Alterations of Dermal Connective Tissue Collagen in Diabetes: Molecular Basis of Aged-Appearing Skin

• Published in: PloS one Vol. 11; no. 4; p. e0153806
• Main Authors: Argyropoulos, Angela J., Robichaud, Patrick, Balimunkwe, Rebecca Mutesi, Fisher, Gary J., Hammerberg, Craig, Yan, Yan, Quan, Taihao
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.04.2016; Public Library of Science (PLoS)
• Subjects: Aging; Aging - metabolism; Atomic force microscopy; Biology and Life Sciences; Biopsy; Cell culture; Collagen; Collagen - metabolism; Connective Tissue - metabolism; Connective tissues; Crosslinking; Dermatology; Dermis; Diabetes; Diabetes mellitus; Diabetes Mellitus - metabolism; Diabetics; Fibrils; Fibroblasts; Foot diseases; Gelatinase A; Glucose - metabolism; Homeostasis; Human subjects; Humans; Interstitial collagenase; Leg ulcers; Liquid oxygen; Lysyl oxidase; Matrix metalloproteinase; Matrix metalloproteinases; Mechanical properties; Medical schools; Medicine and Health Sciences; Microscopy; Microscopy, Atomic Force; Physical Sciences; Physiological aspects; Protein-Lysine 6-Oxidase - metabolism; Proteins; Research and Analysis Methods; Skin; Skin - metabolism; Skin care; Structural integrity; Tissue culture; Traction force; United States; China; Ann Arbor Michigan; United States > US; Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0153806

Alterations of the collagen, the major structural protein in skin, contribute significantly to human skin connective tissue aging. As aged-appearing skin is more common in diabetes, here we investigated the molecular basis of aged-appearing skin in diabetes. Among all known human matrix metalloproteinases (MMPs), diabetic skin shows elevated levels of MMP-1 and MMP-2. Laser capture microdissection (LCM) coupled real-time PCR indicated that elevated MMPs in diabetic skin were primarily expressed in the dermis. Furthermore, diabetic skin shows increased lysyl oxidase (LOX) expression and higher cross-linked collagens. Atomic force microscopy (AFM) further indicated that collagen fibrils were fragmented/disorganized, and key mechanical properties of traction force and tensile strength were increased in diabetic skin, compared to intact/well-organized collagen fibrils in non-diabetic skin. In in vitro tissue culture system, multiple MMPs including MMP-1 and MM-2 were induced by high glucose (25 mM) exposure to isolated primary human skin dermal fibroblasts, the major cells responsible for collagen homeostasis in skin. The elevation of MMPs and LOX over the years is thought to result in the accumulation of fragmented and cross-linked collagen, and thus impairs dermal collagen structural integrity and mechanical properties in diabetes. Our data partially explain why old-looking skin is more common in diabetic patients.