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2012 | 59 | 4 | 507-513
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Molecular factors involved in the development of diabetic foot syndrome

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Diabetes is one of the major challenges of modern medicine, as it is considered a global epidemic of the XXI century. The disease often leads to the development of serious, health threatening complications. Diabetic foot syndrome is a characteristic set of anatomical and molecular changes. At the macroscopic level, major symptoms are neuropathy, ischemia and chronic ulceration of the lower limb. In every third patient, the neuropathy develops into Charcot neuroarthropathy characterized by bone and joints deformation. Interestingly, all these complications are a result of impaired healing processes and are characteristic for diabetes. The specificity of these symptoms comes from impaired molecular mechanisms observed in type 1 and type 2 diabetes. Decreased wound and fracture healing reflect gene expression, cellular response, cell functioning and general metabolism. Here we present a comprehensive literature update on the molecular factors contributing to diabetic foot syndrome.
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  • Department of Molecular Biology, University of Gdansk, Gdańsk, Poland
  • Department of Diabetology and Hypertension, Medical University of Gdańsk, Gdańsk, Poland
  • Department of Molecular Biology, University of Gdansk, Gdańsk, Poland
  • Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
  • Department of Microbiology, University of Szczecin, Szczecin, Poland
  • Department of Molecular Biology, University of Gdansk, Gdańsk, Poland
  • AboElAsrar MA, Elbarbary NS, Elshennawy DE, Omar AM (2012) Insulin-like growth factor-1 cytokines cross-talk in type 1 diabetes mellitus: relationship to microvascular complications and bone mineral density. Cytokine 59: 86-93.
  • Ahmad J, Zubair M, Malik A, Siddiqui MA, Wangnoo SK (2012) Cathepsin-D, adiponectin, TNF-α, IL-6 and hsCRP plasma levels in subjects with diabetic foot and possible correlation with clinical variables: a multicentric stud. Foot 22: 194-199.
  • Apelqvist J (2012) Diagnostics and treatment of the diabetic foot. Endocrine 41: 384-397.
  • Atalay M, Oksala N, Lappalainen J, Laaksonen DE, Sen CK, Roy S (2009) Heat shock proteins in Diabetes and wound healing. Curr Protein Pept Sci 10: 85-95.
  • Badillo AT, Chung S, Zhang L, Zoltick P, Liechty KW (2007) Lentiviral gene transfer of SDF-1alpha to wounds improves diabetic wound healing. J Surg Res 143: 35-42.
  • Bartus CL, Margolis DJ (2004) Reducing the incidence of foot ulceration and amputation in diabetes. Curr Diab Rep 4: 413-418.
  • Beaujouin M, Baghdiguian S, Glondu-Lassis M, Berchem G, Liaudet-Coopman E (2006) Overexpression of both catalytically active and -inactive cathepsin D by cancer cells enhances apoptosis-dependent chemo-sensitivity. Oncogene 25: 1967-1973.
  • Bermudez DM, Xu J, Herdrich BJ, Radu A, Mitchell ME, Liechty KW (2011) Inhibition of stromal cell-derived factor-1α further impairs diabetic wound healing. J Vasc Surg 53: 774-784.
  • Bitar MS, Farook T, John B, Francis IM (1999) Heat-shock protein 72/73 and impaired wound healing in diabetic and hypercortisolemic states. Surgery 125: 594-601.
  • Bitto A, Minutoli L, Galeano MR, Altavilla D, Polito F, Fiumara T, Calò M, Lo Cascio P, Zentilin L, Giacca M, Squadrito F (2008) Angiopoietin-1 gene transfer improves impaired wound healing in genetically diabetic mice without increasing VEGF expression. Clin Sci (Lond) 114: 707-718.
  • Botusan IR, Sunkari VG, Savu O, Catrina AI, Grunler J, Lindberg S, Pereira T, Yla-Herttuala S, Poellinger L, Brismar K, Catrina SB (2008) Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci USA 105: 19426-19431.
  • Bouchard L, Hivert MF, Guay SP, St-Pierre J, Perron P, Brisson D. (2012) Placental adiponectin gene DNA methylation levels are associated with mothers' blood glucose concentration. Diabetes 61: 1272-1280.
  • Boyce BF, Xing L (2008) Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 473: 139-146.
  • Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423: 337-342.
  • Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477: 267-283.
  • Caporali A, Meloni M, Vollenkle C, Bonci D, Sala-Newby GB, Addis R, Spinetti G, Losa S, Masson R, Baker AH, Agami R, le Sage C, Condorelli G, Madeddu P, Martelli F, Emanueli C (2011) Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation 123: 282-291.
  • Catrina SB, Okamoto K, Pereira T, Brismar K, Poellinger L (2004) Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function. Diabetes 53: 3226-3232.
  • Cavanagh PR, Young MJ, Adams JE, Vickers KL, Boulton AJ (1994) Radiographic abnormalities in the feet of patients with diabetic neuropathy. Diabetes Care 17: 201-209.
  • Cornblath DR, McArthur JC (1988) Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex. Neurology 38: 794-796.
  • Cornell S, Dorsey VJ (2012) Diabetes Pharmacotherapy in 2012: Considerations in Medication Selection Postgrad Med 124: 84-94.
  • de Amorim FP, Ornelas SS, Diniz SF, Batista AC, da Silva TA (2008) Imbalance of RANK, RANKL and OPG expression during tibial fracture repair in diabetic rats J Mol Histol 39: 401-408.
  • DeChiara TM, Robertson EJ, Efstratiadis A (1991) Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64: 849-59.
  • Diniz SF, Amorim FP, Cavalcante-Neto FF, Bocca AL, Batista AC, Simm GE, Silva TA (2008) Alloxan-induced diabetes delays repair in a rat model of closed tibial fracture. Braz J Med Biol Res 41: 373-379.
  • Duarte VM, Ramos AM, Rezende LA, Macedo UB, Brandão-Neto J, Almeida MG, Rezende AA (2005) Osteopenia: a bone disorder associated with diabetes mellitus. J Bone Miner Metab 23: 58-68.
  • Duarte PM, Neto JB, Casati MZ, Sallum EA, Nociti FH Jr (2007) Diabetes modulates gene expression in the gingival tissues of patients with chronic periodontitis. Oral Dis 13: 594-599.
  • Engerman RL, Kern TS (1987) Progression of incipient diabetic retinopathy during good glycemic control. Diabetes 36: 808-812.
  • Eubank TD, Marsh CB (2010) Cytokines and Growth factors in the Regulation of Wound Inflammation. In Advances in Wound Care. Chandon KS, ed, pp 211-216. Mary Ann Liebert Inc. publishers, New York, USA.
  • Forsblom CM, Sane T, Groop PH, Tötterman KJ, Kallio M, Saloranta C, Laasonen L, Summanen P, Lepäntalo M, Laatikainen L, Matikainen E, Teppo AM, Koskimies S, Groop L (1998) Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 41: 1253-1262.
  • Frank S, Hübner G, Breier G, Longaker MT, Greenhalgh DG, Werner S (1995) Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem 270: 12607-12613.
  • Gandhi A, Doumas C, O'Connor JP, Parsons JR, Lin SS (2006) The effects of local platelet rich plasma delivery on diabetic fracture healing. Bone 38: 540-546.
  • Gethin G (2007) The significance of surface pH in chronic wounds. Wounds UK 3: 52-54.
  • Gohda J, Akiyama T, Koga T, Takayanagi H, Tanaka S, Inoue J (2005) RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogensis. EMBO J 24: 790-799
  • Goldberg AD, Allis CD, Bernstein E. (2007) Epigenetics: a landscape takes shape. Cell 128: 635-638.
  • Gupta PP, Mohan V (2003) Charcot foot - an iupdate. J Assoc Physicians India 51: 367-72.
  • Guo S, Dipietro LA (2010) Factors affecting wound healing. J Dent Res 89: 219-229.
  • Hammes HP, Klinzing I, Wiegand S, Bretzel RG, Cohen AM, Federlin K (1993) Islet transplantation inhibits diabetic retinopathy in the sucrose-fed diabetic Cohen rat. Invest Ophthalmol Vis Sci 34: 2092-2096.
  • Hao L, Du M, Lopez-Campistrous A, Fernandez-Patron C (2003) Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway. Circ Res 94: 68-76.
  • Hashimoto G, Inoki I, Fujii Y, Aoki T, Ikeda E, Okada Y (2002) Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. J Biol Chem 277: 36288-36295.
  • Hou J, Wang P, Lin L, Liu X, Ma F, An H, Wang Z, Cao X (2009) MicroRNA-146a feedback inhibits RIG-I-dependent type I IFN production in macrophages by targeting TRAF6, IRAK1 and IRAK2. J Immunol 183: 2150-2158.
  • Ihnat MA, Thorpe JE, Kamat CD, Szabó C, Green DE, Warnke LA, Lacza Z, Cselenyák A, Ross K, Shakir S, Piconi L, Kaltreider RC, Ceriello A (2007) Reactive oxygen species mediate a cellular 'memory' of high glucose stress signaling Diabetologia. 50: 1523-1531.
  • Jabłońska-Trypuć A (2007) Molecular mechanism of non-enzymatic glication of proteins and its role in diabetes. Termedia 4: 253-258.
  • Jeffcoate W (2005) Vascular calcification and osteolysis in diabetic neuropathy - is RANK-L the missing link? Diabetologia 47: 1488-1492.
  • Kayal RA, Alblowi J, McKenzie E, Krothapalli N, Silkman L, Gerstenfeld LC, Einhorn TA, Graves T (2009) Diabetes causes the accelerated loss of cartilage during repair which is reversed by insulin treatment. Bone 44: 357-363.
  • Kayal RA, Tsatsas D, Bauer MA, Allen B, Al-Sebaei MO, Kakar S, Leone CW, Morgan EF, Gerstenfeld LC, Einhorn TA, Graves DT (2007) Diminished bone formation during diabetic fracture healing is realted to the premature resorption of cartilage associated with increased osteoclast activity. J Bone Miner Res 22: 560-568.
  • Kim JK, Samaranayake M, Pradhan S (2009) Epigenetic mechanisms in mammals. Cell Mol Life Sci 66: 596-612.
  • Kong A, Steinthorsdottir V, Masson G, Kong A, Steinthorsdottir V, Masson G, Thorleifsson G, Sulem P, Besenbacher S, Jonasdottir A, Sigurdsson A, Kristinsson KT, Jonasdottir A, Frigge ML, Gylfason A, Olason PI, Gudjonsson SA, Sverrisson S, Stacey SN, Sigurgeirsson B, Benediktsdottir KR, Sigurdsson H, Jonsson T, Benediktsson R, Olafsson JH, Johannsson OT, Hreidarsson AB, Sigurdsson G; DIAGRAM Consortium, Ferguson-Smith AC, Gudbjartsson DF, Thorsteinsdottir U, Stefansson K (2009) Parental origin of sequence variants associated with complex diseases. Nature 462: 868-874.
  • Korzon-Burakowska A, Jakóbkiewicz-Banecka J, Fiedosiuk A, Petrova N, Koblik T, Gabig-Cimińska M, Edmonds M, Małecki MT, Węgrzyn G (2012) Osteoprotegerin gene polymorphism in diabetic Charcot neuroarthropathy. Diabetic Med 29: 771-775.
  • Kowluru RA (2003) Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 52: 818-823.
  • Kruglikov I, Kruglikova E (2011) Dual Treatment Strategy by Venous Ulcers: Pilot study to dual-frequency ultrasound application. J Cosmetics Der Sci Appl 1: 157-163.
  • Ladwig GP, Robson MC, Liu R, Kuhn MA, Muir DF, Schultz GS (2002) Ratios of activated matrix metalloproteinase-9 to tissue inhibitor of matrix metalloproteinase-1 in wound fluids are inversely correlated with healing of pressure ulcers. Wound Repair Regen 10: 26-37.
  • Lehmann HC, Chen W, Borzan J, Mankowski JL, Höke (2011) Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy. Ann Neurol 69: 100-110.
  • Li Y, Song YH, Li F, Yang T, Lu YW, Geng YJ (2009) MicroRNA-221 regulates high glucose-induced endothelial dysfunction. Biochem Biophys Res Commun 381: 81-83.
  • Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG, Deery HG, Embil JM, Joseph WS, Karchmer AW, Pinzur MS, Senneville E, Infectious Diseases Society of America (2012) Executive summary: 2012 Infectious Diseases Society of America practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 54: 1679-1684.
  • Lusis AJ (2000) Atherosclerosis. Nature 407: 233-241.
  • Lu H, Kraut D, Gerstenfeld LC, Graves DT (2003) Diabetes interferes with the bone formation by affecting the expression of transcription factors that regulate osteoblast differentiation. Endocrinology 144: 346-352.
  • Mabilleau G, Petrova NL, Edmonds ME, Sabokbar A (2008) Increased osteoclastic activity in acute Charcot osteoarthropathy: the role of receptor activator of nuclear factor kappa B ligand. Diabetologia 51: 1035-1040.
  • Madhyastha R, Madhyastha H, Nakajima Y, Omura S, Maruyama M (2011) MicroRNA signature in diabetic wound healing: promotive role of miR-21 in fibroblast migration. Int Wound J 9: 355-361.
  • Maskos K (2004) Crystal structures of MMPs in complex in complex with physiological and pharmacological inhibitors. Biochimie 87: 249-263.
  • McCawley LJ, Matrisian LM. (2001) Matrix metalloproteinases: they're not just for matrix anymore! Curr Opin Cell Biol 13: 534-540.
  • Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353: 2643-2653.
  • Nicholson SE, Metcalf D, Sprigg NS, Columbus R, Walker F, Silva A, Cary D, Willson TA, Zhang JG, Hilton DJ, Warrenn A, Nicos AN (2005) Suppressor of cytokine signaling (SOCS)-5 is a potential negative regulator of epidermal growth factor signaling. Proc Natl Acad Sci USA 102: 2328-2333.
  • Pałka J, Sobolewski K, Bańkowski E (1991) Cathepsin D inhibitor from potato reverses nhibition of collagen biosynthesis in wounded skin of rats with experimental diabetes. Acta Biochim Pol 38: 115-118.
  • Pirola L, Balcerczyk A, Okabe J, El-Osta A (2010) Epigenetic phenomena linked to diabetic complications. Nat Rev Endocrinol 6: 665-675.
  • Pitocco D, Zelano G, Gioffrè G, Di Stasio E, Zaccardi F, Martini F, Musella T, Scavone G, Galli M, Caputo S, Mancini L, Ghirlanda G (2009) Association Between Osteoprotegerin G1181C and T245G Polymorphisms and Diabetic Charcot Neuroarthropathy. Diabetes Care 32: 1694-1697.
  • Pop-Busui R, Low PA, Waberski BH, Martin CL, Albers JW, Feldman EL, Sommer C, Cleary PA, Lachin JM, Herman WH, DCCT/EDIC Research Group (2009) Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). Circulation 119: 2886-2893.
  • Rajbhandari SM, Jenkins RC, Davies C, Tesfaye S (2002) Charcot neuroarthropathy in diabetes mellitus. Diabetologia 45: 1085-1096.
  • Riddel DR, Owen JS (1999) Nitric oxide and platelet aggregation. Vitam Horm 57: 25-48.
  • Rogers LC, Frykberg RG, Armstrong DG, Boulton AJ, Edmonds M, Van GH, Hartemann A, Game F, Jeffcoate W, Jirkovska A, Jude E, Morbach S, Morrison WB, Pinzur M, Pitocco D, Sanders L, Wukich DK, Uccioli L (2011) The Charcot foot in diabetes. Diabetes Care 34: 2123-2129.
  • Roy S, Sala R, Cagliero E, Lorenzi M (1990) Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory. Proc Natl Acad Sci USA 87: 404-408.
  • Santana RB, Xu L, Chase HB, Amar S, Graves DT, Trackman PC (2003) A role for advanced glycation end products in diminished bone healing in type 1 diabetes. Diabetes 52: 1502-1510.
  • Santini D, Schiavon G, Vincenzi B, Gaeta L, Pantano F, Russo A, Ortega C, Porta C, Galluzzo S, Armento G, La Verde N, Caroti C, Treilleux I, Ruggiero A, Perrone G, Addeo R, Clezardin P, Muda AO, Tonini G (2011) Receptor activator of NF-κB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS One 6: e19234.
  • Scelsi R, Lotta S, Sverzellati S, Poggi P (2005) Morphological alterations of microvasculature and neoangiogenesis in the pressure ulcers repair in paraplegics. Basic Appl Myol 15: 203-208.
  • Singh N, Armstrong DG, Lipsky BA (2005) Preventing foot ulcers in patients with diabetes. Jama 293: 217-228.
  • Siqueira MF, Li J, Chehab L, Desta T, Chino T, Krothpali N, Behl Y, Alikhani M, Yang J, Braasch C, Graves DT. (2010) Impaired wound healing in mouse models of diabetes is mediated by TNF-alpha dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1). Diabetologia 53: 378-388.
  • Slotkin RK, Martienssen R (2007) Transposable elements and the epigenetic regulation of the genome. Nat Rev Genet 8: 272-285.
  • Stojadinovic O, Pastar I, Gordon KA, Tomic-Canic M (2012) Physiology and Pathophysiology of Wound Healing in Diabetes. In The Diabetic Foot. Veves A, Giurini JM, LoGerfo FW eds, pp 127-149. Humana Press Inc. New York.
  • Tang SY, Vashishth D (2010) Non-enzymatic glycation alters microdamage formation in human cancellous bone. Bone 46: 148-154.
  • Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH, EURODIAB Prospective Complications Study Group (2005) Vascular risk factors and diabetic neuropathy. N Engl J Med 352: 341-350.
  • Turner RC (1998) The U.K. Prospective Diabetes Study. A review. Diabetes Care 21: C35-C38.
  • Tyndall WA, Beam HA, Zarro C, O'Connor JP, Lin SS (2003) Decreased platelet derived growth factor expression during fracture healing in diabetic animals. Clin Orthop Relat Res 408: 319-330.
  • Unoki H, Takahashi A, Kawaguchi T, Hara K, Horikoshi M, Andersen G, Ng DP, Holmkvist J, Borch-Johnsen K, Jørgensen T, Sandbaek A, Lauritzen T, Hansen T, Nurbaya S, Tsunoda T, Kubo M, Babazono T, Hirose H, Hayashi M, Iwamoto Y, Kashiwagi A, Kaku K, Kawamori R, Tai ES, Pedersen O, Kamatani N, Kadowaki T, Kikkawa R, Nakamura Y, Maeda S (2008) SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nature Genet 40: 1098-1102.
  • Werner S, Breeden M, Hübner G, Greenhalgh DG, Longaker MT (1994) Induction of keratinocyte growth factor expression is reduced and delayed during wound healing in the genetically diabetic mouse. J Invest Dermatol 103: 469-473.
  • Valcourt U, Merle B, Gineyts E, Viguet-Carrin S, Delmas PD, Garnero P (2007) Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation. J Biol Chem 282: 5691-5703.
  • Vasquez V, Henderson S (2010) Charcot foot? Charcot arthropathy caused by lisfrane fracture-dislocation in a diabetic. West J Emerg Med 11: 146-147.
  • Vestergaard P, Rejnmark L, Mosekilde L (2005) Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetologia 48: 1292-1299.
  • Vestergaard P (2007) Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes - a meta-analysis. Osteoporos Int 18: 427-444.
  • Visse R, Nagase H. (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92: 827-839.
  • Xu J, Wu W, Zhang L, Dorset-Martin W, Morris WM, Mitchell ME, Liechty KW (2012) The Role of microRNA-146a in the pathogenesis of the diabetic wound-healing impairment correction with mesenchymal stem cell treatment. Diabetes 61: 2906-2912
  • Yamagishi N, Nakayama K, Wakatsuki T, Hatayama T (2001) Characteristic changes of stress protein expression in streptozotocin-induced diabetic rats. Life Sci 69: 2603-2609.
  • Yasuda K, Miyake K, Horikawa Y, Hara K, Osawa H, Furuta H, Hirota Y, Mori H, Jonsson A, Sato Y, Yamagata K, Hinokio Y, Wang HY, Tanahashi T, Nakamura N, Oka Y, Iwasaki N, Iwamoto Y, Yamada Y, Seino Y, Maegawa H, Kashiwagi A, Takeda J, Maeda E, Shin HD, Cho YM, Park KS, Lee HK, Ng MC, Ma RC, So WY, Chan JC, Lyssenko V, Tuomi T, Nilsson P, Groop L, Kamatani N, Sekine A, Nakamura Y, Yamamoto K, Yoshida T, Tokunaga K, Itakura M, Makino H, Nanjo K, Kadowaki T, Kasuga M (2008) Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nature Genet 40: 1092-1097.
  • Zhang K, McQuibban GA, Silva C, Butler GS, Johnston JB, Holden J, Clark-Lewis I, Overall CM, Power C (2003) HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nat Neurosci 6: 1064-1071.
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