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Overexpression of the gap junction protein Cx43 as found in diabetic foot ulcers can retard fibroblast migration.
Mendoza-Naranjo A, Cormie P, Serrano AE, Wang CM, Thrasivoulou C, Sutcliffe JE, Gilmartin DJ, Tsui J, Serena TE, Phillips AR, Becker DL. Cell Biol Int. 2012 Mar 28.
Poor healing of diabetic foot ulcers is a major clinical problem that can be extremely debilitating and lead to lower limb amputation. In the normal acute wound, the Connexin 43 gap junction protein is down-regulated at the wound edge as a precursor to cell migration and healing. In fibroblasts from the human chronic diabetic foot ulcer wound edge there was a striking and significant 10-fold elevation of Connexin 43 protein, as well as a 6-fold increase in N-cadherin and a 2-fold increase in Zonular Occludin-1, as compared to unwounded skin. In streptozotocin diabetic rats Connexin 43 was found to be upregulated in intact dermal fibroblasts in direct proportion to blood glucose levels and increased 2-fold further in response to wounding of the skin. To mimic diabetes, 3T3 fibroblasts were cultured under different concentrations of glucose or mannitol and Connexin 43 protein intercellular communication and migration rates were determined. Cultures of fibroblasts in very high (40mM) glucose conditions showed significantly elevated Connexin 43 protein levels, as shown by immunostaining and Western Blot, and significantly increasing gap junctional communication, as shown by dye transfer. In scratch wound healing assays, increased levels of Connexin 43 from high glucose resulted in repressed filopodial extensions and significantly slower migration rates than in either standard conditions (5.5mM glucose) or the osmotic control of mannitol. Conversely, when glucose-induced Connexin 43 upregulation was prevented with Connexin43shRNA transduction, the fibroblasts extended long filopodia and migrated significantly faster. Connexin 43 protein was upregulated in fibroblasts in diabetic foot ulcers as well as after high glucose exposure in culture which correlated with inhibition of fibroblast migration and is likely to contribute to impaired wound healing.