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Journal of Bone and Mineral Metabolism
Published in: Journal of Bone and Mineral Metabolism 1/2010

01-01-2010 | Original Article

Prostaglandin expression profile in hypoxic osteoblastic cells

Authors: Christina M. Lee, Damian C. Genetos, Alice Wong, Clare E. Yellowley

Published in: Journal of Bone and Mineral Metabolism | Issue 1/2010

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Abstract

Conditions such as fracture and unloading have been shown to be associated with tissue and cellular hypoxia in bone. The effects of hypoxia on bone cell physiology and ultimately its impact on bone tissue repair and remodeling are not well understood. In this study, we investigated the role of hypoxia on prostaglandin release from osteoblastic cells cultured in 2% (hypoxia), 5% (potentially cellular normoxia), and 21% (normoxia for standard cell culture conditions) oxygen for up to 24 h. We quantified the effects of reduced oxygen tension on the release of prostaglandin (PG)E2, PGF2α, PGD2, and PGI2. The mechanism by which hypoxia increases PG production was investigated by examining the various regulatory components of the PG biosynthetic pathway. Our data show that PGE2 levels alone are significantly elevated under hypoxic conditions. Also, we show that cyclooxygenase (COX)-1 and COX-2 play an important role in hypoxia-induced PGE2 production, possibly via a mechanism involving changes in their respective activity levels under low oxygen conditions. The effect of hypoxia on PGE2 levels was mimicked by dimethyloxaloglycine, a known activator of the HIF pathway. In addition, we confirmed that HIF-1α was stabilized in osteoblastic cells under hypoxia. Taken together these data suggest a role for the HIF pathway in regulation of PGE2 levels under hypoxic conditions. Previous studies have detected release of prostaglandins from areas of damaged bone, such as a fracture site, and our data may contribute to an understanding of how this release is regulated.
Literature
1.
Grundnes O, Reikeras O (1992) Blood flow and mechanical properties of healing bone. Femoral osteotomies studied in rats. Acta Orthop Scand 63:487–491PubMed
2.
Brighton CT, Krebs AG (1972) Oxygen tension of healing fractures in the rabbit. J Bone Joint Surg [Am] 54:323–332
3.
Heppenstall RB, Grislis G, Hunt TK (1975) Tissue gas tensions and oxygen consumption in healing bone defects. Clin Orthop Relat Res 106:357–365CrossRefPubMed
4.
Piekarski K, Munro M (1977) Transport mechanism operating between blood supply and osteocytes in long bones. Nature (Lond) 269:80–82CrossRef
5.
Dodd JS, Raleigh JA, Gross TS (1999) Osteocyte hypoxia: a novel mechanotransduction pathway. Am J Physiol 277:C598–C602PubMed
6.
Semenza GL (1998) Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 8:588–594CrossRefPubMed
7.
Tsai AG, Johnson PC, Intaglietta M (2007) Is the distribution of tissue pO2 homogeneous? Antioxid Redox Signal 9:979–984CrossRefPubMed
8.
Vanderkooi JM, Erecinska M, Silver IA (1991) Oxygen in mammalian tissue: methods of measurement and affinities of various reactions. Am J Physiol 260:C1131–C1150PubMed
9.
Pennathur-Das R, Levitt L (1987) Augmentation of in vitro human marrow erythropoiesis under physiological oxygen tensions is mediated by monocytes and T lymphocytes. Blood 69:899–907PubMed
10.
Kiaer T, Dahl B, Lausten G (1992) Partial pressures of oxygen and carbon dioxide in bone and their correlation with bone-blood flow: effect of decreased arterial supply and venous congestion on intraosseous oxygen and carbon dioxide in an animal model. J Orthop Res 10:807–812CrossRefPubMed
11.
Kiaer T, Pedersen NW, Kristensen KD, Starklint H (1990) Intra-osseous pressure and oxygen tension in avascular necrosis and osteoarthritis of the hip. J Bone Joint Surg 72:1023–1030
12.
Lee CM, Genetos DC, You Z, Yellowley CE (2007) Hypoxia regulates PGE2 release and EP1 receptor expression in osteoblastic cells. J Cell Physiol 212:182–188CrossRefPubMed
13.
Dekel S, Lenthall G, Francis MJ (1981) Release of prostaglandins from bone and muscle after tibial fracture. An experimental study in rabbits. J Bone Joint Surg [Br] 63B:185–189
14.
Raisz LG, Pilbeam CC, Fall PM (1993) Prostaglandins: mechanisms of action and regulation of production in bone. Osteoporos Int 3(suppl 1):136–140CrossRefPubMed
15.
Sudmann E (1975) Effect of indomethacin on bone remodelling in rabbit ear chambers. Acta Orthop Scand Suppl 160:91–115PubMed
16.
Sudmann E, Hagen T (1976) Indomethacin-induced delayed fracture healing. Arch Orthop Unfallchir 85:151–154CrossRefPubMed
17.
Bo J, Sudmann E, Marton PF (1976) Effect of indomethacin on fracture healing in rats. Acta Orthop Scand 47:588–599PubMed
18.
Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA (2003) Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem 88:873–884CrossRefPubMed
19.
Norrdin RW, Jee WS, High WB (1990) The role of prostaglandins in bone in vivo. Prostaglandins Leukot Essent Fatty Acids 41:139–149CrossRefPubMed
20.
Feyen JH, Di Bon A, van der Plas A, Lowik CW, Nijweide PJ (1985) Effects of exogenous prostanoids on the proliferation of osteoblast-like cells in vitro. Prostaglandins 30:827–840CrossRefPubMed
21.
Flanagan AM, Chambers TJ (1992) Stimulation of bone nodule formation in vitro by prostaglandins E1 and E2. Endocrinology 130:443–448CrossRefPubMed
22.
Hakeda Y, Nakatani Y, Hiramatsu M, Kurihara N, Tsunoi M, Ikeda E, Kumegawa M (1985) Inductive effects of prostaglandins on alkaline phosphatase in osteoblastic cells, clone MC3T3-E1. J Biochem (Tokyo) 97:97–104
23.
Liu XH, Kirschenbaum A, Yao S, Levine AC (2006) Interactive effect of interleukin-6 and prostaglandin E2 on osteoclastogenesis via the OPG/RANKL/RANK system. Ann NY Acad Sci 1068:225–233CrossRefPubMed
24.
Keller J, Klamer A, Bak B, Suder P (1993) Effect of local prostaglandin E2 on fracture callus in rabbits. Acta Orthop Scand 64:59–63PubMed
25.
Hakeda Y, Harada S, Matsumoto T, Tezuka K, Higashino K, Kodama H, Hashimoto-Goto T, Ogata E, Kumegawa M (1991) Prostaglandin F2 alpha stimulates proliferation of clonal osteoblastic MC3T3-E1 cells by up-regulation of insulin-like growth factor I receptors. J Biol Chem 266:21044–21050PubMed
26.
Hakeda Y, Hotta T, Kurihara N, Ikeda E, Maeda N, Yagyu Y, Kumegawa M (1987) Prostaglandin E1 and F2 alpha stimulate differentiation and proliferation, respectively, of clonal osteoblastic MC3T3-E1 cells by different second messengers in vitro. Endocrinology 121:1966–1974CrossRefPubMed
27.
Raisz LG, Alander CB, Fall PM, Simmons HA (1990) Effects of prostaglandin F2 alpha on bone formation and resorption in cultured neonatal mouse calvariae: role of prostaglandin E2 production. Endocrinology 126:1076–1079CrossRefPubMed
28.
Tokuda H, Oiso Y, Kozawa O (1992) Protein kinase C activation amplifies prostaglandin F2 alpha-induced prostaglandin E2 synthesis in osteoblast-like cells. J Cell Biochem 48:262–268CrossRefPubMed
29.
Tokuda H, Harada A, Hirade K, Matsuno H, Ito H, Kato K, Oiso Y, Kozawa O (2003) Incadronate amplifies prostaglandin F2 alpha-induced vascular endothelial growth factor synthesis in osteoblasts. Enhancement of MAPK activity. J Biol Chem 278:18930–18937CrossRefPubMed
30.
Saadeh PB, Mehrara BJ, Steinbrech DS, Dudziak ME, Greenwald JA, Luchs JS, Spector JA, Ueno H, Gittes GK, Longaker MT (1999) Transforming growth factor-beta-1 modulates the expression of vascular endothelial growth factor by osteoblasts. Am J Physiol 277:C628–C637PubMed
31.
Street J, Winter D, Wang JH, Wakai A, McGuinness A, Redmond HP (2000) Is human fracture hematoma inherently angiogenic? Clin Orthop Relat Res 378:224–237CrossRefPubMed
32.
Street J, Bao M, de Guzman L, Bunting S, Peale FV Jr, Ferrara N, Steinmetz H, Hoeffel J, Cleland JL, Daugherty A, van Bruggen N, Redmond HP, Carano RA, Filvaroff EH (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA 99:9656–9661CrossRefPubMed
33.
Tsushita K, Kozawa O, Tokuda H, Oiso Y, Saito H (1992) Proliferative effect of PGD2 on osteoblast-like cells; independent activation of pertussis toxin-sensitive GTP-binding protein from PGE2 or PGF2 alpha. Prostaglandins Leukot Essent Fatty Acids 45:267–274CrossRefPubMed
34.
Koshihara Y, Kawamura M (1989) Prostaglandin D2 stimulates calcification of human osteoblastic cells. Biochem Biophys Res Commun 159:1206–1212CrossRefPubMed
35.
Tasaki Y, Takamori R, Koshihara Y (1991) Prostaglandin D2 metabolite stimulates collagen synthesis by human osteoblasts during calcification. Prostaglandins 41:303–313CrossRefPubMed
36.
Gallant MA, Samadfam R, Hackett JA, Antoniou J, Parent JL, de Brum-Fernandes AJ (2005) Production of prostaglandin D2 by human osteoblasts and modulation of osteoprotegerin, RANKL, and cellular migration by DP and CRTH2 receptors. J Bone Miner Res 20:672–681CrossRefPubMed
37.
Sakai T, Yamaguchi N, Shiroko Y, Sekiguchi M, Fujii G, Nishino H (1984) Prostaglandin D2 inhibits the proliferation of human malignant tumor cells. Prostaglandins 27:17–26CrossRefPubMed
38.
Bennett A, Edwards D, Ali NN, Auger D, Harris M (1980) Prostacyclin potently resorbs bone in vitro. Adv Prostaglandin Thromboxane Res 6:547–548PubMed
39.
Dewhirst FE (1984) 6-Keto-prostaglandin E1-stimulated bone resorption in organ culture. Calcif Tissue Int 36:380–383CrossRefPubMed
40.
Raisz LG, Vanderhoek JY, Simmons HA, Kream BE, Nicolaou KC (1979) Prostaglandin synthesis by fetal rat bone in vitro: evidence for a role of prostacyclin. Prostaglandins 17:905–914CrossRefPubMed
41.
Hanson ES, Rawlins ML, Leibold EA (2003) Oxygen and iron regulation of iron regulatory protein 2. J Biol Chem 278:40337–40342CrossRefPubMed
42.
Wang GL, Semenza GL (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 90:4304–4308CrossRefPubMed
43.
Scutt A, Bertram P (1995) Bone marrow cells are targets for the anabolic actions of prostaglandin E2 on bone: induction of a transition from nonadherent to adherent osteoblast precursors. J Bone Miner Res 10:474–487PubMedCrossRef
44.
Scutt A, Zeschnigk M, Bertram P (1995) PGE2 induces the transition from non-adherent to adherent bone marrow mesenchymal precursor cells via a cAMP/EP2-mediated mechanism. Prostaglandins 49:383–395CrossRefPubMed
45.
Scutt A, Bertram P, Brautigam M (1996) The role of glucocorticoids and prostaglandin E2 in the recruitment of bone marrow mesenchymal cells to the osteoblastic lineage: positive and negative effects. Calcif Tissue Int 59:154–162CrossRefPubMed
46.
Zhang X, Schwarz EM, Young DA, Puzas JE, Rosier RN, O’Keefe RJ (2002) Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest 109:1405–1415PubMed
47.
Hall BK, Miyake T (1995) Divide, accumulate, differentiate: cell condensation in skeletal development revisited. Int J Dev Biol 39:881–893PubMed
48.
Nwadinigwe CU, Anyaehie UE (2007) Effects of cyclooxygenase inhibitors on bone and cartilage metabolism: a review. Niger J Med 16:290–294PubMed
49.
Vuolteenaho K, Moilanen T, Moilanen E (2008) Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process. Basic Clin Pharmacol Toxicol 102:10–14PubMed
50.
Urade Y, Hayaishi O (2000) Prostaglandin D synthase: structure and function. Vitam Horm 58:89–120CrossRefPubMed
51.
Pilbeam CC, Kawaguchi H, Hakeda Y, Voznesensky O, Alander CB, Raisz LG (1993) Differential regulation of inducible and constitutive prostaglandin endoperoxide synthase in osteoblastic MC3T3-E1 cells. J Biol Chem 268:25643–25649PubMed
52.
53.
Okiji T, Morita I, Kawashima N, Kosaka T, Suda H, Murota S (1993) Immunohistochemical detection of prostaglandin I2 synthase in various calcified tissue-forming cells in rat. Arch Oral Biol 38:31–36CrossRefPubMed
54.
Kawaguchi H, Yasuda H (1988) Prostacyclin biosynthesis and phospholipase activity in hypoxic rat myocardium. Circ Res 62:1175–1181PubMed
55.
Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337–1340CrossRefPubMed
56.
Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54CrossRefPubMed
57.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468CrossRefPubMed
58.
Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 20:5197–5206CrossRefPubMed
59.
Yu F, White SB, Zhao Q, Lee FS (2001) HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci USA 98:9630–9635CrossRefPubMed
60.
Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-αlpha to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472CrossRefPubMed
61.
Suda M, Tanaka K, Yasoda A, Natsui K, Sakuma Y, Tanaka I, Ushikubi F, Narumiya S, Nakao K (1998) Prostaglandin E2 (PGE2) autoamplifies its production through EP1 subtype of PGE receptor in mouse osteoblastic MC3T3-E1 cells. Calcif Tissue Int 62:327–331CrossRefPubMed
Metadata
Title
Prostaglandin expression profile in hypoxic osteoblastic cells
Authors
Christina M. Lee
Damian C. Genetos
Alice Wong
Clare E. Yellowley
Publication date
01-01-2010
Publisher
Springer Japan
Published in
Journal of Bone and Mineral Metabolism / Issue 1/2010
Print ISSN: 0914-8779
Electronic ISSN: 1435-5604
DOI
https://doi.org/10.1007/s00774-009-0096-0

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