Alterations of Dermal Connective Tissue Collagen in Diabetes: Molecular Basis of Aged-Appearing Skin.
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.
Department of Psychiatry, University of Washington, Seattle, Washington, United States of America.
Angela J
AJ
Argyropoulos
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Patrick
P
Robichaud
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Rebecca Mutesi
RM
Balimunkwe
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Gary J
GJ
Fisher
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Craig
C
Hammerberg
Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Yan
Y
Yan
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Taihao
0000-0002-0954-5109
T
Quan
D000375:Aging / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism*; D003238:Connective Tissue / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D018625:Microscopy, Atomic Force; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D012867:Skin / Q000378:metabolism*
D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D005947:Glucose