Skin wound healing in diabetic β6 integrin-deficient mice.
Integrin αvβ6 is a heterodimeric cell surface receptor, which is absent from the normal epithelium, but is expressed in wound-edge keratinocytes during re-epithelialization. However, the function of the αvβ6 integrin in wound repair remains unclear. Impaired wound healing in patients with diabetes constitutes a major clinical problem worldwide and has been associated with the accumulation of advanced glycated endproducts (AGEs) in the tissues. AGEs may account for aberrant interactions between integrin receptors and their extracellular matrix ligands such as fibronectin (FN). In this study, we compared healing of experimental excisional skin wounds in wild-type (WT) and β6-knockout (β6(-/-) ) mice with streptozotocin-induced diabetes. Results showed that diabetic β6(-/-) mice had a significant delay in early wound closure rate compared with diabetic WT mice, suggesting that αvβ6 integrin may serve as a protective role in re-epithelialization of diabetic wounds. To mimic the glycosylated wound matrix, we generated a methylglyoxal (MG)-glycated variant of FN. Keratinocytes utilized αvβ6 and β1 integrins for spreading on both non-glycated and FN-MG, but their spreading was reduced on FN-MG. These findings indicated that glycation of FN and possibly other integrin ligands could hamper keratinocyte interactions with the provisional matrix proteins during re-epithelialization of diabetic wounds.
Jacobsen
Jasper N
JN
Laboratory of Periodontal Biology, Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC, Canada.
Steffensen
Bjørn
B
Häkkinen
Lari
L
Krogfelt
Karen A
KA
Larjava
Hannu S
HS
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000276:immunology / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D039641:Integrin beta Chains / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011765:Pyruvaldehyde / Q000378:metabolism; D014945:Wound Healing / Q000276:immunology*
D005353:Fibronectins; D017127:Glycation End Products, Advanced; D039641:Integrin beta Chains; C072170:integrin beta6; D011765:Pyruvaldehyde