title: HES factors regulate specific aspects of chondrogenesis and chondrocyte hypertrophy during cartilage development.
abstract: RBPjκ-dependent Notch signaling regulates multiple processes during cartilage development, including chondrogenesis, chondrocyte hypertrophy and cartilage matrix catabolism. Select members of the HES- and HEY-families of transcription factors are recognized Notch signaling targets that mediate specific aspects of Notch function during development. However, whether particular HES and HEY factors play any role(s) in the processes during cartilage development is unknown. Here, for the first time, we have developed unique in vivo genetic models and in vitro approaches demonstrating that the RBPjκ-dependent Notch targets HES1 and HES5 suppress chondrogenesis and promote the onset of chondrocyte hypertrophy. HES1 and HES5 might have some overlapping function in these processes, although only HES5 directly regulates Sox9 transcription to coordinate cartilage development. HEY1 and HEYL play no discernable role in regulating chondrogenesis or chondrocyte hypertrophy, whereas none of the HES or HEY factors appear to mediate Notch regulation of cartilage matrix catabolism. This work identifies important candidates that might function as downstream mediators of Notch signaling both during normal skeletal development and in Notch-related skeletal disorders.
authors.affiliation: Department of Orthopaedics and Rehabilitation, The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Rutkowski
authors.affiliation: Department of Orthopaedics and Rehabilitation, The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Anat
authors.initials: A
authors.lastname: Kohn
authors.affiliation: Department of Orthopaedics and Rehabilitation, The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Deepika
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Department of Orthopaedic Surgery, Duke Orthopaedic Cellular, Developmental and Genome Laboratories, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Yinshi
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Orthopaedics and Rehabilitation, The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA Department of Orthopaedic Surgery, Duke Orthopaedic Cellular, Developmental and Genome Laboratories, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Mirando
authors.affiliation: Department of Orthopaedics and Rehabilitation, The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA Department of Orthopaedic Surgery, Duke Orthopaedic Cellular, Developmental and Genome Laboratories, Duke University School of Medicine, Durham, NC 27710, USA Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA matthew.hilton@dm.duke.edu.
authors.forename: Matthew J
authors.identifier: 0000-0003-3165-267X
authors.initials: MJ
authors.lastname: Hilton
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001846:Bone Development / Q000235:genetics; D002356:Cartilage / Q000196:embryology* / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology*; D020219:Chondrogenesis / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006984:Hypertrophy; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D012097:Repressor Proteins / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000378:metabolism; D000072056:Transcription Factor HES-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; D055758:SOX9 Transcription Factor; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C489685:Hes5 protein, mouse
keywords: Chondrocyte hypertrophy; Chondrogenesis; HES1; HES5; SOX9