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Restoration of regenerative osteoblastogenesis in aged mice: Modulation of TNF

  1. Elizabeth C Wahl1,
  2. James Aronson2,
  3. Lichu Liu1,
  4. John L Fowlkes3,
  5. Kathryn M Thrailkill3,
  6. Robert C Bunn3,
  7. Robert A Skinner2,
  8. Mike J Miller1,
  9. Gael E Cockrell3,
  10. Lindsey M Clark3,
  11. Yang Ou3,
  12. Carlos M Isales4,
  13. Thomas M Badger5,
  14. Martin J Ronis6,
  15. John Sims7,
  16. Charles K Lumpkin Jr.3,*

Article first published online: 18 DEC 2009

DOI: 10.1359/jbmr.090708

Issue

Journal of Bone and Mineral Research

Journal of Bone and Mineral Research

Volume 25, Issue 1, pages 114–123, January 2010

Additional Information

How to Cite

Wahl, E. C., Aronson, J., Liu, L., Fowlkes, J. L., Thrailkill, K. M., Bunn, R. C., Skinner, R. A., Miller, M. J., Cockrell, G. E., Clark, L. M., Ou, Y., Isales, C. M., Badger, T. M., Ronis, M. J., Sims, J. and Lumpkin, C. K. (2010), Restoration of regenerative osteoblastogenesis in aged mice: Modulation of TNF. J Bone Miner Res, 25: 114–123. doi: 10.1359/jbmr.090708

Author Information

  1. 1

    Arkansas Children's Hospital Research Institute, Little Rock, AR, USA

  2. 2

    Department of Orthopedics, College of Medicine, University of Arkansas for Medical Sciences

  3. 3

    Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences

  4. 4

    Medical College of Georgia, Augusta, GA, USA

  5. 5

    Department of Physiology/Biophysics, College of Medicine, University of Arkansas for Medical Sciences

  6. 6

    Department of Pharmacology/Toxicology, College of Medicine, University of Arkansas for Medical Sciences

  7. 7

    Amgen, Seattle, WA, USA

*Arkansas Children's Hospital Research Institute, Slot 512-20B, 13 Children's Way, Little Rock, AR 72202, USA.

Publication History

  1. Issue published online: 20 JAN 2010
  2. Article first published online: 18 DEC 2009
  3. Manuscript Accepted: 1 JUL 2009
  4. Manuscript Revised: 18 MAY 2009
  5. Manuscript Received: 16 FEB 2009

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References

  • 1
    Gruber R, Koch H, Doll BA, Tegtmeier F, Einhorn TA, Hollinger JO. Fracture healing in the elderly patient. Exp Gerontol. 2006; 41: 1080–1093.
  • 2
    Meyer RA Jr, 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. 2003; 85A: 1243–1254.
  • 3
    Pasco JA, Sanders KM, Hoekstra FM, Henry MJ, Nicholson GC, Kotowicz MA. The human cost of fracture. Osteoporos Int. 2005; 16: 2046–2052.
  • 4
    Burgess E, Nanes MS. Osteoporosis in men: pathophysiology, evaluation, and therapy. Curr Opin Rheumatol. 2002; 14: 421–428.
  • 5
    Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA. Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res. 2008; 87: 107–118.
  • 6
    Silva MJ, Touhey DC. Bone formation after damaging in vivo fatigue loading results in recovery of whole-bone monotonic strength and increased fatigue life. J Orthop Res. 2007; 25: 252–261.
    Direct Link:
  • 7
    Wohl GR, Towler DA, Silva MJ. Stress fracture healing: fatigue loading of the rat ulna induces upregulation in expression of osteogenic and angiogenic genes that mimic the intramembranous portion of fracture repair. Bone. 2009; 44: 320–330.
  • 8
    Aronson J, Gao GG, Shen X, et al. Effect of aging on distraction osteogenesis in the rat. J Orthop Res. 2001; 19: 421–427.
    Direct Link:
  • 9
    Ronis MJJR, Aronson J, Gao GG, et al. Skeletal effects of developmental lead exposure in rats. Toxicol Sci. 2001; 62: 321–329.
  • 10
    Perrien DS, Wahl EC, Hogue WR, et al. IL-1 and TNF antagonists prevent inhibition of fracture healing by ethanol in rats. Toxicol Sci. 2004; 82: 656–660.
  • 11
    Thrailkill KM, Liu L, Wahl EC, et al. Bone formation is impaired in a model of type 1 diabetes. Diabetes. 2005; 54: 2875–2881.
  • 12
    Kanellopoulos AD, Soucacos PN. Management of nonunion with distraction osteogenesis. Injury. 2006; 37: S51–55.
  • 13
    Jain AK, Sinha S. Infected nonunion of the long bones. Clin Orthop Relat Res. 2005; 431: 57–65.
  • 14
    Aronson J. Experimental and clinical experience with distraction osteogenesis. Cleft Palate Craniofac J. 1994; 31: 473–481; discussion 481–282.
  • 15
    Fink B, Krieger M, Strauss JM, et al. Osteoneogenesis and its influencing factors during treatment with the Ilizarov method. Clin Orthop. 1996; 323: 261–272.
  • 16
    Maffulli N, Lombari C, Matarazzo L, Nele U, Pagnotta G, Fixsen JA. A review of 240 patients undergoing distraction osteogenesis for congenital post-traumatic or postinfective lower limb length discrepancy. J Am Coll Surg. 1996; 182: 394–402.
  • 17
    Tay BK, Le AX, Gould SE, Helms JA. Histochemical and molecular analyses of distraction osteogenesis in a mouse model. J Orthop Res. 1998; 16: 636–642.
    Direct Link:
  • 18
    Aronson J, Shen XC, Skinner RA, Hogue WR, Badger TM, Lumpkin CK Jr. A rat model of distraction osteogenesis. J Orthop Res. 1997; 15: 221–226.
    Direct Link:
  • 19
    Aronson J, Liu L, Liu Z, et al. Decreased endosteal intramembranous bone formation accompanies aging in a mouse model of distraction osteogenesis. J Regen Med. 2002; 3: 7–16.
  • 20
    Franceschi C, Bonafe M, Valensin S, et al. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann NY Acad Sci. 2000; 908: 244–254.
  • 21
    Takayanagi H. Inflammatory bone destruction and osteoimmunology. J Periodontal Res. 2005; 40: 287–293.
    Direct Link:
  • 22
    Nanes MS. tumor necrosis factor-alpha: molecular and cellular mechanisms in skeletal pathology. Gene. 2003; 321: 1–15.
  • 23
    Kimble RB, Srivastava S, Ross FP, Matayoshi A, Pacifici R. Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1 and tumor necrosis factor-mediated stimulation macrophage colony stimulating factor production. J Biol Chem. 1996; 271: 28890–28897.
  • 24
    Hashimoto J, Yoshikawa H, Takaoka K, et al. Inhibitory effects of tumor necrosis factor alpha on fracture healing in rats. Bone. 1989; 10: 453–457.
  • 25
    Aggarwal B. Tumor necrosis factors receptor associated signaling molecules and their role in activation of apoptosis, Jnk and Nf-κB. Ann Rheum Dis. 2000; 59: I6–I6.
  • 26
    Lu X, Farmer P, Rubin J, Nanes M. Integration of the NfκB P65 subunit into the vitamin D receptor transcriptional complex: identification of P65 domains that inhibit 1,25-dihydroxyvitamin D3-stimulated transcription. J Cell Biochem. 2004; 92: 833–848.
    Direct Link:
  • 27
    Lu X, Gilbert L, He X, Rubin J, Nanes M. Transcriptional regulation of the Osterix (Osx, Sp7) promoter by tumor necrosis factor identifies disparate effects of mitogen-activated protein kinase and NFκB pathways. J Biol Chem. 2006; 281: 6297–6306.
  • 28
    Gilbert L, Rubin J, Nanes M. The P55 receptor mediates TNF inhibition of osteoblast differentiation independently of apotosis. Am J Physiol Endocrinol Metab. 2005; 288: E1011–1018.
  • 29
    Frost A, Jonsson K, Nilsson O, Ljunggren O. Inflammatory cytokines regulate proliferation of cultured human osteoblasts. Acta Orthop Scand. 1997; 68: 91–96.
  • 30
    Gerstenfeld L, Cho T, Kon T, et al. Impaired intramembranous bone formation during bone repair in the absence of tumor necrosis factor-α signaling. Cells Tissues Organs. 2001; 169: 285–294.
  • 31
    Kunieda T, Minamino T, Nishi J, et al. Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation. 2006; 114: 953–956.
  • 32
    Sasaki M, Ikeda H, Sato Y, Nakanuma Y. Proinflammatory cytokine-induced cellular senescence of biliary epithelial cells is mediated via oxidative stress and activation of ATM pathway: a culture study. Free Radical Res. 2008; 42: 625–632.
  • 33
    Chen JR, Lazarenko OP, Haley RL, Blackburn ML, Badger TM, Ronis MJ. Ethanol impairs estrogen receptor signaling resulting in accelerated activation of senescence pathways, whereas estradiol attenuates the effects of ethanol in osteoblasts. J Bone Miner Res. 2009; 24: 221–230.
    Direct Link:
  • 34
    Wahl EC, Perrien DS, Aronson J, et al. Ethanol-induced inhibition of bone formation in a rat model of distraction osteogenesis: a role for the TNF signaling axis. Alcohol Clin Exp Res. 2005; 29: 1466–1472.
    Direct Link:
  • 35
    Wahl E, Aronson J, Liu L, et al. Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: role of the TNF signaling axis. Toxicol Appl Pharmacol. 2007; 220: 302–310.
  • 36
    Fowlkes JL, Thrailkill KM, Liu L, et al. Effects of systemic and local administration of recombinant human IGF-I (rhIGF-I) on de novo bone formation in an aged mouse model. J Bone Miner Res. 2006; 21: 1359–1366.
    Direct Link:
  • 37
    Skinner RA, Fromowitz FB. Faxitron X-ray Unit in Histologic Evaluation of Breast Biopsies. Tech Sample HT-5. Chicago: ASCP Press; 1989.
  • 38
    Aronson J, Shen X, Gao G, et al. Sustained proliferation accompanies distraction osteogenesis in the rat. J Orthop Res. 1997; 15: 563–569.
    Direct Link:
  • 39
    Perrien D, Brown E, Aronson J, et al. Immunohistochemical study of osteopontin expression during distraction osteogenesis in the rat. J Histochem Cytochem. 2002; 50: 567–574.
  • 40
    Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR. Stimulation of bone resorption and inhibition of bone formation in vitro by tumor necrosis factors. Nature. 1986; 19: 516–518.
  • 41
    Bellosta P, Masramon L, Mansukhani A, Basilico C. P21(WAF1/CIP1) acts as a brake in osteoblast differentiation. J Bone Miner Res. 2003; 18: 818–826.
    Direct Link:
  • 42
    Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007; 13: 156–163.
  • 43
    MacDonald BT, Joiner DM, Oyserman SM, et al. Bone mass is inversely proportional to Dkk1 levels in mice. Bone. 2007; 41: 331–339.
  • 44
    Gregory CA, Singh H, Perry AS, Prockop DJ. The Wnt signaling inhibitor dickkopf-1 is required for reentry into the cell cycle of human adult stem cells from bone marrow. J Biol Chem. 2003; 278: 28067–28078.
  • 45
    Fujita K, Janz S. Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF. Mol Cancer. 2007; 6: 71.
  • 46
    Kim TW, Kim HJ, Lee C, et al. Identification of replicative senescence-associated genes in human umbilical vein endothelial cells by an annealing control primer system. Exp Gerontol. 2008; 43: 286–295.
  • 47
    Meyer MH, Meyer RA Jr. Genes with greater up-regulation in the fracture callus of older rats with delayed healing. J Orthop Res. 2007; 25: 488–494.
    Direct Link:
  • 48
    Amin S, Riggs BL, Melton LJ 3rd, Achenbach SJ, Atkinson EJ, Khosla S. High serum IGFBP-2 is predictive of increased bone turnover in aging men and women. J Bone Miner Res. 2007; 22: 799–807.
    Direct Link:
  • 49
    Benbassat CA, Maki KC, Unterman TG. Circulating levels of insulin-like growth factor (IGF) binding protein-1 and -3 in aging men: relationships to insulin, glucose, IGF, and dehydroepiandrosterone sulfate levels and anthropometric measures. J Clin Endocrinol Metab. 1997; 82: 1484–1491.
  • 50
    Garreta E, Genové E, Borrós S, Semino CE. Osteogenic differentiation of mouse embryonic stem cells and mouse embryonic fibroblasts in a three-dimensional self-assembling peptide scaffold. Tissue Eng. 2006; 12: 2215–2227.
  • 51
    Mendoza MA, Ponce RA, Ou YC, Faustman EM. p21(WAF1/CIP1) inhibits cell cycle progression but not G2/M-phase transition following methylmercury exposure. Toxicol Appl Pharmacol. 2002; 178: 117–125.
  • 52
    Suffys P, Beyaert R, Van Roy F, Fiers W. TNF in combination with interferon-γ is cytotoxic to normal, untransformed mouse and rat embryo fibroblast-like cells. Anticancer Res. 1989; 9: 167–171.
  • 53
    Bialek P, Kern B, Yang X, et al. A twist code determines the onset of osteoblast differentiation. Dev Cell. 2004; 6: 423–435.
  • 54
    Luan Y, Yu XP, Xu K, et al. The retinoblastoma protein is an essential mediator of osteogenesis that links the p204 protein to the Cbfa1 transcription factor thereby increasing its activity. J Biol Chem. 2007; 282: 16860–16870.
  • 55
    Devgan V, Mammucari C, Millar SE, Brisken C, Dotto GP. p21WAF1/CIP1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Genes Dev. 2005; 19: 1485–1495.
  • 56
    Tay B, Le A, Gould S, Helms J. Histochemical and molecular analyses of distraction osteogenesis in a mouse model. J Orthop Res. 1998; 16: 636–642.
    Direct Link:
  • 57
    Isefuku S, Joyner C, Simpson A. A murine model of distraction osteogenesis. Bone. 2000; 27: 661–665.
  • 58
    Carvalho R, Einhorn T, Lehmann W, et al. The role of angiogenesis in a murine model of distraction osteogenesis. Bone. 2004; 34: 849.
  • 59
    Towler DA. The osteogenic-angiogenic interface: novel insights into the biology of bone formation and fracture repair. Curr Osteoporos Rep. 2008; 6: 67–71.
  • 60
    Luedemann C, Bord E, Qin G, et al. Ethanol modulation of TNF-α biosynthesis and signaling in endothelial cells: synergistic augmentation of TNF-alpha mediated endothelial cell dysfunctions by chronic ethanol. Alcohol Clin Exp Res. 2005; 29: 930–938.
    Direct Link:
  • 61
    Kishore R, Qin G, Luedemann C, et al. The cytoskeletal protein ezrin regulates Ec proliferation and angiogenesis via TNF-α-Induced transcriptional repression of cyclin A. J Clin Invest. 2005; 115: 1785–1796.
  • 62
    Qiao M, Shapiro P, Fosbrink M, Rus H, Kumar R, Passaniti A. Cell cycle-dependent phosphorylation of the Runx2 transcription factor by CDC2 regulates endothelial cell proliferation. J Biol Chem. 2006; 281: 7118–7128.
  • 63
    Merkel KD, Erdmann JM, Mchugh KP, Abu-Amer Y, Ross FP, Teitelbaum SL. Tumor necrosis factor-α mediates orthopedic implant osteolysis. Am J Pathol. 1999; 154: 203–210.
  • 64
    Li Y, Li A, Strait K, Zhang H, Nanes MS, Weitzman M. Endogenous TNFα lowers mazimum peak bone mass and inhibits osteoblastic smad activation through NF-κB. J Bone Miner Res. 2007; 22: 646–655.
    Direct Link:
  • 65
    Charatcharoenwitthaya N, Khosla S, Atkinson E, McCready L, Riggs B. Effect of blockade of TNF-α and interleukin-1 action on bone resorption in early postmenopausal women. J Bone Miner Res. 2007; 22: 724–729.
    Direct Link:
  • 66
    Cauley J, Danielson M, Boudreau R, et al. Inflammatory markers and incident fracture risk in older men and women: the Health Aging and Body Composition Study. J Bone Miner Res. 2007; 22: 1088–1095.
    Direct Link:
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