Abstract
Extracellular ATP, and to a lesser extent adenosine, an ATP metabolite, stimulated cell proliferation in osteoblast-like cells (MC3T3-E1). ATP increased cytosolic Ca2+ due to Ca2+ mobilization from intracellular storage in the same concentration range of the nucleotide as that effective for DNA synthesis, suggesting the mediation of the phospholipase C/Ca2+ system in the mitogenic action. Since adenosine induced no Ca2+ mobilization, P2-purinergic receptor appears to be associated with ATP actions. The growth-promoting effect of ATP was not inhibited by H7, a protein kinase C inhibitor, and indomethacin, a cyclooxygenase inhibitor, indicating no involvement of activation of protein kinase C and production of prostaglandins in ATP-induced mitogenic signals. Either ATP or adenosine remarkably and synergistically potentiated platelet derived growth factor-induced DNA synthesis. These findings suggest that extracellular ATP and adenosine may play a physiological role in the regulation of bone formation.
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References
Simmons DJ (1985) Fracture healing perspective. Clin Orthop Rel Res 200:100–113.
Mizuno K, Mineo K, Tachibana T, Sumi M, Matsubara T, Hirohara K (1990) The osteogenetic potential of fracture hematoma. J Bone Joint Surg 72B:822–829.
Tsukamoto T, Matsui T, Fukase M, Fujita T (1991) Plateletderived growth factor B chain homodimer enhances chemotaxis and DNA synthesis in normal osteoblast-like cells (MC3T3-E1). Biochem Biophys Res Commun 175:745–751
Hakeda Y, Kumegawa M (1988) Prostaglandins and bone cell activity. J Bone Miner Metab 6:55–70
Hakeda Y, Hotta T, Kurihara N, Ikeda E, Maeda N, Yagyu Y, Kumegawa M (1987) Prostaglandin E1 and F2 alpha stimulate differentiation and proliferation, and proliferation, respectively, of clonal osteoblastic MC3T3-E1 cells by different second messengers in vitro. Endocrinology 121:1966–1974
Hakeda Y, Harada S, Matsumoto T, Tezuka K, Higashino K, Kodama H, Hashimoto T, Ogata E, Kumegawa M (1991) Prostaglandin F2α stimulates proliferation of clonal osteoblastic MC3T3-E1 cells by up-regulation of insulin-like growth factor I receptors. J Biol Chem 266:21044–21050.
Newby AC, Worku Y, Meghji P, Nakazawa M, Skladanowski AC (1990) Adenosine: a retaliatory metabolite, or not? News Physiol Sci 5:67–70
Gordon JL (1986) Extracellular ATP: effects, sources and fate. Biochem J, 233:309–319
Kumagai H, Sakamoto H, Guggino S, Filburn CR, Sacktor B (1989) Neurotransmitter regulation of cytosolic calcium in osteoblast-like bone cells. Calcif Tissue Int 45:251–254
Reimer WJ, Dixon SJ (1992) Extracellular nucleotides elevate [Ca2+]i in rat osteoblastic cells by interaction with two receptor subtypes. Am J Physiol 263:C1040-C1048
Yu H, Ferrier J (1993) Osteoblast-like cells have a variable mixed population of purino/nucleotide receptors. FEBS Lett 328:209–214
Sistare FD, Rosenzweig BA, Contrera JG, Jordan B (1994) Separate P2T and P2U purinergic receptors with similar second messenger signaling pathways in UMR-106 osteoblasts. J Pharmacol Exp Ther 269:1049–1061
Shimegi S, Okajima F, Kondo Y (1994) Permissive stimulation of Ca2+-induced phospholipase A2 by an adenosine receptor agonist in a pertussis toxin-sensitive manner in FRTL-5 thyroid cells: a new ‘cross-talk’ mechanism in Ca2+ signalling. Biochem J 299:845–851
Burnstock G, Kennedy C (1985) Is there a basis for distinguishing two types of P2-purinoceptor? Gen Pharmacol 16: 433–440
Erlinge D, Yoo H, Edvinsson L, Reis DJ, Wahlestedt C (1993) Mitogenic effects of ATP on vascular smooth muscle cells vs. other growth factors and sympathetic contransmitters. Am J Physiol. 265:H1089-H1097
Daele PVan, Coevorden AVan, Roger PP, Boeynaems J-M (1992) Effects of adenosine nucleotides on the proliferation of aortic endothelial cells. Circ Res 70:82–90
Huang N, Wang D, Heppel LA (1989) Extracellular ATP is a mitogen for 3T3, 3T6, and A431 cells and acts synergistically with other growth factors. Proc Natl Acad Sci USA 86:7904–7908
Okajima F, Sato K, Nazarea M, Sho K, Kondo Y (1989) A permissive role of pertussis toxin substrate G-protein in P2-purinergic stimulation of phosphoinositide turnover and arachidonate release in FRTL-5 thyroid cells. J Biol Chem 264:13029–13037
Gonzalez F, Wand D, Huang N, Heppel LA (1990) Extracellular ATP induced the release of calcium from intracellular stores without the activation of protein kinase C in Swiss 3T6 mouse fibroblasts. Proc Natl Acad Sci USA 87:9717–9721
Wang D, Huang N, Heppel LA (1990) Extracellular ATP shows synergistic enhancement of DNA synthesis when combined with agents that are active in wound healing or as neurotransmitters. Biochem Biophys Res Commun 66:251–258
Meininger CJ, Granger HJ (1990) Mechanisms leading to adenosine-stimulated proliferation of microvascular endothelial cells. Am J Physiol 258 (Heart Circ Physiol 27):H198-H206.
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Shimegi, S. ATP and adenosine act as a mitogen for osteoblast-like cells (MC3T3-E1). Calcif Tissue Int 58, 109–113 (1996). https://doi.org/10.1007/BF02529732
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DOI: https://doi.org/10.1007/BF02529732