Reduced COX-2 Expression in Aged Mice Is Associated With Impaired Fracture Healing

Abstract

The cellular and molecular events responsible for reduced fracture healing with aging are unknown. Cyclooxygenase 2 (COX-2), the inducible regulator of prostaglandin E2 (PGE2) synthesis, is critical for normal bone repair. A femoral fracture repair model was used in mice at either 7–9 or 52–56 wk of age, and healing was evaluated by imaging, histology, and gene expression studies. Aging was associated with a decreased rate of chondrogenesis, decreased bone formation, reduced callus vascularization, delayed remodeling, and altered expression of genes involved in repair and remodeling. COX-2 expression in young mice peaked at 5 days, coinciding with the transition of mesenchymal progenitors to cartilage and the onset of expression of early cartilage markers. In situ hybridization and immunohistochemistry showed that COX-2 is expressed primarily in early cartilage precursors that co-express col-2.COX-2 expression was reduced by 75% and 65% in fractures from aged mice compared with young mice on days 5 and 7, respectively. Local administration of an EP4 agonist to the fracture repair site in aged mice enhanced the rate of chondrogenesis and bone formation to levels observed in young mice, suggesting that the expression of COX-2 during the early inflammatory phase of repair regulates critical subsequent events including chondrogenesis, bone formation, and remodeling. The findings suggest that COX-2/EP4 agonists may compensate for deficient molecular signals that result in the reduced fracture healing associated with aging.

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References 68

1. 1.

   Nieminen S, Nurmi M, Satokari K. Healing of femoral neck fractures; influence of fracture reduction and age. Ann Chir Gynaecol. 1981;70:26-31.

   Not in our library

2. 2.

   Hammer R, Edholm P, Lindholm B. Stability of union after tibial shaft fracture. Analysis by a non-invasive technique. J Bone Joint Surg Br. 1984;66:529-534.

   Not in our library10.1302/0301-620x.66b4.6746687

3. 3.

   Nilsson BE, Edwards P. Age and fracture healing: A statistical analysis of 418 cases of tibial shaft fractures. Geriatrics. 1969;24:112-117.

   Not in our library

4. 4.

   Hee HT, Wong HP, Low YP, Myers L. Predictors of outcome of floating knee injuries in adults: 89 patients followed for 2–12 years. Acta Orthop Scand. 2001;72:385-394.

   Not in our library10.1080/000164701753542050

5. 5.

   Skak SV, Jensen TT. Femoral shaft fracture in 265 children. Log-normal correlation with age of speed of healing. Acta Orthop Scand. 1988;59:704-707.

   Not in our library10.3109/17453678809149430

6. 6.

   Rubin C, Bolander M, Ryaby JP, Hadjiargyrou M. The use of low-intensity ultrasound to accelerate the healing of fractures. J Bone Joint Surg Am. 2001;83:259-270.

   Not in our library10.2106/00004623-200102000-00015

7. 7.

   Meyer RA, Meyer MH, Tenholder M, Wondracek S, Wasserman R, Garges P. Gene expression in older rats with delayed union of femoral fractures. J Bone Joint Surg Am. 2003;85-A:1243-1254.

   Not in our library10.2106/00004623-200307000-00010

8. 8.

   Uusitalo H, Salminen H, Vuorio E. Activation of chondrogenesis in response to injury in normal and transgenic mice with cartilage collagen mutations. Osteoarthritis Cartilage. 2001;9(Suppl A):S174-S179.

   Not in our library

9. 9.

   Lu C, Miclau T, Hu D, Hansen E, Tsui K, Puttlitz C, Marcucio RS. Cellular basis for age-related changes in fracture repair. J Orthop Res. 2005;23:1300-1307.

   Not in our library10.1016/j.orthres.2005.04.003.1100230610

10. 10.

    Zhang X, Naik A, Xie C, Reynolds D, Palmer J, Lin A, Awad H, Guldberg R, Schwarz E, O'Keefe R. Periosteal stem cells are essential for bone revitalization and repair. J Musculoskelet Neuronal Interact. 2005;5:360-362.

    Not in our library

11. 11.

    Skripitz R, Andreassen TT, Aspenberg P. Parathyroid hormone (1–34) increases the density of rat cancellous bone in a bone chamber. A dose-response study. J Bone Joint Surg Br. 2000;82:138-141.

    Not in our library10.1302/0301-620x.82b1.9729

12. 12.

    Kim HK, Bian H, Randall T, Garces A, Gerstenfeld LC, Einhorn TA. Increased VEGF expression in the epiphyseal cartilage after ischemic necrosis of the capital femoral epiphysis. J Bone Miner Res. 2004;19:2041-2048.

    Not in our library10.1359/jbmr.040911

13. 13.

    Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane D, Einhorn TA. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res. 2003;21:670-675.

    Not in our library10.1016/s0736-0266(03)00003-2

14. 14.

    Einhorn TA. Cox-2: Where are we in 2003? The role of cyclooxygenase-2 in bone repair. Arthritis Res Ther. 2003;5:5-7.

    Not in our library10.1186/ar607

15. 15.

    Lewinson D, Bialik GM, Hochberg Z. Differential effects of hypothyroidism on the cartilage and the osteogenic process in the mandibular condyle: Recovery by growth hormone and thyroxine. Endocrinology. 1994;135:1504-1510.

    Not in our library10.1210/endo.135.4.7925111

16. 16.

    Hayami T, Endo N, Tokunaga K, Yamagiwa H, Hatano H, Uchida M, Takahashi HE. Spatiotemporal change of rat collagenase (MMP-13) mRNA expression in the development of the rat femoral neck. J Bone Miner Metab. 2000;18:185-193.

    Not in our library10.1007/s007740070019

17. 17.

    Einhorn TA. Do inhibitors of cyclooxygenase-2 impair bone healing. J Bone Miner Res. 2002;17:977-978.

    Not in our library10.1359/jbmr.2002.17.6.977

18. 18.

    Simon AM, Manigrasso MB, O'Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res. 2002;17:963-976.

    Not in our library10.1359/jbmr.2002.17.6.963

19. 19.

    Zhang X, Schwarz EM, Young DA, Puzas JE, Rosier RN, O'Keefe RJ. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest. 2002;109:1405-1415.

    Not in our library10.1172/jci15681

20. 20.

    Wei X, Zhang X, Zuscik MJ, Drissi MH, Schwarz EM, O'Keefe RJ. Fibroblasts express RANKL and support osteoclastogenesis in a COX-2-dependent manner after stimulation with titanium particles. J Bone Miner Res. 2005;20:1136-1148.

    Not in our library10.1359/jbmr.050206

21. 21.

    Radi ZA, Khan NK. Effects of cyclooxygenase inhibition on bone, tendon, and ligament healing. Inflamm Res. 2005;54:358-366.

    Not in our library10.1007/s00011-005-1367-4

22. 22.

    Li L, Pettit AR, Gregory LS, Forwood MR. Regulation of bone biology by prostaglandin endoperoxide H synthases (PGHS): A rose by any other name. Cytokine Growth Factor Rev. 2006;17:203-216.

    Not in our library10.1016/j.cytogfr.2006.01.005

23. 23.

    Clark CA, Schwarz EM, Zhang X, Ziran NM, Drissi H, O'Keefe RJ, Zuscik MJ. Differential regulation of EP receptor isoforms during chondrogenesis and chondrocyte maturation. Biochem Biophys Res Commun. 2005;328:764-776.

    Not in our library10.1016/j.bbrc.2004.11.074

24. 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. Bone morphogenetic protein 2 induces cyclo-oxygenase 2 in osteoblasts via a Cbfal binding site: Role in effects of bone morphogenetic protein 2 in vitro and in vivo. J Bone Miner Res. 2002;17:1430-1440.

    Not in our library10.1359/jbmr.2002.17.8.1430

25. 25.

    Zhang X, Xie C, Lin AS, Ito H, Awad H, Lieberman JR, Rubery PT, Schwarz EM, O'Keefe RJ, Guldberg RE. Periosteal progenitor cell fate in segmental cortical bone graft transplantations: Implications for functional tissue engineering. J Bone Miner Res. 2005;20:2124-2137.

    Not in our library10.1359/jbmr.050806

26. 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. Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation. Proc Natl Acad Sci USA. 2002;99:4580-4585.

    Not in our library10.1073/pnas.062053399

27. 27.

    Bonnarens F, Einhorn TA. Production of a standard closed fracture in laboratory animal bone. J Orthop Res. 1984;2:97-101.

    Not in our library10.1002/jor.1100020115

28. 28.

    Quinn JM, Horwood NJ, Elliott J, Gillespie MT, Martin TJ. Fibroblastic stromal cells express receptor activator of NF-kappa B ligand and support osteoclast differentiation. J Bone Miner Res. 2000;15:1459-1466.

    Not in our library10.1359/jbmr.2000.15.8.1459

29. 29.

    Nakazawa T, Nakajima A, Shiomi K, Moriya H, Einhorn TA, Yamazaki M. Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1–34) on chondrogenesis in a model of experimental fracture healing. Bone. 2005;37:711-719.

    Not in our library10.1016/j.bone.2005.06.013

30. 30.

    Ferguson C, Alpern E, Miclau T, Helms JA. Does adult fracture repair recapitulate embryonic skeletal formation. Mech Dev. 1999;87:57-66.

    Not in our library10.1016/s0925-4773(99)00142-2

31. 31.

    Mungo DV, Zhang X, O'Keefe RJ, Rosier RN, Puzas JE, Schwarz EM. COX-1 and COX-2 expression in osteoid osteomas. J Orthop Res. 2002;20:159-162.

    Not in our library10.1016/s0736-0266(01)00065-1

32. 32.

    Sapirstein A, Saito H, Texel SJ, Samad TA, O'Leary E, Bonventre JV. Cytosolic phospholipase A2alpha regulates induction of brain cyclooxygenase-2 in a mouse model of inflammation. Am J Physiol Regul Integr Comp Physiol. 2005;288:R1774-R1782.

    Not in our library10.1152/ajpregu.00815.2004

33. 33.

    Maes C, Carmeliet P, Moermans K, Stockmans I, Smets N, Collen D, Bouillon R, Carmeliet G. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev. 2002;111:61-73.

    Not in our library10.1016/s0925-4773(01)00601-3

34. 34.

    Goldring MB, Tsuchimochi K, Ijiri K. The control of chondrogenesis. J Cell Biochem. 2006;97:33-44.

    Not in our library10.1002/jcb.20652

35. 35.

    Stanka P, Bellack U, Lindner A. On the morphology of the terminal microvasculature during endochondral ossification in rats. Bone Miner. 1991;13:93-101.

    Not in our library10.1016/0169-6009(91)90076-c

36. 36.

    Li M, Healy DR, Li Y, Simmons HA, Crawford DT, Ke HZ, Pan LC, Brown TA, Thompson DD. Osteopenia and impaired fracture healing in aged EP4 receptor knockout mice. Bone. 2005;37:46-54.

    Not in our library10.1016/j.bone.2005.03.016

37. 37.

    Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post-natal developmental process: Molecular, spatial, and temporal aspects of its regulation. J Cell Biochem. 2003;88:873-884.

    Not in our library10.1002/jcb.10435

38. 38.

    Dong YF, Soung do Y, Schwarz EM, O'Keefe RJ, Drissi H. Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor. J Cell Physiol. 2006;208:77-86.

    Not in our library10.1002/jcp.20656

39. 39.

    Zheng Q, Zhou G, Morello R, Chen Y, Garcia-Rojas X, Lee B. Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J Cell Biol. 2003;162:833-842.

    Not in our library10.1083/jcb.200211089

40. 40.

    Lu C, Miclau T, Hu D, Hansen E, Tsui K, Puttlitz C, Marcucio RS. Cellular basis for age-related changes in fracture repair. J Orthop Res. 2005;23:1300-1307.

    Not in our library10.1016/j.orthres.2005.04.003.1100230610

41. 41.

    Beale BS. Orthopedic problems in geriatric dogs and cats. Vet Clin North Am Small Anim Pract. 2005;35:655-674.

    Not in our library10.1016/j.cvsm.2005.01.001

42. 42.

    Meyer RA, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM. Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res. 2001;19:428-435.

    Not in our library10.1016/s0736-0266(00)90034-2

43. 43.

    O'Keefe RJ, Tiyapatanaputi P, Xie C, Li TF, Clark C, Zuscik MJ, Chen D, Drissi H, Schwarz E, Zhang X. COX-2 has a critical role during incorporation of structural bone allografts. Ann N Y Acad Sci. 2006;1068:532-542.

    Not in our library10.1196/annals.1346.012

44. 44.

    Robertson G, Xie C, Chen D, Awad H, Schwarz EM, O'Keefe RJ, Guldberg RE, Zhang X. Alteration of femoral bone morphology and density in COX-2−/− mice. Bone. 2006;39:767-772.

    Not in our library10.1016/j.bone.2006.04.006

45. 45.

    Pino MS, Nawrocki ST, Cognetti F, Abruzzese JL, Xiong HQ, McConkey DJ. Prostaglandin E2 drives cyclooxygenase-2 expression via cyclic AMP response element activation in human pancreatic cancer cells. Cancer Biol Ther. 2005;4:1263-1269.

    Not in our library10.4161/cbt.4.11.2138

46. 46.

    Zhang X, Morham SG, Langenbach R, Young DA, Xing L, Boyce BF, Puzas EJ, Rosier RN, O'Keefe RJ, Schwarz EM. Evidence for a direct role of cyclo-oxygenase 2 in implant wear debris-induced osteolysis. J Bone Miner Res. 2001;16:660-670.

    Not in our library10.1359/jbmr.2001.16.4.660

47. 47.

    Li TF, Zuscik MJ, Ionescu AM, Zhang X, Rosier RN, Schwarz EM, Drissi H, O'Keefe RJ. PGE2 inhibits chondrocyte differentiation through PKA and PKC signaling. Exp Cell Res. 2004;300:159-169.

    Not in our library10.1016/j.yexcr.2004.06.019

48. 48.

    Zhang X, Ziran N, Goater JJ, Schwarz EM, Puzas JE, Rosier RN, Zuscik M, Drissi H, O'Keefe RJ. Primary murine limb bud mesenchymal cells in long-term culture complete chondrocyte differentiation: TGF-beta delays hypertrophy and PGE2 inhibits terminal differentiation. Bone. 2004;34:809-817.

    Not in our library10.1016/j.bone.2003.12.026

49. 49.

    Arikawa T, Omura K, Morita I. Regulation of bone morphogenetic protein-2 expression by endogenous prostaglandin E2 in human mesenchymal stem cells. J Cell Physiol. 2004;200:400-406.

    Not in our library10.1002/jcp.20031

50. 50.

    Takiguchi T, Kobayashi M, Nagashima C, Yamaguchi A, Nishihara T, Hasegawa K. Effect of prostaglandin E2 on recombinant human bone morphogenetic protein-2-stimulated osteoblastic differentiation in human periodontal ligament cells. J Periodontal Res. 1999;34:431-436.

    Not in our library10.1111/j.1600-0765.1999.tb02278.x

51. 51.

    Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet. 2006;38:1424-1429.

    Not in our library10.1038/ng1916

52. 52.

    Hagino H, Kuraoka M, Kameyama Y, Okano T, Teshima R. Effect of a selective agonist for prostaglandin E receptor subtype EP4 (ONO-4819) on the cortical bone response to mechanical loading. Bone. 2005;36:444-453.

    Not in our library10.1016/j.bone.2004.12.013

53. 53.

    Ito M, Nakayama K, Konaka A, Sakata K, Ikeda K, Maruyama T. Effects of a prostaglandin EP4 agonist, ONO-4819, and risedronate on trabecular microstructure and bone strength in mature ovariectomized rats. Bone. 2006;39:453-459.

    Not in our library10.1016/j.bone.2006.02.054

54. 54.

    Shamir D, Keila S, Weinreb M. 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. 2004;34:157-162.

    Not in our library10.1016/j.bone.2003.09.008

55. 55.

    Nakajima M, Negishi Y, Tanaka H, Kawashima K. 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. 2004;320:1069-1075.

    Not in our library10.1016/j.bbrc.2004.06.057

56. 56.

    Toyoda H, Terai H, Sasaoka R, Oda K, Takaoka K. Augmentation of bone morphogenetic protein-induced bone mass by local delivery of a prostaglandin E EP4 receptor agonist. Bone. 2005;37:555-562.

    Not in our library10.1016/j.bone.2005.04.042

57. 57.

    Miyamoto M, Ito H, Mukai S, Kobayashi T, Yamamoto H, Kobayashi M, Maruyama T, Akiyama H, Nakamura T. Simultaneous stimulation of EP2 and EP4 is essential to the effect of prostaglandin E2 in chondrocyte differentiation. Osteoarthritis Cartilage. 2003;11:644-652.

    Not in our library10.1016/s1063-4584(03)00118-3

58. 58.

    Liu XH, Kirschenbaum A, Yao S, Levine AC. Interactive effect of interleukin-6 and prostaglandin E2 on osteoclastogenesis via the OPG/RANKL/RANK system. Ann NY Acad Sci. 2006;1068:225-233.

    Not in our library10.1196/annals.1346.047

59. 59.

    Kobayashi T, Lyons KM, McMahon AP, Kronenberg HM. BMP signaling stimulates cellular differentiation at multiple steps during cartilage development. Proc Natl Acad Sci USA. 2005;102:18023-18027.

    Not in our library10.1073/pnas.0503617102

60. 60.

    Usui M, Xing L, Drissi H, Zuscik M, O'Keefe R, Chen D, Boyce BF. Murine and chicken chondrocytes regulate osteoclastogenesis by producing RANKL in response to BMP2. J Bone Miner Res. 2008;23:314-325.

    Not in our library10.1359/jbmr.071025

61. 61.

    Weinreb M, Grosskopf A, Shir N. The anabolic effect of PGE2 in rat bone marrow cultures is mediated via the EP4 receptor subtype. Am J Physiol. 1999;276:E376-E383.

    Not in our library10.1152/ajpendo.1999.276.2.e376

62. 62.

    Nakagawa K, Imai Y, Ohta Y, Takaoka K. Prostaglandin E2 EP4 agonist (ONO-4819) accelerates BMP-induced osteoblastic differentiation. Bone. 2007;41:543-548.

    Not in our library10.1016/j.bone.2007.06.013

63. 63.

    Cameron KO, Lefker BA, Chu-Moyer MY, Crawford DT, Jardine PD, DeNinno SL, Gilbert S, Grasser WA, Ke H, Lu B, Owen TA, Paralkar VM, Qi H, Scott DO, Thompson DD, Tjoa CM, Zawistoski MP. Discovery of highly selective EP4 receptor agonists that stimulate new bone formation and restore bone mass in ovariectomized rats. Bioorg Med Chem Lett. 2006;16:1799-1802.

    Not in our library10.1016/j.bmcl.2006.01.018

64. 64.

    Aguirre JI, Leal ME, Rivera MF, Vanegas SM, Jorgensen M, Wronski TJ. 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. 2007;22:877-888.

    Not in our library10.1359/jbmr.070313

65. 65.

    Li TF, Dong Y, Ionescu AM, Rosier RN, Zuscik MJ, Schwarz EM, O'Keefe RJ, Drissi H. Parathyroid hormone-related peptide (PTHrP) inhibits Runx2 expression through the PKA signaling pathway. Exp Cell Res. 2004;299:128-136.

    Not in our library10.1016/j.yexcr.2004.05.025

66. 66.

    Minina E, Kreschel C, Naski MC, Ornitz DM, Vortkamp A. Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev Cell. 2002;3:439-449.

    Not in our library10.1016/s1534-5807(02)00261-7

67. 67.

    Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP, Vortkamp A. BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development. 2001;128:4523-4534.

    Not in our library10.1242/dev.128.22.4523

68. 68.

    Ogita M, Rached MT, Dworakowski E, Bilezikian JP, Kousteni S. Differentiation and Proliferation of Periosteal Osteoblast Progenitors are Differentially Regulated by Estrogens and Intermittent PTH Administration. Endocrinology. 2008;149:5713-5723.

    Not in our library10.1210/en.2008-0369

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