We study the mechanisms by which proteins control normal calcification of bone and prevent abnormal calcification of soft tissues. Our focus in these studies is on two vitamin K dependent proteins we have discovered, the 50 residue bone Gla protein (BGP) and the 83 residue matrix Gla protein (MGP). Studies using the vitamin K antagonist warfarin and targeted gene deletion have shown that BGP and MGP both inhibit calcification in vivo. Impaired BGP expression causes the spread of calcification from bone into adjacent cartilaginous structures and impaired MGP expression causes calcification of arteries.
We are presently investigating the relationship between the impaired synthesis of MGP in aging humans and the calcification of arteries as well as the development of atherosclerotic plaque. Our hypothesis is that calcification of the artery in aging humans is caused in part by dietary vitamin K deficiency, and that artery calcification contributes to the formation of the atherosclerotic plaque. This hypothesis is supported by the observation that the extent of artery calcification is the best predictor of future myocardial infarction found to date. It is also supported by the fact that animals on a cholesterol rich diet will not form atherosclerotic plaques unless arteries have been previously induced to calcify.
We are also investigating the in vitro mechanism by which MGP and BGP bind to the surface of hydroxyapatite crystals and prevent their growth and the relationship between the structure of these proteins and their ability to inhibit calcification. We are particularly interested in the role of the vitamin K-dependent calcium binding amino acid, g-carboxyglutamic acid (Gla), in the activities of these proteins and have developed a variety of methods to detect and modify Gla residues.
We have shown that MGP and BGP are normally expressed in bone and that the expression of both proteins by osteoblasts is strongly induced by the active metabolite of vitamin D, 1,25(OH)2D3. 1,25(OH)2D3 restores serum calcium levels to normal by reducing the rate at which serum calcium is deposited in bone. We believe that the induction of BGP and MGP by 1,25(OH)2D3 is part of the mechanism by which the hormone regulates bone calcification, and we are studying the mechanisms by which the expression of these proteins mediate the action of vitamin D on bone.
We have recently found that the only class of drugs currently approved for the treatment of osteoporosis, the bisphosphonates, have strong and specific effects on the levels of BGP and MGP in serum. There is a similarity in the chemical structure of bisphonates and the g-carboxyglutamyl side chain, and we believe that these effects of bisphonates on MGP and BGP are due in part to the competition of the drug with these proteins for binding to sites in bone mineral. We are presently investigating the relationship between the action of bisphonates on bone and the effect of these drugs on the metabolism of MGP and BGP.
This is a partial listing of recent publications from the Paul Price laboratory. Full text versions of these and other manuscripts can be found at the Price lab website.
Price PA, Roublick AM, Williamson MK. (2006). Artery calcification in uremic rats is increased by a low protein diet and prevented by treatment with ibandronate. Kidney International November; 70:1577-1583.
Hamlin NJ, Ong KG, Price PA. (2006). A serum factor that recalcifies demineralized bone is conserved in bony fish and sharks but is not found in invertebrates. Calcified Tissue International. 76:326-334.
Price PA, Chan WS, Jolson DM, Williamson MK. (2006). The elastic lamellae of devitalized arteries calcify when incubated in serum: evidence for a serum calcification factor. Arterioscler Thromb Vasc Biol. May; 26(5):1079-85.
Hamlin NJ and Price PA. (2004). Mineralization of decalcified bone occurs under cell culture conditions and requires bovine serum but not cells. Calcified Tissue International. 10.1007/s00223-004-0190-1 Published online: 28 May.
Price PA, June HH, Hamlin NJ, Williamson MK. (2004). Evidence for a serum factor that initiates the re-calcification of demineralized bone. J Biol Chem. Apr 30;279(18):19169-80. Epub 2004 Feb 20.
Simes DC, Williamson MK, Schaff BJ, Gavaia PJ, Ingleton PM, Price PA, Cancela ML. (2004). Characterization of osteocalcin (BGP) and matrix Gla protein (MGP) fish specific antibodies: validation for immunodetection studies in lower vertebrates. Calcif Tissue Int. Feb;74(2):170-80. Epub 2003 Dec 15.
Price PA, Williamson MK, Nguyen TM, Than TN. (2004). Serum levels of the fetuin-mineral complex correlate with artery calcification in the rat. J Biol Chem. Jan 16;279(3):1594-600. Epub 2003 Oct 24.
Price PA and Lim JE. (2003). The Inhibition of Calcium Phosphate Precipitation by Fetuin is Accomanied by the Formation of a Fetuin-Mineral Complex. J Biol Chem. 278(24):22144-52.
Price PA, Nguyen TMT and Williamson MK. (2003). Biochemical Characterization of the Serum Fetuin-Mineral Complex. J Biol Chem. 278(24):22153-60.
Simes DC, Williamson MK, Ortiz-Delgado JB, Viegas CS, Price PA, Cancela ML. (2003). Purification of matrix Gla protein from a marine teleost fish, Argyrosomus regius: calcified cartilage and not bone as the primary site of MGP accumulation in fish. J Bone Miner Res Feb;18(2):244-59.
Price PA, Omid N, Than TN, Williamson MK. (2002). The Amino Bisphosphonate Ibandronate Prevents Calciphylaxis in the Rat at Doses that Inhibit Bone Resorption. Calcif Tissue. Int. Oct;71(4):356-63.
Price PA, June HH, Buckley JR, Williamson MK. (2002). SB 242784, a selective inhibitor of the osteoclastic V-H+ATPase, inhibits arterial calcification in the rat. Circ Res Sep 20;91(6):547-52.
Price PA, Caputo JM, Williamson MK. (2002). Bone origin of the serum complex of calcium, phosphate, fetuin, and matrix Gla protein: Biochemical evidence for the cancellous bone-remodeling compartment. J.Bone Min. Research.; 17(7):1171-79.
Price PA, Thomas GR, Pardini AW, Figueira WF, Caputo JM, Williamson MK. (2002). Discovery of a high molecular weight complex of calcium, phosphate, fetuin, and matrix gamma-carboxyglutamic acid protein in the serum of etidronate-treated rats. J Biol Chem. Feb 8;277(6):3926-34.