Calcified Tissue International

, Volume 93, Issue 4, pp 355–364 | Cite as

The Role of Fetuin-A in Physiological and Pathological Mineralization

  • Laura Brylka
  • Willi Jahnen-Dechent
Original Research


Mineralization in higher vertebrates is restricted to bones and teeth. Pathological calcification is mostly known in vasculature but can basically affect all soft tissues. Simply put, tissue mineralization occurs through the interplay of three key determinants: extracellular matrix suitable for mineralization, extracellular levels of inorganic phosphate and calcium, and the levels of mineralization inhibitors that may be expressed systemically or locally. In this article we describe the role of a prototypic systemic inhibitor protein of mineralization, the hepatic plasma protein α2-Heremans-Schmid glycoprotein/fetuin-A. Fetuin-A mediates the formation of stable colloidal mineral–protein complexes called calciprotein particles (CPPs). Thus, fetuin-A is important in the stabilization and clearance of amorphous mineral precursor phases. Efficient clearance of CPPs and, thus, of excess mineral from circulation prevents local buildup of mineral and calcification of soft tissue. Besides calcium phosphate binding, fetuin-A also acts as a carrier for lipids, which may influence calcification, inflammation, and apoptosis. Fetuin-A-deficient (Ahsg /) mice show impaired growth of their long bones and premature growth plate closure. We posit that the absence of fetuin-A in the growth plate causes simultaneous lack of calcification inhibition and excess lipid hormone signaling, leading to premature growth plate mineralization and shortened long bones. This suggests that fetuin-A regulates endochondral ossification through mineralization inhibition and lipid (hormone) binding.


Fetuin-A Ectopic calcification Chondrocyte Matrix protein Osteoblast 


  1. 1.
    Neuman MW (1982) Blood:bone equilibrium. Calcif Tissue Int 34:117–120PubMedCrossRefGoogle Scholar
  2. 2.
    Neuman WF (1980) Bone material and calcification mechanisms. In: Urist M (ed) Fundamental and clinical bone physiology. Lippincott Williams and Wilkins, Philadelphia, pp 83–107Google Scholar
  3. 3.
    Pedersen K (1944) Fetuin, a new globulin isolated from serum. Nature 154:575CrossRefGoogle Scholar
  4. 4.
    Schäfer C, Jahnen-Dechent W, Brandenburg V (2005) Klinische relevanz des serumproteins fetuin-A—Einem regulator der kalzifizierung. Laborwelt 6:9–12Google Scholar
  5. 5.
    Nie Z (1992) Fetuin: its enigmatic property of growth promotion. Am J Physiol 263:551–562Google Scholar
  6. 6.
    Termine JD (1988) Non-collagen proteins in bone. Ciba Found Symp 136:178–202PubMedGoogle Scholar
  7. 7.
    Dickson IR, Poole AR, Veis A (1975) Localisation of plasma alpha2HS glycoprotein in mineralising human bone. Nature 256:430–432PubMedCrossRefGoogle Scholar
  8. 8.
    Triffitt JT, Owen ME, Ashton BA, Wilson JM (1978) Plasma disappearance of rabbit alpha2HS-glycoprotein and its uptake by bone tissue. Calcif Tissue Res 26:155–161PubMedCrossRefGoogle Scholar
  9. 9.
    Schultze HE, Heide K, Haupt H (1962) Charakterisierung eines niedermolekularen A2-mukoids aus humanserum. Naturwissenschaften 49:15–17CrossRefGoogle Scholar
  10. 10.
    Heremans J (1960) Les globulines sériques du système gamma. Arscia, BrusselsGoogle Scholar
  11. 11.
    Bürgi W, Schmid K (1961) Preparation and properties of Zn-alpha 2-glycoprotein of normal human plasma. J Biol Chem 236:1066–1074PubMedGoogle Scholar
  12. 12.
    Olivier E, Soury E, Ruminy P, Husson A, Parmentier F, Daveau M, Salier J (2000) Fetuin-B, a second member of the fetuin family in mammals. Biochem J 350:589–597PubMedCrossRefGoogle Scholar
  13. 13.
    Lee C, Bongcam-Rudloff E, Söllner C, Jahnen-Dechent W, Claesson-Welsh L (2009) Type 3 cystatins; fetuins, kininogen and histidine-rich glycoprotein. Front Biosci 14:2911–2922CrossRefGoogle Scholar
  14. 14.
    Kellermann J, Haupt H, Auerswald E, Müller-Esterl W (1989) The arrangement of disulfide loops in human alpha 2-HS glycoprotein: similarity to the disulfide bridge structures of cystatins and kininogens. J Biol Chem 264:14121–14128PubMedGoogle Scholar
  15. 15.
    Yamamoto K, Sinohara H (1993) Isolation and characterization of mouse countertrypsin, a new trypsin inhibitor belonging to the mammalian fetuin family. J Biol Chem 268:17750–17753PubMedGoogle Scholar
  16. 16.
    Heiss A, DuChesne A, Denecke B, Grötzinger J, Yamamoto K, Renné T, Jahnen-Dechent W (2003) Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A: formation of colloidal calciprotein particles. J Biol Chem 278:13333–13341PubMedCrossRefGoogle Scholar
  17. 17.
    Schäfer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, Müller-Esterl W, Schinke T, Jahnen-Dechent W (2003) The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 112:357–366PubMedGoogle Scholar
  18. 18.
    Jahnen-Dechent W, Heiss A, Schäfer C, Ketteler M (2011) Fetuin-A regulation of calcified matrix metabolism. Circ Res 108:1494–1509PubMedCrossRefGoogle Scholar
  19. 19.
    Wessling J (2007) Gene deletion and functional analysis of fetuin-B. Dissertation RWTH, AachenGoogle Scholar
  20. 20.
    Li W, Zhu S, Li J, Huang Y, Zhou R, Fan X, Yang H, Gong X, Eissa NT, Jahnen-Dechent W, Wang P, Tracey KJ, Sama AE, Wang H (2011) A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation. PLoS ONE 6:e16945PubMedCrossRefGoogle Scholar
  21. 21.
    Kumbla L, Cayatte AJ, Subbiah MT (1989) Association of a lipoprotein-like particle with bovine fetuin. FASEB J 3:2075–2080PubMedGoogle Scholar
  22. 22.
    Cayatte AJ, Kumbla L, Subbiah MT (1990) Marked acceleration of exogenous fatty acid incorporation into cellular triglycerides by fetuin. J Biol Chem 265:5883–5888PubMedGoogle Scholar
  23. 23.
    Kumbla L, Bhadra S, Subbiah MT (1991) Multifunctional role for fetuin (fetal protein) in lipid transport. FASEB J 5:2971–2975PubMedGoogle Scholar
  24. 24.
    Demetriou M, Binkert C, Sukhu B, Tenenbaum H, Dennis J (1996) Fetuin/alpha2-HS glycoprotein is a transforming growth factor-beta type II receptor mimic and cytokine antagonist. J Biol Chem 271:12755–12761PubMedCrossRefGoogle Scholar
  25. 25.
    Libby P, Ridker PM, Hansson GK (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473:317–325PubMedCrossRefGoogle Scholar
  26. 26.
    Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, Ray S, Majumdar SS, Bhattacharya S (2012) Fetuin-A acts as an endogenous ligand of Tlr4 to promote lipid-induced insulin resistance. Nat Med 18:1279–1285PubMedCrossRefGoogle Scholar
  27. 27.
    Seto J, Busse B, Gupta HS, Schäfer C, Krauss S, Dunlop JWC, Masic A, Kerschnitzki M, Zaslansky P, Boesecke P, Catala-Lehnen P, Schinke T, Fratzl P, Jahnen-Dechent W (2012) Accelerated growth plate mineralization and foreshortened proximal limb bones in fetuin-A knockout mice. PLoS ONE 7:e47338PubMedCrossRefGoogle Scholar
  28. 28.
    Golub EE (2011) Biomineralization and matrix vesicles in biology and pathology. Semin Immunopathol 33:409–417PubMedCrossRefGoogle Scholar
  29. 29.
    Boonrungsiman S, Gentleman E, Carzaniga R, Evans ND, McComb DW, Porter AE, Stevens MM (2012) The role of intracellular calcium phosphate in osteoblast-mediated bone apatite formation. Proc Natl Acad Sci USA 109:14170–14175PubMedCrossRefGoogle Scholar
  30. 30.
    Mahamid J, Aichmayer B, Shimoni E, Ziblat R, Li C, Siegel S, Paris O, Fratzl P, Weiner S, Addadi L (2010) Mapping amorphous calcium phosphate transformation into crystalline mineral from the cell to the bone in zebrafish fin rays. Proc Natl Acad Sci USA 107:6316–6321PubMedCrossRefGoogle Scholar
  31. 31.
    Nudelman F, Pieterse K, George A, Bomans PHH, Friedrich H, Brylka LJ, Hilbers PAJ, de With G, Sommerdijk NAJM (2010) The role of collagen in bone apatite formation in the presence of hydroxyapatite nucleation inhibitors. Nat Mater 9:1004–1009PubMedCrossRefGoogle Scholar
  32. 32.
    McNally EA, Schwarcz HP, Botton GA, Arsenault AL (2012) A model for the ultrastructure of bone based on electron microscopy of ion-milled sections. PLoS ONE 7:e29258PubMedCrossRefGoogle Scholar
  33. 33.
    Kinney JH, Pople JA, Driessen CH, Breunig TM, Marshall GW, Marshall SJ (2001) Intrafibrillar mineral may be absent in dentinogenesis imperfecta type II (Di-II). J Dent Res 80:1555–1559PubMedCrossRefGoogle Scholar
  34. 34.
    Hart PS, Hart TC (2007) Disorders of human dentin. Cells Tissues Organs 186:70–77PubMedCrossRefGoogle Scholar
  35. 35.
    Kinney JH, Habelitz S, Marshall SJ, Marshall GW (2003) The importance of intrafibrillar mineralization of collagen on the mechanical properties of dentin. J Dent Res 82:957–961PubMedCrossRefGoogle Scholar
  36. 36.
    Keeley FW, Sitarz EE (1985) Identification and quantitation of alpha 2-HS-glycoprotein in the mineralized matrix of calcified plaques of atherosclerotic human aorta. Atherosclerosis 55:63–69PubMedCrossRefGoogle Scholar
  37. 37.
    Moe SM, Reslerova M, Ketteler M, O’Neill K, Duan D, Koczman J, Westenfeld R, Jahnen-Dechent W, Chen NX (2005) Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int 67:2295–2304PubMedCrossRefGoogle Scholar
  38. 38.
    Emoto M, Mori K, Lee E, Kawano N, Yamazaki Y, Tsuchikura S, Morioka T, Koyama H, Shoji T, Inaba M, Nishizawa Y (2010) Fetuin-A and atherosclerotic calcified plaque in patients with type 2 diabetes mellitus. Metabolism 59:873–878PubMedCrossRefGoogle Scholar
  39. 39.
    Schinke T, Amendt C, Trindl A, Pöschke O, Müller-Esterl W, Jahnen-Dechent W (1996) The serum protein alpha2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells: a possible role in mineralization and calcium homeostasis. J Biol Chem 271:20789–20796PubMedCrossRefGoogle Scholar
  40. 40.
    Toroian D, Price PA (2007) The essential role of fetuin in the serum-induced calcification of collagen. Calcif Tissue Int 82:116–126PubMedCrossRefGoogle Scholar
  41. 41.
    Zmuda JM, Eichner JE, Ferrell RE, Bauer DC, Kuller LH, Cauley JA (1998) Genetic variation in alpha 2HS-glycoprotein is related to calcaneal broadband ultrasound attenuation in older women. Calcif Tissue Int 63:5–8PubMedCrossRefGoogle Scholar
  42. 42.
    Price PA, Toroian D, Lim JE (2009) Mineralization by inhibitor exclusion: the calcification of collagen with fetuin. J Biol Chem 284:17092–17101PubMedCrossRefGoogle Scholar
  43. 43.
    Toroian D, Lim JE, Price PA (2007) The size exclusion characteristics of type i collagen: implications for the role of noncollagenous bone constituents in mineralization. J Biol Chem 282:22437–22447PubMedCrossRefGoogle Scholar
  44. 44.
    Szweras M, Liu D, Partridge EA, Pawling J, Sukhu B, Clokie C, Jahnen-Dechent W, Tenenbaum HC, Swallow CJ, Grynpas MD, Dennis JW (2002) Alpha 2-HS glycoprotein/fetuin, a transforming growth factor-beta/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling. J Biol Chem 277:19991–19997PubMedCrossRefGoogle Scholar
  45. 45.
    Li T-F, O’Keefe RJ, Chen D (2005) TGF-beta signaling in chondrocytes. Front Biosci 10:681–688PubMedCrossRefGoogle Scholar
  46. 46.
    Shu B, Zhang M, Xie R, Wang M, Jin H, Hou W, Tang D, Harris SE, Mishina Y, O’Keefe RJ, Hilton MJ, Wang Y, Chen D (2011) Bmp2, but not Bmp4, is crucial for chondrocyte proliferation and maturation during endochondral bone development. J Cell Sci 124:3428–3440PubMedCrossRefGoogle Scholar
  47. 47.
    Merx MW, Schäfer C, Westenfeld R, Brandenburg V, Hidajat S, Weber C, Ketteler M, Jahnen-Dechent W (2005) Myocardial stiffness, cardiac remodeling, and diastolic dysfunction in calcification-prone fetuin-A-deficient mice. J Am Soc Nephrol 16:3357–3364PubMedCrossRefGoogle Scholar
  48. 48.
    Westenfeld R, Schäfer C, Smeets R, Brandenburg VM, Floege J, Ketteler M, Jahnen-Dechent W (2007) Fetuin-A (AHSG) prevents extraosseous calcification induced by uraemia and phosphate challenge in mice. Nephrol Dial Transplant 22:1537–1546PubMedCrossRefGoogle Scholar
  49. 49.
    Jahnen-Dechent W, Schäfer C, Ketteler M, McKee MD (2008) Mineral chaperones: a role for fetuin-A and osteopontin in the inhibition and regression of pathologic calcification. J Mol Med 86:379–389PubMedCrossRefGoogle Scholar
  50. 50.
    Luo G, Ducy P, McKee M, Pinero G, Loyer E, Behringer R, Karsenty G (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix Gla protein. Nature 386:78–81PubMedCrossRefGoogle Scholar
  51. 51.
    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 15:2857–2867PubMedCrossRefGoogle Scholar
  52. 52.
    Reynolds JL, Skepper JN, McNair R, Kasama T, Gupta K, Weissberg PL, Jahnen-Dechent W, Shanahan CM (2005) Multifunctional roles for serum protein fetuin-A in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol 16:2920–2930PubMedCrossRefGoogle Scholar
  53. 53.
    Ghadially F (2001) As you like it, part 3: a critique and historical review of calcification as seen with the electron microscope. Ultrastruct Pathol 25:243–267PubMedCrossRefGoogle Scholar
  54. 54.
    Heiss A, Pipich V, Jahnen-Dechent W, Schwahn D (2010) Fetuin-A is a mineral carrier protein: small angle neutron scattering provides new insight on fetuin-A controlled calcification inhibition. Biophys J 99:3986–3995PubMedCrossRefGoogle Scholar
  55. 55.
    Rochette CN, Rosenfeldt S, Heiss A, Narayanan T, Ballauff M, Jahnen-Dechent W (2009) A shielding topology stabilizes the early stage protein–mineral complexes of fetuin-A and calcium phosphate: a time-resolved small-angle X-ray study. ChemBioChem 10:735–740PubMedCrossRefGoogle Scholar
  56. 56.
    Wald J, Wiese S, Eckert T, Jahnen-Dechent W, Richtering W, Heiss A (2011) Formation and stability kinetics of calcium phosphate–fetuin-A colloidal particles probed by time-resolved dynamic light scattering. Soft Matter 7:2869–2874CrossRefGoogle Scholar
  57. 57.
    Heiss A, Jahnen-Dechent W, Endo H, Schwahn D (2007) Structural dynamics of a colloidal protein–mineral complex bestowing on calcium phosphate a high solubility in biological fluids. Biointerphases 2:16–20PubMedCrossRefGoogle Scholar
  58. 58.
    Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Böhm R, Metzger T, Wanner C, Jahnen-Dechent W, Floege J (2003) Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361:827–833PubMedCrossRefGoogle Scholar
  59. 59.
    Stenvinkel P, Wang K, Qureshi AR, Axelsson J, Pecoits-Filho R, Gao P, Barany P, Lindholm B, Jogestrand T, Heimbürger O, Holmes C, Schalling M, Nordfors L (2005) Low fetuin-A levels are associated with cardiovascular death: impact of variations in the gene encoding fetuin. Kidney Int 67:2383–2392PubMedCrossRefGoogle Scholar
  60. 60.
    Herrmann M, Kinkeldey A, Jahnen-Dechent W (2012) Fetuin-A function in systemic mineral metabolism. Trends Cardiovasc Med 22:197–201PubMedCrossRefGoogle Scholar
  61. 61.
    Herrmann M, Schäfer C, Heiss A, Gräber S, Kinkeldey A, Büscher A, Schmitt MMN, Bornemann J, Nimmerjahn F, Herrmann M, Helming L, Gordon S, Jahnen-Dechent W (2012) Clearance of fetuin-A-containing calciprotein particles is mediated by scavenger receptor-A. Circ Res 111:575–584PubMedCrossRefGoogle Scholar
  62. 62.
    Goldstein JL, Ho YK, Basu SK, Brown MS (1979) Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci USA 76:333–337PubMedCrossRefGoogle Scholar
  63. 63.
    Pasch A, Farese S, Gräber S, Wald J, Richtering W, Floege J, Jahnen-Dechent W (2012) A nanoparticle-based serum test measuring overall calcification inhibition. J Am Soc Nephrol 23:1744–1752PubMedCrossRefGoogle Scholar
  64. 64.
    London GM (2009) Bone–vascular axis in chronic kidney disease: a reality? Clin J Am Soc Nephrol 4:254–257PubMedCrossRefGoogle Scholar
  65. 65.
    Osako MK, Nakagami H, Koibuchi N, Shimizu H, Nakagami F, Koriyama H, Shimamura M, Miyake T, Rakugi H, Morishita R (2010) Estrogen inhibits vascular calcification via vascular RANKL system: common mechanism of osteoporosis and vascular calcification. Circ Res 107:466–475PubMedCrossRefGoogle Scholar
  66. 66.
    Ketteler M, Schlieper G, Floege J (2006) Calcification and cardiovascular health: new insights into an old phenomenon. Hypertension 47:1027–1034PubMedCrossRefGoogle Scholar
  67. 67.
    Weenig RH (2008) Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B. J Am Acad Dermatol 58:458–471PubMedCrossRefGoogle Scholar
  68. 68.
    Gabrielli A, Avvedimento EV, Krieg T (2009) Scleroderma. N Engl J Med 360:1989–2003PubMedCrossRefGoogle Scholar
  69. 69.
    Demetriou ETW, Pietras SM, Holick MF (2010) Hypercalcemia and soft tissue calcification owing to sarcoidosis: the sunlight–cola connection. J Bone Miner Res 25:1695–1699PubMedCrossRefGoogle Scholar
  70. 70.
    Kaklamanos M, Perros P (2007) Milk alkali syndrome without the milk. BMJ 335:397–398PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Helmholtz Institute for Biomedical Engineering, Biointerface GroupRWTH Aachen UniversityAachenGermany

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