Inflammation Research

, Volume 60, Issue 1, pp 3–10 | Cite as

Inflammation as death or life signal in diabetic fracture healing

  • Tamás RőszerEmail author


Increased apoptosis of chondrocytes and osteoblasts and prolonged survival of osteoclasts lead to early destruction of callus tissue and impair bone remodeling in fracture healing of diabetic patients. Diabetes is accompanied by an increased inflammatory state, reactive oxgen species (ROS) generation and accumulation of advanced glycation end products (AGEs), a heterogenous group of toxic metabolites that can induce inflammation. Prolonged hyperglycemia and insulin resistance correlate with increased apoptosis rate and, accordingly, the proapoptotic role of several inflammatory mediators, ROS and AGEs has been also documented. In this review we summarize the most recent reports supporting the idea that inflammatory signaling increases chondrocyte and osteoblast death and prolongs osteoclast survival, resulting in impaired bone regeneration in diabetes. Antagonising inflammatory signal pathways and solution of inflammation may deserve greater attention in the management of diabetic fracture healing.


Diabetes mellitus Apoptosis Inflammation Bone homeostasis Regeneration 



The Author is supported by a Hungarian Research Fund (OTKA #76091) Grant. Thank you to Dr. Christian Hellriegel for the valuable discussion.


  1. 1.
    Retzepi M, Donos N. The effect of diabetes mellitus on osseous healing. Clin Oral Implants Res. 2010;21(7):673–81.CrossRefPubMedGoogle Scholar
  2. 2.
    Botushanov NP, Orbetzova MM. Bone mineral density and fracture risk in patients with type 1 and type 2 diabetes mellitus. Folia Med (Plovdiv). 2009;51:12–7.Google Scholar
  3. 3.
    Bouillon R. Diabetic bone disease. Calcif Tissue Int. 1991;49:155–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Yaturu S, Humphrey S, Landry C, Jain SK. Decreased bone mineral density in men with metabolic syndrome alone and with type 2 diabetes. Med Sci Monit. 2009;15:CR5–9.PubMedGoogle Scholar
  5. 5.
    Loder RT. The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop Relat Res. 1988;232:210–6.PubMedGoogle Scholar
  6. 6.
    Folk JW, Starr AJ, Early JS. Early wound complications of operative treatment of calcaneus fractures: analysis of 190 fractures. J Orthop Trauma. 1999;13:369–72.CrossRefPubMedGoogle Scholar
  7. 7.
    Ketenjian AY, Jafri AM, Arsenis C. Studies on the mechanism of callus cartilage differentiation and calcification during fracture healing. Orthop Clin North Am. 1978;9:43–65.PubMedGoogle Scholar
  8. 8.
    Kayal RA, Siqueira M, Alblowi J, McLean J, Krothapalli N, Faibish D, et al. TNF-alpha mediates diabetes enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO-1. J Bone Miner Res. 2010;25:1604–15.Google Scholar
  9. 9.
    Kayal RA, Alblowi J, McKenzie E, Krothapalli N, Silkman L, Gerstenfeld L, et al. Diabetes causes the accelerated loss of cartilage during fracture repair which is reversed by insulin treatment. Bone. 2009;44:357–63.CrossRefPubMedGoogle Scholar
  10. 10.
    Stolzing A, Sellers D, Llewelyn O, Scutt A. Diabetes induced changes in rat mesenchymal stem cells. Cells Tissues Organs. 2010;191:453–65.CrossRefPubMedGoogle Scholar
  11. 11.
    Hamada Y, Fujii H, Fukagawa M. Role of oxidative stress in diabetic bone disorder. Bone. 2009;45(Suppl 1):S35–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Sheweita SA, Khoshhal KI. Calcium metabolism and oxidative stress in bone fractures: role of antioxidants. Curr Drug Metab. 2007;8:519–25.CrossRefPubMedGoogle Scholar
  13. 13.
    Yamagishi S, Nakamura K, Inoue H. Possible participation of advanced glycation end products in the pathogenesis of osteoporosis in diabetic patients. Med Hypotheses. 2005;65:1013–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Motyl K, McCabe LR. Streptozotocin, type I diabetes severity and bone. Biol Proced Online. 2009. [Epub ahead of print].Google Scholar
  15. 15.
    Juhan-Vague I, Morange PE, Alessi MC. The insulin resistance syndrome: implications for thrombosis and cardiovascular disease. Pathophysiol Haemost Thromb. 2002;32:269–73.CrossRefPubMedGoogle Scholar
  16. 16.
    Tzanavari T, Giannogonas P, Karalis KP. TNF-alpha and obesity. Curr Dir Autoimmun. 2010;11:145–56.CrossRefPubMedGoogle Scholar
  17. 17.
    Kaneto H, Katakami N, Matsuhisa M, Matsuoka TA. Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediat Inflamm. 2010;2010:453892.Google Scholar
  18. 18.
    Wu W, Wang M, Sun Z, Wang X, Miao J, Zheng Z. The predictive value of TNF-alpha and IL-6 and the incidence of macrovascular complications in patients with type 2 diabetes. Acta Diabetol. 2010. [Epub ahead of print].Google Scholar
  19. 19.
    Mandrup-Poulsen T, Pickersgill L, Donath MY. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol. 2010;6:158–66.CrossRefPubMedGoogle Scholar
  20. 20.
    Todd JA. Etiology of type 1 diabetes. Immunity.2010;32:457–67.Google Scholar
  21. 21.
    Takino JI, Kobayashi Y, Takeuchi M. The formation of intracellular glyceraldehyde-derived advanced glycation end-products and cytotoxicity. J Gastroenterol. 2010;45:646–55.Google Scholar
  22. 22.
    Hasnan J, Yusof MI, Damitri TD, Faridah AR, Adenan AS, Norbaini TH. Relationship between apoptotic markers (Bax and Bcl-2) and biochemical markers in type 2 diabetes mellitus. Singapore Med J; 51:50–5.Google Scholar
  23. 23.
    Civera M, Urios A, Garcia-Torres ML, Ortega J, Martinez-Valls J, Cassinello N, et al. Relationship between insulin resistance, inflammation and liver cell apoptosis in patients with severe obesity. Diabetes Metab Res Rev. 2010;26:187–92.CrossRefPubMedGoogle Scholar
  24. 24.
    Desta T, Li J, Chino T, Graves DT. Altered fibroblast proliferation and apoptosis in diabetic gingival wounds. J Dent Res. 2010;89:609–14.CrossRefPubMedGoogle Scholar
  25. 25.
    Burgering BM, Medema RH. Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol. 2003;73:689–701.CrossRefPubMedGoogle Scholar
  26. 26.
    Rached MT, Kode A, Silva BC, Jung DY, Gray S, Ong H, et al. FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J Clin Invest. (2010) 120:357–68.Google Scholar
  27. 27.
    Blanco FJ, Ochs RL, Schwarz H, Lotz M. Chondrocyte apoptosis induced by nitric oxide. Am J Pathol. 1995;146:75–85.PubMedGoogle Scholar
  28. 28.
    Goldring MB, Berenbaum F. The regulation of chondrocyte function by proinflammatory mediators: prostaglandins and nitric oxide. Clin Orthop Relat Res. 2004;427:S37–46.CrossRefPubMedGoogle Scholar
  29. 29.
    Peng H, Zhou JL, Liu SQ, Hu QJ, Ming JH, Qiu B. Hyaluronic acid inhibits nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes in vitro. Inflamm Res; 59:519–30.Google Scholar
  30. 30.
    Wu S, Fadoju D, Rezvani G, De Luca F. Stimulatory effects of insulin-like growth factor-I on growth plate chondrogenesis are mediated by nuclear factor-kappaB p65. J Biol Chem. 2008;283:34037–44.CrossRefPubMedGoogle Scholar
  31. 31.
    Nilsson A, Ohlsson C, Isaksson OG, Lindahl A, Isgaard J. Hormonal regulation of longitudinal bone growth. Eur J Clin Nutr. 1994;48(Suppl 1):S150–8. discussion S158–60.PubMedGoogle Scholar
  32. 32.
    Iwata K, Asawa Y, Fujihara Y, Tanaka Y, Nishizawa S, Nakagawa T, et al. The effects of rapid- or intermediate-acting insulin on the proliferation and differentiation of cultured chondrocytes. Curr Aging Sci. 2010;3:26–33.Google Scholar
  33. 33.
    Rashid G, Luzon AA, Korzets Z, Klein O, Zeltzer E, Bernheim J. The effect of advanced glycation end-products and aminoguanidine on TNFalpha production by rat peritoneal macrophages. Perit Dial Int. 2001;21:122–9.PubMedGoogle Scholar
  34. 34.
    Csaki C, Mobasheri A, Shakibaei M. Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL-1beta-induced NF-kappaB-mediated inflammation and apoptosis. Arthritis Res Ther. 2009;11:R165.CrossRefPubMedGoogle Scholar
  35. 35.
    Gangoiti MV, Cortizo AM, Arnol V, Felice JI, McCarthy AD. Opposing effects of bisphosphonates and advanced glycation end-products on osteoblastic cells. Eur J Pharmacol. 2008;600:140–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Puddu A, Storace D, Odetti P, Viviani GL. Advanced glycation end-products affect transcription factors regulating insulin gene expression. Biochem Biophys Res Commun. 2010;395:122–5.Google Scholar
  37. 37.
    Torreggiani M, Liu H, Wu J, Zheng F, Cai W, Striker G, et al. Advanced glycation end product receptor-1 transgenic mice are resistant to inflammation, oxidative stress, and post-injury intimal hyperplasia. Am J Pathol. 2009;175:1722–32.CrossRefPubMedGoogle Scholar
  38. 38.
    Aggarwal BB. Targeting Inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annu Rev Nutr. 2010;30:173–99.Google Scholar
  39. 39.
    Hofso D, Ueland T, Hager H, Jenssen T, Bollerslev J, Godang K, et al. Inflammatory mediators in morbidly obese subjects: associations with glucose abnormalities and changes after oral glucose. Eur J Endocrinol. 2009;161:451–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Boyce BF, Yao Z, Xing L. Functions of nuclear factor kappaB in bone. Ann N Y Acad Sci. 2010;1192:367–75.CrossRefPubMedGoogle Scholar
  41. 41.
    Kim SJ, Im DS, Kim SH, Ryu JH, Hwang SG, Seong JK, et al. Beta-catenin regulates expression of cyclooxygenase-2 in articular chondrocytes. Biochem Biophys Res Commun. 2002;296:221–6.CrossRefPubMedGoogle Scholar
  42. 42.
    Wehling N, Palmer GD, Pilapil C, Liu F, Wells JW, Muller PE, et al. Interleukin-1beta and tumor necrosis factor alpha inhibit chondrogenesis by human mesenchymal stem cells through NF-kappaB-dependent pathways. Arthritis Rheum. 2009;60:801–12.CrossRefPubMedGoogle Scholar
  43. 43.
    Cullen SJ, Ponnappan S, Ponnappan U. Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-kappaB activation. Biochem Pharmacol. 2010;79:706–14.CrossRefPubMedGoogle Scholar
  44. 44.
    Shembade N, Ma A, Harhaj EW. Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes. Science; 327:1135–9.Google Scholar
  45. 45.
    Wu S, De Luca F. Inhibition of the proteasomal function in chondrocytes down-regulates growth plate chondrogenesis and longitudinal bone growth. Endocrinology. 2006;147:3761–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Chang TL, Chang CJ, Lee WY, Lin MN, Huang YW, Fan K. The roles of ubiquitin and 26S proteasome in human obesity. Metabolism. 2009;58:1643–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Sakamoto K, Sato Y, Shinka T, Sei M, Nomura I, Umeno M, et al. Proteasome subunits mRNA expressions correlate with male BMI: implications for a role in obesity. Obesity (Silver Spring). 2009;17:1044–9.CrossRefGoogle Scholar
  48. 48.
    Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol. 2006;212:167–78.CrossRefPubMedGoogle Scholar
  49. 49.
    Soldatos G, Cooper ME, Jandeleit-Dahm KA. Advanced-glycation end products in insulin-resistant states. Curr Hypertens Rep. 2005;7:96–102.CrossRefPubMedGoogle Scholar
  50. 50.
    Webster L, Abordo EA, Thornalley PJ, Limb GA. Induction of TNF alpha and IL-1 beta mRNA in monocytes by methylglyoxal- and advanced glycated endproduct-modified human serum albumin. Biochem Soc Trans. 1997;25:250S.PubMedGoogle Scholar
  51. 51.
    Alikhani M, Alikhani Z, Boyd C, MacLellan CM, Raptis M, Liu R, et al. Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone. 2007;40:345–53.CrossRefPubMedGoogle Scholar
  52. 52.
    Santana RB, Xu L, Chase HB, Amar S, Graves DT, Trackman PC. A role for advanced glycation end products in diminished bone healing in type 1 diabetes. Diabetes. 2003;52:1502–10.CrossRefPubMedGoogle Scholar
  53. 53.
    Chan WH, Wu HJ, Shiao NH. Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2. J Cell Biochem. 2007;100:1056–69.CrossRefPubMedGoogle Scholar
  54. 54.
    Ambrogini E, Almeida M, Martin-Millan M, Paik JH, Depinho RA, Han L, et al. FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice. Cell Metab. 2010;11:136–46.CrossRefPubMedGoogle Scholar
  55. 55.
    Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Kurioka S, Yano S, et al. Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2009;94:45–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, et al. Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus. Osteoporos Int. 2010. [Epub ahead of print].Google Scholar
  57. 57.
    van’t Hof RJ, Ralston SH. Nitric oxide and bone. Immunology 2001; 103:255–61.Google Scholar
  58. 58.
    Grassi F, Fan X, Rahnert J, Weitzmann MN, Pacifici R, Nanes MS, et al. Bone re/modeling is more dynamic in the endothelial nitric oxide synthase(−/−) mouse. Endocrinology. 2006;147:4392–9.CrossRefPubMedGoogle Scholar
  59. 59.
    Baldik Y, Diwan AD, Appleyard RC, Fang ZM, Wang Y, Murrell GA. Deletion of iNOS gene impairs mouse fracture healing. Bone. 2005;37:32–6.CrossRefPubMedGoogle Scholar
  60. 60.
    Collin-Osdoby P, Nickols GA, Osdoby P. Bone cell function, regulation, and communication: a role for nitric oxide. J Cell Biochem. 1995;57:399–408.CrossRefPubMedGoogle Scholar
  61. 61.
    Charbonneau A, Marette A. Inducible nitric oxide synthase induction underlies lipid-induced hepatic insulin resistance in mice: potential role of tyrosine nitration of insulin signaling proteins. Diabetes. 2010;59:861–71.CrossRefPubMedGoogle Scholar
  62. 62.
    Nishio K, Shigemitsu M, Kodama Y, Itoh S, Konno N, Satoh R, et al. The effect of pioglitazone on nitric oxide synthase in patients with type 2 diabetes mellitus. J Cardiometab Syndr. 2008;3:200–4.CrossRefPubMedGoogle Scholar
  63. 63.
    Son MJ, Lee SB, Byun YJ, Lee HO, Kim HS, Kwon OJ, et al. Sodium nitroprusside induces autophagic cell death in glutathione-depleted osteoblasts. J Biochem Mol Toxicol. 2010. [Epub ahead of print].Google Scholar
  64. 64.
    Farmer DG, Kennedy S. RAGE, vascular tone and vascular disease. Pharmacol Ther. 2009;124:185–94.CrossRefPubMedGoogle Scholar
  65. 65.
    Rapuano BE, Bockman RS. Tumor necrosis factor-alpha stimulates phosphatidylinositol breakdown by phospholipase C to coordinately increase the levels of diacylglycerol, free arachidonic acid and prostaglandins in an osteoblast (MC3T3–E1) cell line. Biochim Biophys Acta. 1991;1091:374–84.CrossRefPubMedGoogle Scholar
  66. 66.
    Shin SW, Seo CY, Han H, Han JY, Jeong JS, Kwak JY, et al. 15d-PGJ2 induces apoptosis by reactive oxygen species-mediated inactivation of Akt in leukemia and colorectal cancer cells and shows in vivo antitumor activity. Clin Cancer Res. 2009;15:5414–25.CrossRefPubMedGoogle Scholar
  67. 67.
    Lee SJ, Kim MS, Park JY, Woo JS, Kim YK. 15-Deoxy-delta 12, 14-prostaglandin J2 induces apoptosis via JNK-mediated mitochondrial pathway in osteoblastic cells. Toxicology. 2008;248:121–9.CrossRefPubMedGoogle Scholar
  68. 68.
    Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46.CrossRefPubMedGoogle Scholar
  69. 69.
    Heikkinen S, Auwerx J, Argmann CA. PPARgamma in human and mouse physiology. Biochim Biophys Acta. 2007;1771:999–1013.PubMedGoogle Scholar
  70. 70.
    Bell-Parikh LC, Ide T, Lawson JA, McNamara P, Reilly M, FitzGerald GA. Biosynthesis of 15-deoxy-delta12, 14-PGJ2 and the ligation of PPARgamma. J Clin Invest. 2003;112:945–55.PubMedGoogle Scholar
  71. 71.
    Jung JY, Yoo CI, Kim HT, Kwon CH, Park JY, Kim YK. Role of mitogen-activated protein kinase (MAPK) in troglitazone-induced osteoblastic cell death. Toxicology. 2007;234:73–82.CrossRefPubMedGoogle Scholar
  72. 72.
    Kim SH, Yoo CI, Kim HT, Park JY, Kwon CH, Kim YK. Activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) induces cell death through MAPK-dependent mechanism in osteoblastic cells. Toxicol Appl Pharmacol. 2006;215:198–207.CrossRefPubMedGoogle Scholar
  73. 73.
    Lin TH, Yang RS, Tang CH, Lin CP, Fu WM. PPARgamma inhibits osteogenesis via the down-regulation of the expression of COX-2 and iNOS in rats. Bone. 2007;41:562–74.CrossRefPubMedGoogle Scholar
  74. 74.
    Szymczyk KH, Freeman TA, Adams CS, Srinivas V, Steinbeck MJ. Active caspase-3 is required for osteoclast differentiation. J Cell Physiol. 2006;209:836–44.CrossRefPubMedGoogle Scholar
  75. 75.
    Cloos C, Wahl P, Hasslacher C, Traber L, Kistner M, Jurkuhn K, et al. Urinary glycosylated, free and total pyridinoline and free and total deoxypyridinoline in diabetes mellitus. Clin Endocrinol (Oxf). 1998;48:317–23.CrossRefGoogle Scholar
  76. 76.
    Kemink SA, Hermus AR, Swinkels LM, Lutterman JA, Smals AG. Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology. J Endocrinol Invest. 2000;23:295–303.PubMedGoogle Scholar
  77. 77.
    Liu R, Bal HS, Desta T, Krothapalli N, Alyassi M, Luan Q, et al. Diabetes enhances periodontal bone loss through enhanced resorption and diminished bone formation. J Dent Res. 2006;85:510–4.CrossRefPubMedGoogle Scholar
  78. 78.
    Luegmayr E, Glantschnig H, Wesolowski GA, Gentile MA, Fisher JE, Rodan GA, et al. Osteoclast formation, survival and morphology are highly dependent on exogenous cholesterol/lipoproteins. Cell Death Differ. 2004;11(Suppl 1):S108–18.CrossRefPubMedGoogle Scholar
  79. 79.
    Hie M, Yamazaki M, Tsukamoto I. Curcumin suppresses increased bone resorption by inhibiting osteoclastogenesis in rats with streptozotocin-induced diabetes. Eur J Pharmacol. 2009;621:1–9.CrossRefPubMedGoogle Scholar
  80. 80.
    Kawashima Y, Fritton JC, Yakar S, Epstein S, Schaffler MB, Jepsen KJ, et al. Type 2 diabetic mice demonstrate slender long bones with increased fragility secondary to increased osteoclastogenesis. Bone. 2009;44:648–55.CrossRefPubMedGoogle Scholar
  81. 81.
    Cornish J, MacGibbon A, Lin JM, Watson M, Callon KE, Tong PC, et al. Modulation of osteoclastogenesis by fatty acids. Endocrinology. 2008;149:5688–95.CrossRefPubMedGoogle Scholar
  82. 82.
    Wakeyama H, Akiyama T, Kadono Y, Nakamura M, Oshima Y, Nakamura K, et al. Posttranslational regulation of Bim by caspase-3. Ann N Y Acad Sci. 2007;1116:271–80.CrossRefPubMedGoogle Scholar
  83. 83.
    Wakeyama H, Akiyama T, Takahashi K, Amano H, Kadono Y, Nakamura M, et al. Negative feedback loop in the Bim-caspase-3 axis regulating apoptosis and activity of osteoclasts. J Bone Miner Res. 2007;22:1631–9.CrossRefPubMedGoogle Scholar
  84. 84.
    Oh SR, Sul OJ, Kim YY, Kim HJ, Yu R, Suh JH, et al. Saturated fatty acids enhance osteoclast survival. J Lipid Res. 2010;51:892–9.CrossRefPubMedGoogle Scholar
  85. 85.
    Ruan M, Pederson L, Bradley EW, Bamberger AM, Oursler MJ. Transforming growth factor-{beta} coordinately induces suppressor of cytokine signaling 3 and leukemia inhibitory factor to suppress osteoclast apoptosis. Endocrinology. 2010;151:1713–22.Google Scholar
  86. 86.
    Perez-Sayans M, Somoza-Martin JM, Barros-Angueira F, Rey JM, Garcia-Garcia A. RANK/RANKL/OPG role in distraction osteogenesis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;109:679–86.Google Scholar
  87. 87.
    Grauslund J, Rasmussen LM, Green A, Sjolie AK. Does osteoprotegerin relate to micro- and macrovascular complications in long-term type 1 diabetes? Scand J Clin Lab Invest. 2010;70:188–93.Google Scholar
  88. 88.
    Lappin DF, Eapen B, Robertson D, Young J, Hodge PJ. Markers of bone destruction and formation and periodontitis in type 1 diabetes mellitus. J Clin Periodontol. 2009;36:634–41.CrossRefPubMedGoogle Scholar
  89. 89.
    Nabipour I, Kalantarhormozi M, Larijani B, Assadi M, Sanjdideh Z. Osteoprotegerin in relation to type 2 diabetes mellitus and the metabolic syndrome in postmenopausal women. Metabolism. 2010;59:742–7.Google Scholar
  90. 90.
    Terekeci HM, Senol MG, Top C, Sahan B, Celik S, Sayan O, et al. Plasma osteoprotegerin concentrations in type 2 diabetic patients and its association with neuropathy. Exp Clin Endocrinol Diabetes. 2009;117:119–23.CrossRefPubMedGoogle Scholar
  91. 91.
    Jorgensen GM, Vind B, Nybo M, Rasmussen LM, Hojlund K. Acute hyperinsulinemia decreases plasma osteoprotegerin with diminished effect in type 2 diabetes and obesity. Eur J Endocrinol. 2009;161:95–101.CrossRefPubMedGoogle Scholar
  92. 92.
    Lee SK, Huang H, Lee SW, Kim KH, Kim KK, Kim HM, et al. Involvement of iNOS-dependent NO production in the stimulation of osteoclast survival by TNF-alpha. Exp Cell Res. 2004;298:359–68.CrossRefPubMedGoogle Scholar
  93. 93.
    van’t Hof RJ, Ralston SH. Cytokine-induced nitric oxide inhibits bone resorption by inducing apoptosis of osteoclast progenitors and suppressing osteoclast activity. J Bone Miner Res. 1997;12:1797–804.CrossRefPubMedGoogle Scholar
  94. 94.
    Evans KE, Fox SW. Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus. BMC Cell Biol. 2007;8:4.CrossRefPubMedGoogle Scholar
  95. 95.
    Wan Y, Chong LW, Evans RM. PPAR-gamma regulates osteoclastogenesis in mice. Nat Med. 2007;13:1496–503.CrossRefPubMedGoogle Scholar
  96. 96.
    Peraza MA, Burdick AD, Marin HE, Gonzalez FJ, Peters JM. The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR). Toxicol Sci. 2006;90:269–95.CrossRefPubMedGoogle Scholar
  97. 97.
    Kaji H, Naito J, Inoue Y, Sowa H, Sugimoto T, Chihara K. Statin suppresses apoptosis in osteoblastic cells: role of transforming growth factor-beta-Smad3 pathway. Horm Metab Res. 2008;40:746–51.CrossRefPubMedGoogle Scholar
  98. 98.
    Luisetto G, Camozzi V. Statins, fracture risk, and bone remodeling. J Endocrinol Invest. 2009;32:32–7.PubMedGoogle Scholar
  99. 99.
    Hsu MJ, Chang CK, Chen MC, Chen BC, Ma HP, Hong CY, et al. Apoptosis signal-regulating kinase 1 in peptidoglycan-induced COX-2 expression in macrophages. J Leukoc Biol. 2010;87:1069–82.CrossRefPubMedGoogle Scholar

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© Springer Basel AG 2010

Authors and Affiliations

  1. 1.Research Group of Apoptosis and GenomicsHungarian Academy of SciencesDebrecenHungary
  2. 2.Department of Regenerative CardiologySpanish National Cardiovascular Research Center (CNIC)MadridSpain

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