"The Roles of Insulin like Growth Factorsand Calcium on the Extent of Fibrosis inDiabetic WoundsBackground and significance: Diabetes is the most common endocrine disorder and is one ofthe most challenging health problems of our time. It has life-threatening complications affectingseveral organs and systems, with increased risk for ocular, renal, cardiac, cerebral, nervous andperipheral vascular disease. Over time, especially in genetically susceptible individuals, chronichyperglycemia in diabetes can cause tissue injury. One pathological response to tissue injury isthe development of fibrosis, which involves predominant extracellular matrix (ECM)accumulation and may contribute to the failure of wound healing seen in diabetic skin. Diabeticwounds are slow and non-healing that can last for weeks despite adequate and appropriate care.Such wounds are difficult to manage. Conventional treatments are labour intensive andexpensive, including combinations of debridement, antibiotics, and pressure relief and arterialreconstruction. They often fail, and after 12 months of treatment 25% of patients have activeprimary or recurrent ulceration (Jeffcoateet al., 2006) which places significant burdens onhealthcare resources. Diabetic wound healing is thus a debilitating complication and poses aserious challenge in clinical practice.Advanced glycation products (metabolites of the high glucose levels in diabetes) and connectivetissue growth factor (CTGF), a member of the insulin-like growth factor binding protein(IGFBP) super family, are involved in diabetic fibrosis. IGFBP-5 is increased in the fibroticdisease systemic sclerosis where it may contribute to impaired wound healing. However, IGFBP-5 may serve as an antagonist to CTGF and TGF-ß, as IGFBP-5 inhibits keratinocyte migration inskin wound models (Wright et al., 2013), and IGFBP-5 also inhibits TGF-ß actions. Calcium isthought to act as a signaling molecule in wound repair and could mitigate some of the fibroticmechanisms in diabetic wound healing.IGFBP-5 and CTGF in wound healing and fibrosis: IGFBP-5 is one of the members ofinsulin-like growth factor binding protein family which bind to and modulate the biologicalactions of insulin-like growth factors (IGF) by interference with receptor binding althoughtheseIGFBPs also have IGF-independent actions. In wound healing, IGF-I is upregulated innormal skin wounds(Todorovicet al., 2008) but is downregulated in diabetic wounds(Brown etal., 1997). IGFBP-5 expression is increased in diabetes(Park et al., 2006; Bergmenet al.,2005),and IGFBP-5-mediated cell migration is inhibited by hyperglycemia(Schaeffer et al.,2010: Yasuokaet al., 2006).IGFBP-5 increases fibroblast/myofibroblast transformation andincreases production of collagen and fibronectin, which contributes to skin fibrosis anddisordered wound healing in diabetes.CTGF, a member of the insulin-like growth factor binding protein (IGFBP) super family, is alsoinvolved in diabetic fibrosis. CTGF interacts with transforming growth factor ß (TGF-ß) toincrease undesirable fibroblast/myofibroblast transformation (Twigget al., 2002), increasing therisk of scarring during wound healing. CTGF expression alters in dermal fibroblasts exposed tohigh glucose levels (Wright et al., 2013).Calcium in wound healing: Calcium is involved in skin homeostasis and acts as a modulator inkeratinocyte proliferation and differentiation. Dermal fibroblasts are also regulated by calciumbut to a lesser degree. Normal calcium metabolism in the skin is dependent on cell membraneand cytosolic calcium binding proteins (calmodulin, cadherins), but their modulation through growth factors in normal or damaged tissue is not well documented. There is known about howcalcium release from the circulation or through the action of growth factors and their bindingproteins, influences cell migration and remodeling in skin wounds (Lansdown, 2002).It is knownthat calcium waves carried by gap junctions between cells are generated as a response to skininjury (Tsutsumiet al., 2013), and that calcium also assists keratinocyte migration viametalloproteinase 9 (MMP-9) production during re-epithelialization (Morris et al., 2006). Bothof these properties of calcium during wound healing may be disrupted in fibrosis. Indeed calciumchannel blockers are used in fibrotic diseases such as Raynaud’s phenomenon in systemicsclerosis to reduce symptoms (Chung et al., 2006).It appears that CTGF and IGFBP-5 act to decrease wound healing capacity, by increasingfibrosis, whereas calcium can act to increase it. It may be that the positive effects of calcium arenot effective in diabetes and fibrosis. By determining the possible interaction of CTGF, IGFBP-5and calcium in contributing to fibrosis in diabetic skin and retarding wound closure, Therefindings will open new avenues for therapeutic developments in the treatment of diabeticcomplications.References:Bergman PB, Moravski CJ, Edmondson SR, Russo VC, Bach LA, Wilkinson-Berka JL,Werther GA(2005): Expression of the IGF system in normal and diabetic transgenic (mRen- 2)27 rat eye.Invest Ophthalmol Vis Sci,46:2708-2715Brown DL, Kane CD, Chernausek SD, Greenhalgh DG(1997): Differential expression andlocalization of insulin-like growth factors I and II in cutaneous wounds of diabetic andnondiabeticmice.Am J Pathol, 151:715-724Chung L, Lin J, Furst DE, Fiorentino D (2006) Systemic and localized scleroderma. Clinicsin Dermatology,24, 374– 392Jeffcoate WJ, Chipchase SY, Ince P, Game FL (2006) Assessing the outcome of themanagement of diabetic foot ulcers using ulcer-related and person-related measures.Diabetes Care,29:1784-7Lansdown ABG (2002): Calcium: a potential central regulator in wound healing in theskin.Wound Rep Reg,10:271–285.Morris VL, Chan, BMC (2007): Interaction of epidermal growth factor, Ca2+, andmatrixmetalloproteinase-9 in primary keratinocyte migration.Wound Rep Reg15: 907–915Park IS, Kiyomoto H, Alvarez F, Xu YC, Abboud HE, Abboud SL(2008): Preferentialexpression of insulin-like growth factor binding proteins-1, -3, and -5 during early diabeticrenal hypertrophy in rats, Am J Kidney Dis, 32:1000-1010 Schaeffer V, Hansen KM, Morris DR, Abrass CK(2010): Reductions in laminin beta2mRNA translation are responsible for impaired IGFBP-5-mediated mesangial cell migrationin the presence of high glucose.Am J Physiol Renal Physiol, 298:F314-322Singh N,Armstrong DG,Lipsky BA(2005):Preventing foot ulcers in patients withdiabetes.JAMA,293: 217-28. 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