title: Fibromodulin-deficiency alters temporospatial expression patterns of transforming growth factor-β ligands and receptors during adult mouse skin wound healing.
abstract: Fibromodulin (FMOD) is a small leucine-rich proteoglycan required for scarless fetal cutaneous wound repair. Interestingly, increased FMOD levels have been correlated with decreased transforming growth factor (TGF)-β1 expression in multiple fetal and adult rodent models. Our previous studies demonstrated that FMOD-deficiency in adult animals results in delayed wound closure and increased scar size accompanied by loose package collagen fiber networks with increased fibril diameter. In addition, we found that FMOD modulates in vitro expression and activities of TGF-β ligands in an isoform-specific manner. In this study, temporospatial expression profiles of TGF-β ligands and receptors in FMOD-null and wild-type (WT) mice were compared by immunohistochemical staining and quantitative reverse transcriptase-polymerase chain reaction using a full-thickness, primary intention wound closure model. During the inflammatory stage, elevated inflammatory infiltration accompanied by increased type I TGF-β receptor levels in individual inflammatory cells was observed in FMOD-null wounds. This increased inflammation was correlated with accelerated epithelial migration during the proliferative stage. On the other hand, significantly more robust expression of TGF-β3 and TGF-β receptors in FMOD-null wounds during the proliferative stage was associated with delayed dermal cell migration and proliferation, which led to postponed granulation tissue formation and wound closure and increased scar size. Compared with WT controls, expression of TGF-β ligands and receptors by FMOD-null dermal cells was markedly reduced during the remodeling stage, which may have contributed to the declined collagen synthesis capability and unordinary collagen architecture. Taken together, this study demonstrates that a single missing gene, FMOD, leads to conspicuous alternations in TGF-β ligand and receptor expression at all stages of wound repair in various cell types. Therefore, FMOD critically coordinates temporospatial distribution of TGF-β ligands and receptors in vivo, suggesting that FMOD modulates TGF-β bioactivity in a complex way beyond simple physical binding to promote proper wound healing.
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Calvin
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Chingyun
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Department of Emergency Medicine, State University of New York Downstate/Kings Country Hospital Center, New York, New York, United States of America.
authors.forename: Joyce Z
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Todd Matthew
authors.initials: TM
authors.lastname: Rackohn
authors.affiliation: Department of Psychobiology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Dwarak Reddy
authors.initials: DR
authors.lastname: Enjamuri
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Murphy
authors.affiliation: Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.affiliation: UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California Los Angeles, Los Angeles, California, United States of America; Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000172:deficiency*; D005347:Fibroblasts / Q000502:physiology; D000071235:Fibromodulin; D015870:Gene Expression; D005786:Gene Expression Regulation; D008024:Ligands; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D011509:Proteoglycans / Q000172:deficiency*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014945:Wound Healing
chemical_list: D016326:Extracellular Matrix Proteins; C000604332:Fmod protein, mouse; D008024:Ligands; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000071235:Fibromodulin