title: A heterocyclic molecule kartogenin induces collagen synthesis of human dermal fibroblasts by activating the smad4/smad5 pathway.
abstract: Declined production of collagen by fibroblasts is one of the major causes of aging appearance. However, only few of compounds found in cosmetic products are able to directly increase collagen synthesis. A novel small heterocyclic compound called kartogenin (KGN) was found to stimulate collagen synthesis of mesenchymal stem cells (MSCs). So, we hypothesized and tested that if KGN could be applied to stimulate the collagen synthesis of fibroblasts. Human dermal fibroblasts in vitro were treated with various concentrations of KGN, with dimethyl sulfoxide (DMSO) serving as the negative control. Real-time reverse-transcription polymerase chain reaction, Western blot, and immunofluorescence analyses were performed to examine the expression of collagen and transforming growth factor beta (TGF-β) signaling pathway. The production of collagen was also tested in vivo by Masson's trichrome stain and immunohistochemistry in the dermis of mice administrated with KGN. Results showed that without obvious influence on fibroblasts' apoptosis and viability, KGN stimulated type-I collagen synthesis of fibroblasts at the mRNA and protein levels in a time-dependent manner, but KGN did not induce expression of α-skeletal muscle actin (α-sma) or matrix metallopeptidase1 (MMP1), MMP9 in vitro. Smad4/smad5 of the TGF-β signaling pathway was activated by KGN while MAPK signaling pathway remained unchanged. KGN also increased type-I collagen synthesis in the dermis of BALB/C mice. Our results indicated that KGN promoted the type-I collagen synthesis of dermal fibroblasts in vitro and in the dermis of mice through activation of the smad4/smad5 pathway. This molecule could be used in wound healing, tissue engineering of fibroblasts, or aesthetic and reconstructive procedures.
authors.affiliation: Depart of Plastic & Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Depart of Plastic & Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: xlzhang@sibs.ac.cn.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Depart of Plastic & Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: dr.liqingfeng@yahoo.com.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Li
mesh_terms: D000813:Anilides / Q000008:administration & dosage*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010795:Phthalic Acids / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*; D051902:Smad5 Protein / Q000378:metabolism*
chemical_list: D000813:Anilides; D024042:Collagen Type I; D006571:Heterocyclic Compounds; D010795:Phthalic Acids; C497796:SMAD4 protein, human; C497797:SMAD5 protein, human; D051901:Smad4 Protein; D051902:Smad5 Protein; C572342:kartogenin
keywords: Collagen I; Fibroblasts; Kartogenin; Smad5; Small molecule