Lysophosphatidic acid inhibits TGF-beta-mediated stimulation of type I collagen mRNA stability via an ERK-dependent pathway in dermal fibroblasts.
Lysophosphatidic acid (LPA) is a serum-derived pleiotropic mediator with a potential role in wound repair. Since extracellular matrix (ECM) deposition is a critical part of wound healing, this study was designed to examine whether LPA is involved in ECM regulation. Using human dermal fibroblasts, we demonstrate that LPA counteracts transforming growth factor-beta (TGF-beta) stimulation of type I collagen mRNA and protein. This factor elicits its inhibitory effects at the posttranscriptional level via destabilization of type I collagen mRNA. Furthermore, using the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059, we show that the extracellular signal-regulated kinase (ERK) pathway is a negative regulator of the TGF-beta-induced stabilization of type I collagen mRNA, and that the activation of the ERK pathway by LPA mediates their inhibitory effects on collagen production. In conclusion, this study describes a novel function for LPA as an antagonist of TGF-beta induced ECM deposition. These findings may be relevant to physiologic wound repair and may be useful in designing therapeutic agents to prevent excessive scarring.
Sato
Madoka
M
Department of Dermatology, Dokkyo University School of Medicine, Mibu, Tochigi, 321-0293, Japan. satomad@excite.co.jp
Shegogue
Daniel
D
Hatamochi
Atsushi
A
Yamazaki
Soji
S
Trojanowska
Maria
M
D015152:Blotting, Northern; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D024042:Collagen Type I; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008246:Lysophospholipids; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D012313:RNA; D003094:Collagen; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases; C032881:lysophosphatidic acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one