS. The Caenorhabditis elegans homologue of the extracellular calcium binding protein SPARC/osteonectin affects nematode body morphology and mobility. Mol Biol Cell 1993;4:941–52.

    Google Scholar 

  45. Delany AM, Amling M, Priemel M, Howe C, Baron R, Canalis E. Osteopenia and decreased bone formation in osteonectin-deficient mice. J Clin Invest 2000;105:915–23.

    Google Scholar 

  46. Clezardin P, Malaval L, Ehrensperger AS, Delmas PD, Dechavanne M, McGregor JL. Complex formation of human thrombospondin with osteonectin. Eur J Biochem 1988;175:275–84.

    Google Scholar 

  47. Brekken RA, Sage EH. SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol 2001;19:816–27.

    Google Scholar 

  48. Robey PG, Young MF, Fisher LW, McClain TD. Thrombospondin is an osteoblast-derived component of mineralized extracellular matrix. J Cell Biol 1989;108:719–27.

    Google Scholar 

  49. Bornstein P, Armstrong LC, Hankenson KD, Kyriakides TR, Yang Z. Thrombospondin 2, a matricellular protein with diverse functions. Matrix Biol 2000;19:557–68.

    Google Scholar 

  50. Hankenson KD, Bain SD, Kyriakides TR, Smith EA, Goldstein SA, Bornstein P. Increased marrow-derived osteoprogenitor cells and endosteal bone formation in mice lacking thrombospondin 2. J Bone Miner Res 2000;15:851–62.

    Google Scholar 

  51. Hankenson KD, Bornstein P. The secreted protein thrombospondin 2 is an autocrin inhibitor of marrow stromal cell proliferation. J Bone Miner Res 2002;17:415–25.

    Google Scholar 

  52. Kim JE, Kim EH, Han EH, Park RW, Park IH, Jun SH, et al. A TGF-beta-inducible cell adhesion molecule, betaig-h3, is downregulated in melorheostosis and involved in osteogenesis. J Cell Biochem 2000;77:169–78.

    Google Scholar 

  53. Dieudonne SC, Kerr JM, Xu T, Sommer B, DeRubeis AR, Kuznetsov SA, et al. Differential display of human marrow stromal cells reveals unique mRNA expression patterns in response to dexamethasone. J Cell Biochem 1999;76:231–43.

    Google Scholar 

  54. Boskey AL. Matrix proteins and mineralization: an overview. Connect Tissue Res 1996;35:357–363.

    Google Scholar 

  55. Boskey AL. Biomineralization: conflicts, challenges, and opportunities. J Cell Biochem Suppl 1998;31:83–91.

    Google Scholar 

  56. Price PA. Gla-containing proteins of bone. Connect Tissue Res 1989;21:51–7.

    Google Scholar 

  57. Price PA, Williamson MK, Haba T, Dell RB, Jee WS. Excessive mineralization with growth plate closure in rats on chronic warfarin treatment. Proc Natl Acad Sci USA 1982;79:7734–8.

    Google Scholar 

  58. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, et al. Increased bone formation in osteocalcin-deficient mice. Nature 1996;382:448–52.

    Google Scholar 

  59. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997;386:78–81.

    Google Scholar 

  60. Schinke T, McKee MD, Kiviranta R, Karsenty G. Molecular determinants of arterial calcification. Ann Med 1998;30:538–41.

    Google Scholar 

  61. Boskey AL, Gadaleta S, Gundberg C, Doty SB, Ducy P, Karsenty G. Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into the function of osteocalcin. Bone 1998;23:187–96.

    Google Scholar 

  62. Sugiyama T, Kawai S. Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K. J Bone Miner Metab 2001;19:146–9.

    Google Scholar 

  63. Fisher LW, Fedarko NS. Six genes expressed in bones and teeth constitute the current members of the SIBLING family of proteins. Calcif Tissue Int, in press.

  64. Gorski JP, Shimizu K. Isolation of new phosphorylated glycoprotein from mineralized phase of bone that exhibits limited homology to adhesive protein osteopontin. J Biol Chem 1988;263:15938–45.

    Google Scholar 

  65. Yoshitake H, Rittling SR, Denhardt DT, Noda M. Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption. Proc Natl Acad Sci USA 1999;96:8156–60.

    Google Scholar 

  66. Ishijima M, Rittling SR, Yamashita T, Tsuji K, Kurosawa H, Nifuji A, et al. Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin. J Exp Med 2001;193:399–404.

    Google Scholar 

  67. Ihara H, Denhardt DT, Furuya K, Yamashita T, Muguruma Y, Tsuji K, et al. Parathyroid hormone-induced bone resorption does not occur in the absence of osteopontin. J Biol Chem 2001;276:13065–71.

    Google Scholar 

  68. Asou Y, Rittling SR, Yoshitake H, Tsuji K, Shinomiya K, Nifuji A, et al. Osteopontin facilitates angiogenesis, accumulation of osteoclasts, and resorption in ectopic bone. Endocrinology 2001;142:1325–32.

    Google Scholar 

  69. Dodds RA, Connor JR, James IE, Rykaczewski EL, Appelbaum E, Dul E, et al. Human osteoclasts, not osteoblasts, deposit osteopontin onto resorption surfaces: an in vitro and ex vivo study of remodeling bone. J Bone Miner Res 1995;10:1666–80.

    Google Scholar 

  70. Bellahcene A, Castronovo V. Expression of bone matrix proteins in human breast cancer: potential roles in microcalcification formation and in the genesis of bone metastases. Bull Cancer 1997;84:17–24.

    Google Scholar 

  71. Waltregny D, Bellahcene A, Van Riet I, Fisher LW, Young M, Fernandez P, et al. Prognostic value of bone sialoprotein expression in clinically localized human prostate cancer. J Natl Cancer Inst 1998;90:1000–8.

    Google Scholar 

  72. Jain A, Karadag A, Fohr B, Fisher LW, Fedarko NS. Three SIBLINGs enhance factor H's cofactor activity enabling MCP-like cellular evasion of complement-mediated attack. J Biol Chem 2002;277:13700–8.

    Google Scholar 

  73. Nemoto H, Rittling SR, Yoshitake H, Furuya K, Amagasa T, Tsuji K, et al. Osteopontin deficiency reduces experimental tumor cell metastasis to bone and soft tissues. J Bone Miner Res 2001;16:652–9.

    Google Scholar 

  74. Zhang X, Zhao J, Li C, Gao S, Qiu C, Liu P, et al. DSPP mutation in dentinogenesis imperfecta Shields type II. Nat Genet 2001;27:151–2.

    Google Scholar 

  75. Xiao S, Yu C, Chou X, Yuan W, Wang Y, Bu L, et al. Dentinogenesis imperfecta 1 with or without progressive hearing loss is associated with distinct mutations in DSPP. Nat Genet 2001;27:201–4.

    Google Scholar 

  76. Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MJ, et al. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics 2000;67:54–68.

    Google Scholar 

  77. Fedarko NS, Jain A, Karadag A, Van Eman MR, Fisher LW. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res 2001;7:4060–6.

    Google Scholar 

  78. Shaarawy M, Hasan M. Serum bone sialoprotein: a marker of bone resorption in postmenopausal osteoporosis. Scand J Clin Lab Invest 2001;61:513–21.

    Google Scholar 

  79. Iozzo RV. Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem 1998;67:609–52.

    Google Scholar 

  80. Iozzo RV. The family of the small leucine-rich proteoglycans: key regulators of matrix assembly and cellular growth. Crit Rev Biochem Mol Biol 1997;32:141–74.

    Google Scholar 

  81. Hocking AM, Shinomura T, McQuillan DJ. Leucine-rich repeat glycoproteins of the extracellular matrix. Matrix Biol 1998;17:1–19.

    Google Scholar 

  82. Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 1990;346:281–4.

    Google Scholar 

  83. Hildebrand A, Romaris M, Rasmussen LM, Heinegard D, Twardzik DR, Border WA, et al. Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. Biochem J 1994;302:527–34.

    Google Scholar 

  84. Xu T, Bianco P, Fisher LW, Longenecker G, Smith E, Goldstein S, et al. Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice. Nat Genet 1998;20:78–82.

    Google Scholar 

  85. Chen XD, Shi S, Xu T, Robey PG, Young MF. Age-related osteoporosis in biglycan-deficient mice is related to defects in bone marrow stromal cells. J Bone Miner Res 2002;17:331–40.

    Google Scholar 

  86. Corsi A, Xu T, Chen X-D, Boyde A, Liang J, Mankani M, et al. Phenotypic effects of biglycan deficiency are linked to collagen fibril abnormalities, are synergized by decorin deficiency, and mimic Ehlers-Danlos changes in bone and connective tissues. J Bone Miner Res 2002;17:1180-9.

    Google Scholar 

  87. Ameye L, Aria D, Jepsen K, Oldberg O, Xu T, Young MF. Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification and osteoarthritis. FASEB J 2002;16:673–80.

    Google Scholar 

  88. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997;89:755–64.

    Google Scholar 

  89. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997;89:747–54.

    Google Scholar 

  90. Lian JB, Stein GS, Stein JL, van Wijnen AJ. Osteocalcin gene promoter: unlocking the secrets for regulation of osteoblast growth and differentiation. J Cell Biochem Suppl 1998;31:62–72.

    Google Scholar 

  91. Raouf A, Seth A. Ets transcription factors and targets in osteogenesis. Oncogene 2000;19:6455–63.

    Google Scholar 

  92. Karsenty G. Minireview: transcriptional control of osteoblast differentiation. Endocrinology 2001;142:2731–3.

    Google Scholar 

  93. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 2002;108:17–29.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marian F. Young.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Young, M.F. Bone matrix proteins: their function, regulation, and relationship to osteoporosis. Osteoporos Int 14 (Suppl 3), 35–42 (2003). https://doi.org/10.1007/s00198-002-1342-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-002-1342-7

Keywords

Navigation