title: Smad6 is induced by BMP-2 and modulates chondrocyte differentiation.
abstract: BMPs regulate cartilage differentiation and have been approved for clinical use as stimulators of bone repair. BMP signaling is complex and there are multiple potential points of regulation, including modulation of Smad signaling, which is inhibited by both Smad6 and Smad7. In the current manuscript we assessed the expression and biological function of Smad6 during chondrocyte differentiation. We found that the induction of chondrocyte differentiation by BMP-2 in chicken sternal embryonic chondrocytes was accompanied by a marked increase in Smad6 mRNA and protein levels. A morpholino antisense oligonucleotide complementary to Smad6 reduced the expression of Smad6 protein and enhanced the stimulatory effect of BMP-2 on both colX and alkaline phosphatase activity. In contrast, over-expression of Smad6 blocked BMP-2 mediated induction of the type X collagen promoter, b2-640 Luc. Therefore, expression studies as well as gain and loss of function experiments suggest that Smad6 participates in an important negative feedback loop whereby BMP-2 mediated effects on chondrocyte differentiation are reduced by induction of Smad6. Additional studies are required to determine the extent to which this pathway participates in pathologic processes involving cartilage.
authors.affiliation: Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, NY 14642, USA. regis_okeefe@urmc.rochester.edu
authors.forename: Xeufeng
authors.initials: X
authors.lastname: Li
authors.forename: Andreia M
authors.initials: AM
authors.lastname: Ionescu
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: Xinping
authors.initials: X
authors.lastname: Zhang
authors.forename: Hicham
authors.initials: H
authors.lastname: Drissi
authors.forename: J Edward
authors.initials: JE
authors.lastname: Puzas
authors.forename: Randy N
authors.initials: RN
authors.lastname: Rosier
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zuscik
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D002642:Chick Embryo; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D051905:Smad6 Protein; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta
chemical_list: D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D051905:Smad6 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta