Abstract
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.
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References
Neuman MW (1982) Blood:bone equilibrium. Calcif Tissue Int 34:117–120
Neuman WF (1980) Bone material and calcification mechanisms. In: Urist M (ed) Fundamental and clinical bone physiology. Lippincott Williams and Wilkins, Philadelphia, pp 83–107
Pedersen K (1944) Fetuin, a new globulin isolated from serum. Nature 154:575
Schäfer C, Jahnen-Dechent W, Brandenburg V (2005) Klinische relevanz des serumproteins fetuin-A—Einem regulator der kalzifizierung. Laborwelt 6:9–12
Nie Z (1992) Fetuin: its enigmatic property of growth promotion. Am J Physiol 263:551–562
Termine JD (1988) Non-collagen proteins in bone. Ciba Found Symp 136:178–202
Dickson IR, Poole AR, Veis A (1975) Localisation of plasma alpha2HS glycoprotein in mineralising human bone. Nature 256:430–432
Triffitt JT, Owen ME, Ashton BA, Wilson JM (1978) Plasma disappearance of rabbit alpha2HS-glycoprotein and its uptake by bone tissue. Calcif Tissue Res 26:155–161
Schultze HE, Heide K, Haupt H (1962) Charakterisierung eines niedermolekularen A2-mukoids aus humanserum. Naturwissenschaften 49:15–17
Heremans J (1960) Les globulines sériques du système gamma. Arscia, Brussels
Bürgi W, Schmid K (1961) Preparation and properties of Zn-alpha 2-glycoprotein of normal human plasma. J Biol Chem 236:1066–1074
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 350:589–597
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 14:2911–2922
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 264:14121–14128
Yamamoto K, Sinohara H (1993) Isolation and characterization of mouse countertrypsin, a new trypsin inhibitor belonging to the mammalian fetuin family. J Biol Chem 268:17750–17753
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 278:13333–13341
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 112:357–366
Jahnen-Dechent W, Heiss A, Schäfer C, Ketteler M (2011) Fetuin-A regulation of calcified matrix metabolism. Circ Res 108:1494–1509
Wessling J (2007) Gene deletion and functional analysis of fetuin-B. Dissertation RWTH, Aachen
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:e16945
Kumbla L, Cayatte AJ, Subbiah MT (1989) Association of a lipoprotein-like particle with bovine fetuin. FASEB J 3:2075–2080
Cayatte AJ, Kumbla L, Subbiah MT (1990) Marked acceleration of exogenous fatty acid incorporation into cellular triglycerides by fetuin. J Biol Chem 265:5883–5888
Kumbla L, Bhadra S, Subbiah MT (1991) Multifunctional role for fetuin (fetal protein) in lipid transport. FASEB J 5:2971–2975
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 271:12755–12761
Libby P, Ridker PM, Hansson GK (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473:317–325
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 18:1279–1285
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:e47338
Golub EE (2011) Biomineralization and matrix vesicles in biology and pathology. Semin Immunopathol 33:409–417
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 109:14170–14175
Mahamid J, Aichmayer B, Shimoni E, Ziblat R, Li C, Siegel S, Paris O, Fratzl P, Weiner S, Addadi L (2010) Map** amorphous calcium phosphate transformation into crystalline mineral from the cell to the bone in zebrafish fin rays. Proc Natl Acad Sci USA 107:6316–6321
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 9:1004–1009
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:e29258
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 80:1555–1559
Hart PS, Hart TC (2007) Disorders of human dentin. Cells Tissues Organs 186:70–77
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 82:957–961
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 55:63–69
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 67:2295–2304
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 59:873–878
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 271:20789–20796
Toroian D, Price PA (2007) The essential role of fetuin in the serum-induced calcification of collagen. Calcif Tissue Int 82:116–126
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 63:5–8
Price PA, Toroian D, Lim JE (2009) Mineralization by inhibitor exclusion: the calcification of collagen with fetuin. J Biol Chem 284:17092–17101
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 282:22437–22447
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 277:19991–19997
Li T-F, O’Keefe RJ, Chen D (2005) TGF-beta signaling in chondrocytes. Front Biosci 10:681–688
Shu B, Zhang M, **e R, Wang M, ** 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 124:3428–3440
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 16:3357–3364
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 22:1537–1546
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 86:379–389
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 386:78–81
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
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 16:2920–2930
Ghadially F (2001) As you like it, part 3: a critique and historical review of calcification as seen with the electron microscope. Ultrastruct Pathol 25:243–267
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 99:3986–3995
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 10:735–740
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 7:2869–2874
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 2:16–20
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 361:827–833
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 67:2383–2392
Herrmann M, Kinkeldey A, Jahnen-Dechent W (2012) Fetuin-A function in systemic mineral metabolism. Trends Cardiovasc Med 22:197–201
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 111:575–584
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 76:333–337
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 23:1744–1752
London GM (2009) Bone–vascular axis in chronic kidney disease: a reality? Clin J Am Soc Nephrol 4:254–257
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 107:466–475
Ketteler M, Schlieper G, Floege J (2006) Calcification and cardiovascular health: new insights into an old phenomenon. Hypertension 47:1027–1034
Weenig RH (2008) Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B. J Am Acad Dermatol 58:458–471
Gabrielli A, Avvedimento EV, Krieg T (2009) Scleroderma. N Engl J Med 360:1989–2003
Demetriou ETW, Pietras SM, Holick MF (2010) Hypercalcemia and soft tissue calcification owing to sarcoidosis: the sunlight–cola connection. J Bone Miner Res 25:1695–1699
Kaklamanos M, Perros P (2007) Milk alkali syndrome without the milk. BMJ 335:397–398
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Brylka, L., Jahnen-Dechent, W. The Role of Fetuin-A in Physiological and Pathological Mineralization. Calcif Tissue Int 93, 355–364 (2013). https://doi.org/10.1007/s00223-012-9690-6
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DOI: https://doi.org/10.1007/s00223-012-9690-6