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Spatial distribution of osteoblast-specific transcription factor Cbfa1 and bone formation in atherosclerotic arteries

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Abstract

The mechanisms of ectopic bone formation in arteries are poorly understood. Osteoblasts might originate either from stem cells that penetrate atherosclerotic plaques from the blood stream or from pluripotent mesenchymal cells that have remained in the arterial wall from embryonic stages of the development. We have examined the frequency of the expression and spatial distribution of osteoblast-specific factor-2/core binding factor-1 (Osf2/Cbfa1) in carotid and coronary arteries. Cbfa1-expressing cells were rarely observed but were found in all tissue specimens in the deep portions of atherosclerotic plaques under the necrotic cores. The deep portions of atherosclerotic plaques under the necrotic cores were characterized by the lack of capillaries of neovascularization. In contrast, plaque shoulders, which were enriched by plexuses of neovacularization, lacked Cbfa1-expressing cells. No bone formation was found in any of the 21 carotid plaques examined and ectopic bone was observed in only two of 12 coronary plaques. We speculate that the sparse invasion of sprouts of neovacularization into areas underlying the necrotic cores, where Cbfa1-expressing cells reside, might explain the rarity of events of ectopic bone formation in the arterial wall. This study has also revealed that Cbfa1-expressing cells contain alpha-smooth muscle actin and myofilaments, indicating their relationship with arterial smooth muscle cells.

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References

  • Abedin M, Tintut Y, Demer LL (2004a) Mesenchymal stem cells and the artery wall. Circ Res 95:671–676

    Article  PubMed  CAS  Google Scholar 

  • Abedin M, Tintut Y, Demer LL (2004b) Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol 24:1161–1170

    Article  PubMed  CAS  Google Scholar 

  • Anderson HC (2003) Matrix vesicles and calcification. Curr Rheumatol Rep 5:222–226

    Article  PubMed  Google Scholar 

  • Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85:221–228

    PubMed  CAS  Google Scholar 

  • Babaev VR, Bobryshev YV, Stenina OV, Tararak EM, Gabbiani G (1990) Heterogeneity of smooth muscle cells in atheromatous plaque of human aorta. Am J Pathol 136:1031–1042

    PubMed  CAS  Google Scholar 

  • Banerjee C, McCabe LR, Choi JY, Hiebert SW, Stein JL, Stein GS, Lian JB (1997) Runt homology domain proteins in osteoblast differentiation: AML3/CBFA1 is a major component of a bone-specific complex. J Cell Biochem 66:1–8

    Article  PubMed  CAS  Google Scholar 

  • Bobryshev YV (2005a) Transdifferentiation of smooth muscle cells into chondrocytes in atherosclerotic arteries in situ: implications for diffuse intimal calcification. J Pathol 205:641–650

    Article  PubMed  Google Scholar 

  • Bobryshev YV (2005b) Intracellular localization of oxidized low-density lipoproteins in atherosclerotic plaque cells revealed by electron microscopy combined with laser capture microdissection. J Histochem Cytochem 53:793–797

    Article  PubMed  CAS  Google Scholar 

  • Bobryshev YV, Lord RSA (1996) Langhans cells of human arterial intima: uniform by stellate appearance but different by nature. Tissue Cell 28:177–194

    Article  PubMed  CAS  Google Scholar 

  • Bobryshev YV, Lord RSA (1998) Mapping of vascular dendritic cells in atherosclerotic arteries suggests their involvement in local immune-inflammatory reactions. Cardiovasc Res 37:799–810

    Article  PubMed  CAS  Google Scholar 

  • Bobryshev YV, Lord RSA, Warren BA (1995) Calcified deposit formation in intimal thickenings of the human aorta. Atherosclerosis 118:9–21

    Article  PubMed  CAS  Google Scholar 

  • Bobryshev YV, Cherian SM, Inder SJ, Lord RSA (1999) Neovascular expression of VE-cadherin in human atherosclerotic arteries and its relation to intimal inflammation. Cardiovasc Res 43:1003–1017

    Article  PubMed  CAS  Google Scholar 

  • Bobryshev YV, Killingsworth MC, Huynh TG, Lord RS, Grabs AJ, Valenzuela SM (2007) Are calcifying matrix vesicles in atherosclerotic lesions of cellular origin? Basic Res Cardiol 102:133–143

    Article  PubMed  CAS  Google Scholar 

  • Bostrom K, Watson KE, Horn S, Wortham C, Herman IM, Demer LL (1993) Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest 91:1800–1809

    Article  PubMed  CAS  Google Scholar 

  • Buergher L, Oppenheimer A (1998) Bone formation in sclerotic arteries. J Exp Med 10:354–367

    Article  Google Scholar 

  • Campbell GR, Campbell JH, Manderson JA, Horrigan S, Rennick RE (1988) Arterial smooth muscle. A multifunctional mesenchymal cell. Arch Pathol Lab Med 112:977–986

    PubMed  CAS  Google Scholar 

  • Canfield AE, Doherty MJ, Wood AC, Farrington C, Ashton B, Begum N, Harvey B, Poole A, Grant ME, Boot-Handford RP (2000) Role of pericytes in vascular calcification: a review. Z Kardiol 89 (Suppl 2):20–27

    Article  PubMed  Google Scholar 

  • Caplice NM, Bunch TJ, Stalboerger PG, Wang S, Simper D, Miller DV, Russell SJ, Litzow MR, Edwards WD (2003) Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proc Natl Acad Sci USA 100:4754–4759

    Article  PubMed  CAS  Google Scholar 

  • Deneke T, Langner K, Grewe PH, Harrer E, Muller KM (2001) Ossification in atherosclerotic carotid arteries. Z Kardiol 90 (Suppl 3):106–115

    PubMed  Google Scholar 

  • Dhore CR, Cleutjens JP, Lutgens E, Cleutjens KB, Geusens PP, Kitslaar PJ, Tordoir JH, Spronk HM, Vermeer C, Daemen MJ (2001) Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol 21:1998–2003

    Article  PubMed  CAS  Google Scholar 

  • Doherty MJ, Ashton BA, Walsh S, Beresford JN, Grant ME, Canfield AE (1998) Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res 13:828–838

    Article  PubMed  CAS  Google Scholar 

  • Doherty TM, Fitzpatrick LA, Inoue D, Qiao JH, Fishbein MC, Detrano RC, Shah PK, Rajavashisth TB (2004) Molecular, endocrine, and genetic mechanisms of arterial calcification. Endocr Rev 25:629–672

    Article  PubMed  CAS  Google Scholar 

  • Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754

    Article  PubMed  CAS  Google Scholar 

  • Fitzpatrick LA, Severson A, Edwards WD, Ingram RT (1994) Diffuse calcification in human coronary arteries. Association of osteopontin with atherosclerosis. J Clin Invest 94:1597–1604

    Article  PubMed  CAS  Google Scholar 

  • Grant K, Jerome WG (2002) Laser capture microdissection as an aid to ultrastructural analysis. Microsc Microanal 8:170–175

    Article  PubMed  CAS  Google Scholar 

  • Gruber HE (1994) Perspectives on the endoplasmic reticulum as an “architectural editor” with special reference to human chondrocytes and osteoblasts. Int Rev Exp Pathol 35:177–189

    PubMed  CAS  Google Scholar 

  • Halayko AJ, Solway J (2001) Molecular mechanisms of phenotypic plasticity in smooth muscle cells. J Appl Physiol 90:358–368

    PubMed  CAS  Google Scholar 

  • Hsu HH, Camacho NP (1999) Isolation of calcifiable vesicles from human atherosclerotic aortas. Atherosclerosis 143:353–362

    Article  PubMed  CAS  Google Scholar 

  • Hu Y, Zhang Z, Torsney E, Afzal AR, Davison F, Metzler B, Xu Q (2004) Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest 113:1258–1265

    PubMed  CAS  Google Scholar 

  • Jeziorska M, McCollum C, Wooley DE (1998) Observations on bone formation and remodelling in advanced atherosclerotic lesions of human carotid arteries. Virchows Arch 433:559–565

    Article  PubMed  CAS  Google Scholar 

  • Komori T (2006) Regulation of osteoblast differentiation by transcription factors. J Cell Biochem 99:1233–1239

    Article  PubMed  CAS  Google Scholar 

  • Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764

    Article  PubMed  CAS  Google Scholar 

  • Lord RSA (1986) Surgery of occlusive cerebrovascular disease. Mosby, St Louis

    Google Scholar 

  • Mackie EJ (2003) Osteoblasts: novel roles in orchestration of skeletal architecture. Int J Biochem Cell Biol 35:1301–1305

    Article  PubMed  CAS  Google Scholar 

  • Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771

    Article  PubMed  CAS  Google Scholar 

  • Proudfoot D, Skepper JN, Shanahan CM, Weissberg PL (1994) Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression. Arterioscler Thromb Vasc Biol 18:379–388

    Google Scholar 

  • Proudfoot D, Skepper JN, Hegyi L, Farzaneh-Far A, Shanahan CM, Weissberg PL (2001) The role of apoptosis in the initiation of vascular calcification. Z Kardiol 90 (Suppl 3):43–46

    PubMed  Google Scholar 

  • Qiao JH, Mertens RB, Fishbein MC, Geller SA (2003) Cartilaginous metaplasia in calcified diabetic peripheral vascular disease: morphologic evidence of enchondral ossification. Hum Pathol 34:402–407

    Article  PubMed  CAS  Google Scholar 

  • Rattazzi M, Bennett BJ, Bea F, Kirk EA, Ricks JL, Speer M, Schwartz SM, Giachelli CM, Rosenfeld ME (2005) Calcification of advanced atherosclerotic lesions in the innominate arteries of ApoE-deficient mice: potential role of chondrocyte-like cells. Arterioscler Thromb Vasc Biol 25:1420–1425

    Article  PubMed  CAS  Google Scholar 

  • Ross MH, Kaye GI, Pawlina W (2003) Histology, 4th edn. Lippincott Williams & Wilkins, Philadelphia Tokyo, pp 180–202

    Google Scholar 

  • Sata M (2003) Circulating vascular progenitor cells contribute to vascular repair, remodeling, and lesion formation. Trends Cardiovasc Med 13:249–253

    Article  PubMed  Google Scholar 

  • Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R (2002) Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 8:403–409

    Article  PubMed  CAS  Google Scholar 

  • Shao JS, Cai J, Towler DA (2006) Molecular mechanisms of vascular calcification: lessons learned from the aorta. Arterioscler Thromb Vasc Biol 26:1423–1430

    Article  PubMed  CAS  Google Scholar 

  • Soboleva EL, Popkova V, Saburova O, Tararak E, Smirnov V (1994) Circulating cells of bone marrow origin and atherosclerosis. Atherosclerosis 109:348

    Article  Google Scholar 

  • Soboleva EL, Saburova OV, Prokopheva LV, Tararak EM, Smirnov VN (1995) Stem cells in blood of patients with primary hypercholesterolemia. Atherosclerosis 115:S60

    Article  Google Scholar 

  • Speer MY, Giachelli CM (2004) Regulation of cardiovascular calcification. Cardiovasc Pathol 13:63–70

    Article  PubMed  CAS  Google Scholar 

  • Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW (1995) A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation 92:1355–1374

    PubMed  CAS  Google Scholar 

  • Steitz SA, Speer MY, Curinga G, Yang HY, Haynes P, Aebersold R, Schinke T, Karsenty G, Giachelli CM (2001) Smooth muscle cell phenotypic transition associated with calcification—upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 89:1147–1154

    Article  PubMed  CAS  Google Scholar 

  • Tintut Y, Alfonso Z, Saini T, Radcliff K, Watson K, Boström K, Demer LL (2003) Multilineage potential of cells from the artery wall. Circulation 108:2505–2510

    Article  PubMed  Google Scholar 

  • Torsney E, Hu Y, Xu Q (2005) Adventitial progenitor cells contribute to arteriosclerosis. Trends Cardiovasc Med 15:64–68

    Article  PubMed  CAS  Google Scholar 

  • Torsney E, Mandal K, Halliday A, Jahangiri M, Xu Q (2007) Characterisation of progenitor cells in human atherosclerotic vessels. Atherosclerosis 191:259–264

    Article  PubMed  CAS  Google Scholar 

  • Tyson KL, Reynolds JL, McNair R, Zhang Q, Weissberg PL, Shanahan CM (2003) Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol 23:489–494

    Article  PubMed  CAS  Google Scholar 

  • Virchow R (1863) Cellular pathology as based upon physiological and pathological histology. Dover, New York

    Google Scholar 

  • Wada T, McKee MD, Steitz S, Giachelli CM (1999) Calcification of vascular smooth muscle cell cultures: inhibition by osteopontin. Circ Res 84:166–178

    PubMed  CAS  Google Scholar 

  • Watson KE, Bostrom K, Ravindranath R, Lam T, Nortin B, Demer LL (1994) TGF-beta-1 and 25-hydoxycholesterol stimulate osteoblast-like vascular cells to calcify. J Clin Invest 93:2106–2113

    Article  PubMed  CAS  Google Scholar 

  • Wilkinson FL, Liu Y, Rucka AK, Jeziorska M, Hoyland JA, Heagerty AM, Canfield AE, Alexander MY (2007) Contribution of VCAF−positive cells to neovascularization and calcification in atherosclerotic plaque development. J Pathol 211:362–369

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Faculty of Medicine, University of New South Wales, Kensington, NSW, 2052, Australia

    Yuri V. Bobryshev

  2. Surgical Professorial Unit, St Vincent’s Hospital Sydney, Darlinghurst, NSW, 2010, Australia

    Yuri V. Bobryshev

  3. Department of Anatomical Pathology, South Western Area Pathology Service, Liverpool, NSW, 2170, Australia

    Murray C. Killingsworth

  4. Suite 601, St Vincent’s Hospital Sydney, Darlinghurst, NSW, 2010, Australia

    Reginald S. A. Lord

  5. School of Medicine, University of Western Sydney, Campbelltown, NSW, 2055, Australia

    Reginald S. A. Lord

  6. Division of Surgery, Campbelltown Hospital, Campbelltown, NSW, 2055, Australia

    Reginald S. A. Lord

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  1. Yuri V. Bobryshev
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  2. Murray C. Killingsworth
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  3. Reginald S. A. Lord
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Correspondence to Yuri V. Bobryshev.

Additional information

This work was supported by the Vascular Fund, St. Vincent’s Hospital, Sydney, and a grant from the School of Medicine, University of Western Sydney.

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Bobryshev, Y.V., Killingsworth, M.C. & Lord, R.S.A. Spatial distribution of osteoblast-specific transcription factor Cbfa1 and bone formation in atherosclerotic arteries. Cell Tissue Res 333, 225–235 (2008). https://doi.org/10.1007/s00441-008-0637-1

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  • DOI: https://doi.org/10.1007/s00441-008-0637-1

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