RRC ID 43941
Author Kawamura I, Maeda S, Imamura K, Setoguchi T, Yokouchi M, Ishidou Y, Komiya S.
Title SnoN suppresses maturation of chondrocytes by mediating signal cross-talk between transforming growth factor-β and bone morphogenetic protein pathways.
Journal J Biol Chem
Abstract Hypertrophic maturation of chondrocytes is a crucial step in endochondral ossification, whereas abnormally accelerated differentiation of hypertrophic chondrocytes in articular cartilage is linked to pathogenesis of osteoarthritis. This cellular process is promoted or inhibited by bone morphogenetic protein (BMP) or transforming growth factor-β (TGF-β) signaling, respectively, suggesting that these signaling pathways cross-talk during chondrocyte maturation. Here, we demonstrated that expression of Tgfb1 was increased, followed by phosphorylation of Smad2, during BMP-2-induced hypertrophic maturation of ATDC5 chondrocytes. Application of a TGF-β type I receptor inhibitor compound, SB431542, increased the expression of Id1, without affecting the phosphorylation status of Smad1/5/8, indicating that the activated endogenous TGF-β pathway inhibited BMP signaling downstream of the Smad activation step. We searched for TGF-β-inducible effectors that are able to inhibit BMP signaling in ATDC5 cells and identified SnoN. Overexpression of SnoN suppressed the activity of a BMP-responsive luciferase reporter in COS-7 cells as well as expression of Id1 in ATDC5 cells and, subsequently, the expression of Col10a1, a hallmark of hypertrophic chondrocyte maturation. siRNA-mediated loss of SnoN showed opposite effects in BMP-treated ATDC5 cells. In adult mice, we found the highest level of SnoN expression in articular cartilage. Importantly, SnoN was expressed, in combination with phosphorylated Smad2/3, in prehypertrophic chondrocytes in the growth plate of mouse embryo bones and in chondrocytes around the ectopically existing hypertrophic chondrocytes of human osteoarthritis cartilage. Our results indicate that SnoN mediates a negative feedback mechanism evoked by TGF-β to inhibit BMP signaling and, subsequently, hypertrophic maturation of chondrocytes.
Volume 287(34)
Pages 29101-13
Published 2012-8-17
DOI 10.1074/jbc.M112.349415
PII M112.349415
PMID 22767605
PMC PMC3436559
MeSH Animals Benzamides / pharmacology Bone Morphogenetic Protein 2 / genetics Bone Morphogenetic Protein 2 / metabolism* COS Cells Cartilage, Articular / metabolism Cartilage, Articular / pathology Chlorocebus aethiops Chondrocytes / metabolism* Chondrocytes / pathology Dioxoles / pharmacology Gene Expression Regulation* Humans Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism* Mice Osteoarthritis / genetics Osteoarthritis / metabolism Osteoarthritis / pathology Phosphorylation / drug effects Phosphorylation / genetics Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism* Signal Transduction* Smad2 Protein / genetics Smad2 Protein / metabolism Transforming Growth Factor beta1 / antagonists & inhibitors Transforming Growth Factor beta1 / biosynthesis* Transforming Growth Factor beta1 / genetics
IF 4.106
Times Cited 32
Human and Animal Cells