Melton LJ III, Leibson CL, Achenbach SJ, et al: Fracture risk in type 2 diabetes: update of a population-based study. J Bone Miner Res 23: 1334, 2008.
Melton LJ III, Riggs BL, Leibson CL, et al: A bone structural basis for fracture risk in diabetes. J Clin Endocrinol Metab 93: 4804, 2008.
Schwartz AV, Sellmeyer DE, Ensrud KE, et al: Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab 86: 32, 2001.
Lavery LA, Peters EJ, Williams JR, et al: Reevaluating the way we classify the diabetic foot: restructuring the diabetic foot risk classification system of the International Working Group on the Diabetic Foot. Diabetes Care 31: 154, 2008.
Wukich DK, Kline AJ: The management of ankle fractures in patients with diabetes. J Bone Joint Surg Am 90: 1570, 2008.
Papa J, Myerson M, Girard P: Salvage, with arthrodesis, in intractable diabetic neuropathic arthropathy of the foot and ankle. J Bone Joint Surg Am 75: 1056, 1993.
Tisdel CL, Marcus RE, Heiple KG: Triple arthrodesis for diabetic peritalar neuroarthropathy. Foot Ankle Int 16: 332, 1995.
Glowacki J: Angiogenesis in fracture repair. Clin Orthop Relat Res 355 (suppl): S82, 1998.
Beamer B, Hettrich C, Lane J: Vascular endothelial growth factor: an essential component of angiogenesis and fracture healing. HSS J 6: 85, 2010.
Tsubaki M, Kato C, Manno M, et al: Macrophage inflammatory protein-1α (MIP-1α) enhances a receptor activator of nuclear factor κB ligand (RANKL) expression in mouse bone marrow stromal cells and osteoblasts through MAPK and PI3K/Akt pathways. Mol Cell Biochem 304: 53, 2007.
Cao JJ: Effects of obesity on bone metabolism. J Orthop Surg Res 6: 30, 2011.
Elefteriou F, Takeda S, Ebihara K, et al: Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci U S A 101: 3258, 2004.
Brussee V, Guo G, Dong Y, et al: Distal degenerative sensory neuropathy in a long-term type 2 diabetes rat model. Diabetes 57: 1664, 2008.
Calcutt NA, Chaplan SR: Spinal pharmacology of tactile allodynia in diabetic rats. Br J Pharmacol 122: 1478, 1997.
Bonnarens F, Einhorn TA: Production of a standard closed fracture in laboratory animal bone. J Orthop Res 2: 97, 1984.
Macey LR, Kana SM, Jingushi S, et al: Defects of early fracture-healing in experimental diabetes. J Bone Joint Surg Am 71: 722, 1989.
Garcia P, Holstein JH, Histing T, et al: A new technique for internal fixation of femoral fractures in mice: impact of stability on fracture healing. J Biomech 41: 1689, 2008.
Clark JB, Palmer CJ, Shaw WN: The diabetic Zucker fatty rat. Proc Soc Exp Biol Med 173: 68, 1983.
Chen D, Wang MW: Development and application of rodent models for type 2 diabetes. Diabetes Obes Metab 7: 307, 2005.
Bekker PJ, Holloway D, Nakanishi A, et al: The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 16: 348, 2001.
Bolander ME: Regulation of fracture repair by growth factors. Proc Soc Exp Biol Med 200: 165, 1992.
Kawaguchi H, Kurokawa T, Hanada K, et al: Stimulation of fracture repair by recombinant human basic fibroblast growth factor in normal and streptozotocin-diabetic rats. Endocrinology 135: 774, 1994.
Tyndall WA, Beam HA, Zarro C, et al: Decreased platelet derived growth factor expression during fracture healing in diabetic animals. Clin Orthop Relat Res 408: 319, 2003.
Blakytny R, Jude E: The molecular biology of chronic wounds and delayed healing in diabetes. Diabet Med 23: 594, 2006.
Jude EB, Blakytny R, Bulmer J, et al: Transforming growth factor-β 1, 2, 3 and receptor type I and II in diabetic foot ulcers. Diabet Med 19: 440, 2002.
Wieman TJ; Becaplermin Gel Studies Group: Clinical efficacy of becaplermin (rhPDGF-BB) gel. Am J Surg 176: 74S, 1998.
Wieman TJ, Smiell JM, Su Y: Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers: a phase III randomized placebo-controlled double-blind study. Diabetes Care 21: 822, 1998.
Bennett SP, Griffiths GD, Schor AM, et al: Growth factors in the treatment of diabetic foot ulcers. Br J Surg 90: 133, 2003.
Tsang MW, Wong WK, Hung CS, et al: Human epidermal growth factor enhances healing of diabetic foot ulcers. Diabetes Care 26: 1856, 2003.
Wildemann B, Bamdad P, Holmer C, et al: Local delivery of growth factors from coated titanium plates increases osteotomy healing in rats. Bone 34: 862, 2004.
Wildemann B, Schmidmaier G, Brenner N, et al: Quantification, localization, and expression of IGF-I and TGF-β1 during growth factor-stimulated fracture healing. Calcif Tissue Int 74: 388, 2004.
Weiss S, Zimmermann G, Pufe T, et al: The systemic angiogenic response during bone healing. Arch Orthop Trauma Surg 129: 989, 2009.
Zimmermann G, Henle P, Kusswetter M, et al: TGF-β1 as a marker of delayed fracture healing. Bone 36: 779, 2005.
Zimmermann G, Moghaddam A, Reumann M, et al: TGF-β1 as a pathophysiological factor in fracture healing [in German]. Unfallchirurg 110: 130, 2007.
Gandhi A, Doumas C, O'Connor JP, et al: The effects of local platelet rich plasma delivery on diabetic fracture healing. Bone 38: 540, 2006.
Kukita T, Nomiyama H, Ohmoto Y, et al: Macrophage inflammatory protein-1 α (LD78) expressed in human bone marrow: its role in regulation of hematopoiesis and osteoclast recruitment. Lab Invest 76: 399, 1997.
Choi SJ, Cruz JC, Craig F, et al: Macrophage inflammatory protein 1-α is a potential osteoclast stimulatory factor in multiple myeloma. Blood 96: 671, 2000.
Hamrick MW, Pennington C, Newton D, et al: Leptin deficiency produces contrasting phenotypes in bones of the limb and spine. Bone 34: 376, 2004.
van Dielen FM, van't Veer C, Schols AM, et al: Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals. Int J Obes Relat Metab Disord 25: 1759, 2001.
Diaz VA, Mainous AG III, Baker R, et al: How does ethnicity affect the association between obesity and diabetes? Diabet Med 24: 1199, 2007.
Mahdy RA, Nada WM, Hadhoud KM, et al: The role of vascular endothelial growth factor in the progression of diabetic vascular complications. Eye 24: 1576, 2010.
Tavakkoly-Bazzaz J, Amoli MM, Pravica V, et al: VEGF gene polymorphism association with diabetic neuropathy. Mol Biol Rep 37: 3625, 2010.
Persons with diabetes have a higher incidence of fractures compared with persons without diabetes. However, there is little published information concerning the deleterious effect of late-stage diabetes on fracture healing. There are no studies using animal models that evaluate the effect of advanced diabetes on fracture healing. The purpose of our study was to evaluate cytokine expression, specifically macrophage inflammatory protein 1 (MIP-1) and vascular endothelial growth factor, in fracture healing in a type 2 diabetes rat model.
We evaluated biomarker expression after femur fracture using a rat model. The two groups consisted of 24 Zucker diabetic rats (study group) and 12 Zucker lean rats (control group). An independent reviewer was used to assess delayed union. We evaluated serum samples 2, 4, 7, and 14 days after surgery for MIP-1, vascular endothelial growth factor, leptin, and other cytokine levels.
At 3 weeks, Kaplan-Meier estimates showed that 45.8% of femur fractures in Zucker diabetic rats had healed, whereas 81.8% of those in Zucker lean rats had healed (P = .02). A logistic regression model to predict fast healing that included the three cytokines and diabetes status showed that the only factor achieving significance was MIP-1α. Vascular endothelial growth factor was the only biomarker to show significance compared with delayed healing.
These results confirm significant differences in biomarker expression between diabetic and nondiabetic rats during bone healing. The key factors for bone healing may appear early in the healing process, whereas differences in diabetes versus nondiabetes are seen later in the healing process. Increased levels of MIP-1α were associated with the likelihood of delayed healing.