Reduced COX-2 expression in aged mice is associated with impaired fracture healing

Journal of Bone and Mineral Research

Volumn 24, Issue 2, 2009, Pages 251-264

  Naik, Amish A ^a   Xie, Chao ^a   Zuscik, Michael J ^a   Kingsley, Paul ^a   Schwarz, Edward M ^a   Awad, Hani ^a   Guldberg, Robert ^b   Drissi, Hicham ^c   Puzas, J Edward ^a   Boyce, Brendan ^a   Zhang, Xinping ^a   O'Keefe, Regis J ^a  

^a UNIVERSITY OF ROCHESTER MEDICAL CENTER   (United States)

^b GEORGIA INSTITUTE OF TECHNOLOGY   (United States)

^c UNIVERSITY OF CONNECTICUT   (United States)

Author keywords

Aging; Cyclooxygenases; Endochondral ossification; Fracture; Prostaglandin E2

Indexed keywords

BIOLOGICAL MARKER; CYCLOOXYGENASE 2;

AGING; ANGIOGENESIS; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE REMODELING; CALLUS; CARTILAGE; CHONDROGENESIS; COL 2 GENE; CONTROLLED STUDY; COX 2 GENE; FEMALE; FEMUR FRACTURE; FRACTURE NONUNION; GENE; HISTOLOGY; IMMUNOHISTOCHEMISTRY; IN SITU HYBRIDIZATION; MESENCHYMAL STEM CELL; MOUSE; NONHUMAN; OSSIFICATION; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION;

AGING; ANIMALS; BONE REMODELING; BONY CALLUS; CHONDROGENESIS; CYCLOOXYGENASE 2; FEMALE; FRACTURE HEALING; FRACTURES, BONE; GENE EXPRESSION REGULATION; MICE; MICE, INBRED C57BL; NEOVASCULARIZATION, PHYSIOLOGIC; OSTEOCLASTS; OSTEOGENESIS; PHENOTYPE; PROTEIN TRANSPORT; RANK LIGAND; RECEPTORS, PROSTAGLANDIN E; STEM CELLS;

EID: 58649121014     PISSN: 08840431     EISSN: None     Source Type: Journal    
DOI: 10.1359/jbmr.081002     Document Type: Article

References (68)

1. Nieminen S, Nurmi M, Satokari K 1981 Healing of femoral neck fractures; influence of fracture reduction and age. Ann Chir Gynaecol 70:26-31.
2. Hammer R, Edholm P, Lindholm B 1984 Stability of union after tibial shaft fracture. Analysis by a non-invasive technique. J Bone Joint Surg Br 66:529-534.
3. Nilsson BE, Edwards P 1969 Age and fracture healing: A statistical analysis of 418 cases of tibial shaft fractures. Geriatrics 24:112-117.
4. Hee HT, Wong HP, Low YP, Myers L 2001 Predictors of outcome of floating knee injuries in adults: 89 patients followed for 2-12 years. Acta Orthop Scand 72:385-394.
5. Skak SV, Jensen TT 1988 Femoral shaft fracture in 265 children. Log-normal correlation with age of speed of healing. Acta Orthop Scand 59:704-707.
6. Rubin C, Bolander M, Ryaby JP, Hadjiargyrou M 2001 The use of low-intensity ultrasound to accelerate the healing of fractures. J Bone Joint Surg Am 83:259-270.
7. Meyer RA Jr, Meyer MH, Tenholder M, Wondracek S, Wasserman R Garges P 2003 Gene expression in older rats with delayed union of femoral fractures. J Bone Joint Surg Am 85-A:1243-1254.
8. Uusitalo H, Salminen H, Vuorio E 2001 Activation of chondrogenesis in response to injury in normal and transgenic mice with cartilage collagen mutations. Osteoarthritis Cartilage 9(Suppl A):S174-S179.
9. Lu C, Miclau T, Hu D, Hansen E, Tsui K, Puttlitz C, Marcucio RS 2005 Cellular basis for age-related changes in fracture repair. J Orthop Res 23:1300-1307.
10. Zhang X, Naik A, Xie C, Reynolds D, Palmer J, Lin A, Awad H, Guldberg R, Schwarz E, O'Keefe R 2005 Periosteal stem cells are essential for bone revitalization and repair. J Musculoskelet Neuronal Interact 5:360-362.
11. Skripitz R, Andreassen TT, Aspenberg P 2000 Parathyroid hormone (1-34) increases the density of rat cancellous bone in a bone chamber. A dose-response study. J Bone Joint Surg Br 82:138-141.
12. Kim HK, Bian H, Randall T, Garces A, Gerstenfeld LC, Einhorn TA 2004 Increased VEGF expression in the epiphyseal cartilage after ischemic necrosis of the capital femoral epiphysis. J Bone Miner Res 19:2041-2048.
13. Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane D, Einhorn TA 2003 Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res 21:670-675.
14. Einhorn TA 2003 Cox-2: Where are we in 2003? The role of cyclooxygenase-2 in bone repair. Arthritis Res Ther 5:5-7.
15. Lewinson D, Bialik GM, Hochberg Z 1994 Differential effects of hypothyroidism on the cartilage and the osteogenic process in the mandibular condyle: Recovery by growth hormone and thyroxine. Endocrinology 135:1504-1510.
16. Hayami T, Endo N, Tokunaga K, Yamagiwa H, Hatano H, Uchida M, Takahashi HE 2000 Spatiotemporal change of rat collagenase (MMP-13) mRNA expression in the development of the rat femoral neck. J Bone Miner Metab 18:185-193.
17. Einhorn TA 2002 Do inhibitors of cyclooxygenase-2 impair bone healing? J Bone Miner Res 17:977-978.
18. Simon AM, Manigrasso MB, O'Connor JP 2002 Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res 17:963-976.
19. 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 109:1405-1415.
20. Wei X, Zhang X, Zuscik MJ, Drissi MH, Schwarz EM, O'Keefe RJ 2005 Fibroblasts express RANKL and support osteoclastogenesis in a COX-2-dependent manner after stimulation with titanium particles. J Bone Miner Res 20:1136-1148.
21. Radi ZA, Khan NK 2005 Effects of cyclooxygenase inhibition on bone, tendon, and ligament healing. Inflamm Res 54:358-366.
22. Li L, Pettit AR, Gregory LS, Forwood MR 2006 Regulation of bone biology by prostaglandin endoperoxide H synthases (PGHS): A rose by any other name. Cytokine Growth Factor Rev 17:203-216.
23. Clark CA, Schwarz EM, Zhang X, Ziran NM, Drissi H, O'Keefe RJ, Zuscik MJ 2005 Differential regulation of EP receptor isoforms during chondrogenesis and chondrocyte maturation. Biochem Biophys Res Commun 328:764-776.
24. Chikazu D, Li X, Kawaguchi H, Sakuma Y, Voznesensky OS, Adams DJ, Xu M, Hoshio K, Katavic V, Herschman HR, Raisz LG, Pilbeam CC 2002 Bone morphogenetic protein 2 induces cyclo-oxygenase 2 in osteoblasts via a Cbfa1 binding site: Role in effects of bone morphogenetic protein 2 in vitro and in vivo. J Bone Miner Res 17:1430-1440.
25. Zhang X, Xie C, Lin AS, Ito H, Awad H, Lieberman JR, Rubery PT, Schwarz EM, O'Keefe RJ, Guldberg RE 2005 Periosteal progenitor cell fate in segmental cortical bone graft transplantations: Implications for functional tissue engineering. J Bone Miner Res 20:2124-2137.
26. Yoshida K, Oida H, Kobayashi T, Maruyama T, Tanaka M, Katayama T, Yamaguchi K, Segi E, Tsuboyama T, Matsushita M, Ito K, Ito Y, Sugimoto Y, Ushikubi F, Ohuchida S, Kondo K, Nakamura T, Narumiya S 2002 Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation. Proc Natl Acad Sci USA 99:4580-4585.
27. Bonnarens F, Einhorn TA 1984 Production of a standard closed fracture in laboratory animal bone. J Orthop Res 2:97-101.
28. Quinn JM, Horwood NJ, Elliott J, Gillespie MT, Martin TJ 2000 Fibroblastic stromal cells express receptor activator of NF-kappa B ligand and support osteoclast differentiation. J Bone Miner Res 15:1459-1466.
29. Nakazawa T, Nakajima A, Shiomi K, Moriya H, Einhorn TA, Yamazaki M 2005 Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing. Bone 37:711-719.
30. Ferguson C, Alpern E, Miclau T, Helms JA 1999 Does adult fracture repair recapitulate embryonic skeletal formation? Mech Dev 87:57-66.
31. Mungo DV, Zhang X, O'Keefe RJ, Rosier RN, Puzas JE, Schwarz EM 2002 COX-1 and COX-2 expression in osteoid osteomas. J Orthop Res 20:159-162.
32. Sapirstein A, Saito H, Texel SJ, Samad TA, O'Leary E, Bonventre JV 2005 Cytosolic phospholipase A2alpha regulates induction of brain cyclooxygenase-2 in a mouse model of inflammation. Am J Physiol Regul Integr Comp Physiol 288:R1774-R1782.
33. Maes C, Carmeliet P, Moermans K, Stockmans I, Smets N, Collen D, Bouillon R, Carmeliet G 2002 Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev 111:61-73.
34. Goldring MB, Tsuchimochi K, Ijiri K 2006 The control of chondrogenesis. J Cell Biochem 97:33-44.
35. Stanka P, Bellack U, Lindner A 1991 On the morphology of the terminal microvasculature during endochondral ossification in rats. Bone Miner 13:93-101.
36. Li M, Healy DR, Li Y, Simmons HA, Crawford DT, Ke HZ, Pan LC, Brown TA, Thompson DD 2005 Osteopenia and impaired fracture healing in aged EP4 receptor knockout mice. Bone 37:46-54.
37. 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 88:873-884.
38. Dong YF, Soung do Y, Schwarz EM, O'Keefe RJ, Drissi H 2006 Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor. J Cell Physiol 208:77-86.
39. Zheng Q, Zhou G, Morello R, Chen Y, Garcia-Rojas X, Lee B 2003 Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J Cell Biol 162:833-842.
40. Lu C, Miclau T, Hu D, Hansen E, Tsui K, Puttlitz C, Marcucio RS 2005 Cellular basis for age-related changes in fracture repair. J Orthop Res 23:1300-1307.
41. Beale BS 2005 Orthopedic problems in geriatric dogs and cats. Vet Clin North Am Small Anim Pract 35:655-674.
42. Meyer RA Jr, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM 2001 Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res 19:428-435.
43. O'Keefe RJ, Tiyapatanaputi P, Xie C, Li TF, Clark C, Zuscik MJ, Chen D, Drissi H, Schwarz E, Zhang X 2006 COX-2 has a critical role during incorporation of structural bone allografts. Ann N Y Acad Sci 1068:532-542.
44. Robertson G, Xie C, Chen D, Awad H, Schwarz EM, O'Keefe RJ, Guldberg RE, Zhang X 2006 Alteration of femoral bone morphology and density in COX-2-/- mice. Bone 39:767-772.
45. Pino MS, Nawrocki ST, Cognetti F, Abruzzese JL, Xiong HQ, McConkey DJ 2005 Prostaglandin E2 drives cyclooxygenase-2 expression via cyclic AMP response element activation in human pancreatic cancer cells. Cancer Biol Ther 4:1263-1269.
46. Zhang X, Morham SG, Langenbach R, Young DA, Xing L, Boyce BF, Puzas EJ, Rosier RN, O'Keefe RJ, Schwarz EM 2001 Evidence for a direct role of cyclo-oxygenase 2 in implant wear debris-induced osteolysis. J Bone Miner Res 16:660-670.
47. Li TF, Zuscik MJ, Ionescu AM, Zhang X, Rosier RN, Schwarz EM, Drissi H, O'Keefe RJ 2004 PGE2 inhibits chondrocyte differentiation through PKA and PKC signaling. Exp Cell Res 300:159-169.
48. Zhang X, Ziran N, Goater JJ, Schwarz EM, Puzas JE, Rosier RN, Zuscik M, Drissi H, O'Keefe RJ 2004 Primary murine limb bud mesenchymal cells in long-term culture complete chondrocyte differentiation: TGF-beta delays hypertrophy and PGE2 inhibits terminal differentiation. Bone 34:809-817.
49. Arikawa T, Omura K, Morita I 2004 Regulation of bone morphogenetic protein-2 expression by endogenous prostaglandin E2 in human mesenchymal stem cells. J Cell Physiol 200:400-406.
50. Takiguchi T, Kobayashi M, Nagashima C, Yamaguchi A, Nishihara T, Hasegawa K 1999 Effect of prostaglandin E2 on recombinant human bone morphogenetic proteins-stimulated osteoblastic differentiation in human periodontal ligament cells. J Periodontal Res 34:431-436.
51. Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V 2006 BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet 38:1424-1429.
52. Hagino H, Kuraoka M, Kameyama Y, Okano T, Teshima R 2005 Effect of a selective agonist for prostaglandin E receptor subtype EP4 (ONO-4819) on the cortical bone response to mechanical loading. Bone 36:444-453.
53. Ito M, Nakayama K, Konaka A, Sakata K, Ikeda K, Maruyama T 2006 Effects of a prostaglandin EP4 agonist, ONO-4819, and risedronate on trabecular microstructure and bone strength in mature ovariectomized rats. Bone 39:453-459.
54. Shamir D, Keila S, Weinreb M 2004 A selective EP4 receptor antagonist abrogates the stimulation of osteoblast recruitment from bone marrow stromal cells by prostaglandin E2 in vivo and in vitro. Bone 34:157-162.
55. Nakajima M, Negishi Y, Tanaka H, Kawashima K 2004 p21(Cip-1/SDI-1/WAF-1) expression via the mitogen-activated protein kinase signaling pathway in insulin-induced chondrogenic differentiation of ATDC5 cells. Biochem Biophys Res Commun 320:1069-1075.
56. Toyoda H, Terai H, Sasaoka R, Oda K, Takaoka K 2005 Augmentation of bone morphogenetic protein-induced bone mass by local delivery of a prostaglandin E EP4 receptor agonist. Bone 37:555-562.
57. Miyamoto M, Ito H, Mukai S, Kobayashi T, Yamamoto H, Kobayashi M, Maruyama T, Akiyama H, Nakamura T 2003 Simultaneous stimulation of EP2 and EP4 is essential to the effect of prostaglandin E2 in chondrocyte differentiation. Osteoarthritis Cartilage 11:644-652.
58. 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 1068:225-233.
59. Kobayashi T, Lyons KM, McMahon AP, Kronenberg HM 2005 BMP signaling stimulates cellular differentiation at multiple steps during cartilage development. Proc Natl Acad Sci USA 102:18023-18027.
60. Usui M, Xing L, Drissi H, Zuscik M, O'Keefe R, Chen D, Boyce BF 2008 Murine and chicken chondrocytes regulate osteoclastogenesis by producing RANKL in response to BMP2. J Bone Miner Res 23:314-325.
61. Weinreb M, Grosskopf A, Shir N 1999 The anabolic effect of PGE2 in rat bone marrow cultures is mediated via the EP4 receptor subtype. Am J Physiol 276:E376-E383.
62. Nakagawa K, Imai Y, Ohta Y, Takaoka K 2007 Prostaglandin E2 EP4 agonist (ONO-4819) accelerates BMP-induced osteoblastic differentiation. Bone 41:543-548.
63. Cameron KO, Lefker BA, Chu-Moyer MY, Crawford DT, Jardine PD, DeNinno SL, Gilbert S, Crasser WA, Ke H, Lu B, Owen TA, Paralkar VM, Qi H, Scott DO, Thompson DD, Tjoa CM, Zawistoski MP 2006 Discovery of highly selective EP4 receptor agonists that stimulate new bone formation and restore bone mass in ovariectomized rats. Bioorg Med Chem Lett 16:1799-1802.
64. Aguirre JI, Leal ME, Rivera MF, Vanegas SM, Jorgensen M, Wronski TJ 2007 Effects of basic fibroblast growth factor and a prostaglandin E2 receptor subtype 4 agonist on osteoblastogenesis and adipogenesis in aged ovariectomized rats. J Bone Miner Res 22:877-888.
65. Li TF, Dong Y, Ionescu AM, Rosier RN, Zuscik MJ, Schwarz EM, O'Keefe RJ, Drissi H 2004 Parathyroid hormone-related peptide (PTHrP) inhibits Runx2 expression through the PKA signaling pathway. Exp Cell Res 299:128-136.
66. Minina E, Kreschel C, Naski MC, Ornitz DM, Vortkamp A 2002 Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev Cell 3:439-449.
67. Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP, Vortkamp A 2001 BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development 128:4523-4534.
68. Ogita M, Rached MT, Dworakowski E, Bilezikian JP, Kousteni S 2008 Differentiation and Proliferation of Periosteal Osteoblast Progenitors are Differentially Regulated by Estrogens and Intermittent PTH Administration. Endocrinology 149:5713-5723.