| First Author | Kawamura I | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 34 | Pages | 29101-13 |
| PubMed ID | 22767605 | Mgi Jnum | J:192973 |
| Mgi Id | MGI:5467175 | Doi | 10.1074/jbc.M112.349415 |
| Citation | Kawamura I, et al. (2012) SnoN suppresses maturation of chondrocytes by mediating signal cross-talk between transforming growth factor-beta and bone morphogenetic protein pathways. J Biol Chem 287(34):29101-13 |
| abstractText | 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-beta (TGF-beta) 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-beta 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-beta pathway inhibited BMP signaling downstream of the Smad activation step. We searched for TGF-beta-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-beta to inhibit BMP signaling and, subsequently, hypertrophic maturation of chondrocytes. |
