Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure.
The loss of TGFbeta or its downstream mediator, Smad3, key players in tissue repair, accelerates closure of incisional wounds in mice. In contrast, we now report that excisional ear wounds in mice lacking Smad3 enlarge compared with wild-type controls resulting from changes in extracellular matrix molecules, which alter the mechanotransduction properties of these wounds. Specifically, levels of elastin and glycosoaminoglycans are increased, collagen fibers are more compactly organized, and matrix modulators like integrins, TGFbeta1, and matrix metalloproteinases (MMPs) are altered both basally and after wounding in Smad3 knockout mice. Mechanical testing of dorsal skin correlates these changes in matrix composition with functional parameters, specifically an increased elastic modulus, suggesting an imbalance of tissue forces. We propose that the altered mechanical elastic properties translate into a persistent retractile force that is opposed by decreased wound contractile forces contributing to the enlarging ear wound in Smad3 knockout mice. These studies highlight a previously undescribed role for Smad3 in the mechanotransduction of matrix unsupported ear wound closure.
Arany
Praveen R
PR
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Flanders
Kathleen C
KC
Kobayashi
Tetsu
T
Kuo
Catherine K
CK
Stuelten
Christina
C
Desai
Kartiki V
KV
Tuan
Rocky
R
Rennard
Stephen I
SI
Roberts
Anita B
AB
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004431:Ear, External / Q000378:metabolism / Q000473:pathology; D004548:Elasticity; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical; D014945:Wound Healing
D015415:Biomarkers; D039302:Integrin alphaVbeta3; D016023:Integrins; D019030:Receptors, Vitronectin; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C064660:integrin alphaVbeta5; D011505:Protein-Tyrosine Kinases