title: Delayed wound closure in fibromodulin-deficient mice is associated with increased TGF-β3 signaling.
abstract: Fibromodulin (FMOD), a small leucine-rich proteoglycan, mediates scarless fetal skin wound repair through, in part, transforming growth factor-β (TGF-β) modulation. Using an adult fmod-null (fmod(-/-)) mouse model, this study further elucidates the interplay between FMOD and TGF-β expression during cutaneous repair and scar formation. Full-thickness skin wounds on fmod(-/-) and wild-type (WT) mice were closed primarily and analyzed. Histomorphometry revealed delayed dermal cell migration leading to delayed wound closure and significantly increased scar size in fmod(-/-) mice relative to WT, which was partially rescued by exogenous FMOD administration. In addition, fmod(-/-) wounds exhibited early elevation (within 24  hours post-wounding) of type I and type II TGF-β receptors as well as unexpectedly high fibroblast expression of TGF-β3, a molecule with reported antifibrotic and antimigratory effects. Consistent with elevated fibroblastic TGF-β3, fmod(-/-) fibroblasts were significantly less motile than WT fibroblasts. fmod(-/-) fibroblasts were also more susceptible to migration inhibition by TGF-β3, leading to profound delays in dermal cell migration. Increased scarring in fmod(-/-) mice indicates that TGF-β3's antimotility effects predominate over its antifibrotic effects when high TGF-β3 levels disrupt early fibroblastic wound ingress. These studies demonstrate that FMOD presence is critical for proper temporospatial coordination of wound healing events and normal TGF-β bioactivity.
authors.affiliation: Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Calvin
authors.initials: C
authors.lastname: Nguyen
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.forename: Hooman
authors.initials: H
authors.lastname: Khorasani
authors.forename: Joyce Z
authors.initials: JZ
authors.lastname: Wang
authors.forename: Janette N
authors.initials: JN
authors.lastname: Zara
authors.forename: Franklin
authors.initials: F
authors.lastname: Chu
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.forename: Shen
authors.initials: S
authors.lastname: Pang
authors.forename: Anh
authors.initials: A
authors.lastname: Le
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002921:Cicatrix / Q000503:physiopathology; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071235:Fibromodulin; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011509:Proteoglycans / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D053782:Transforming Growth Factor beta3 / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; C000604332:Fmod protein, mouse; D011509:Proteoglycans; D053782:Transforming Growth Factor beta3; D000071235:Fibromodulin; D003094:Collagen