title: Induction of high temperature requirement A1, a serine protease, by TGF-beta1 in articular chondrocytes of mouse models of OA.
abstract: The goal of this study is to determine whether transforming growth factor beta 1 (Tgf-β1) induces the high temperature requirement A1 (HtrA1) in articular chondrocytes of two mouse models of osteoarthritis (OA). Early onset articular cartilage degeneration in the mouse models was characterized by histology. Expression profiles of Tgf-β1, p-Smad1, p-Smad2/3 and HtrA1 in knee joints of the mouse models were examined by immunofluorescene. By in vitro and ex vivo experiments, human primary chondrocytes and articular cartilages from femoral condyles of mice were treated with recombinant human TGF-β1 and an ALK5 chemical inhibitor, SB431542. The level of HTRA1 mRNA in human and mouse articular chondrocytes was examined by real-time PCR. Chondrocyte clusters were present in the articular cartilage of knee joints in the mouse models. Increased expressions of Tgf-β1, p-Smad2/3 and HtrA1 were detected in the articular chondrocyte of knee joints in the mouse models. The increased expressions of p-Smad2/3 and HtrA1 were co-localized in the articular chondrocyte of the knee joints. The expression of p-Smad1 was hardly detectable in the mouse models and their corresponding wild-type littermates. The level of HTRA1 mRNA was increased in human and mouse articular chondrocytes treated with TGF-β1, compared with that in chondrocytes without the treatment of TGF-β1. The TGF-β1-induced expression of HTRA1 in human and mouse articular chondrocytes was inhibited by SB431542. These results suggest that the Tgf-β1 canonical signaling was activated to induce HtrA1 in the articular chondrocytes of the mouse models of OA.
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, and Harvard Medical School, Boston MA, USA. lin_xu@hms.harvard.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Imanoel
authors.initials: I
authors.lastname: Golshirazian
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Asbury
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, and Harvard Medical School, Boston MA, USA. yefu_li@hms.harvard.edu.
authors.forename: Yefu
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D024161:Collagen Type XI / Q000172:deficiency / Q000235:genetics; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005260:Female; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010003:Osteoarthritis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D024161:Collagen Type XI; D004149:Dioxoles; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; C492073:HtrA1 protein, mouse; D012697:Serine Endopeptidases