title: Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance.
abstract: OBJECTIVE
  Notch signaling has been identified as a critical regulator in cartilage development and joint maintenance, and loss of Notch signaling in all joint tissues results in an early and progressive osteoarthritis (OA)-like pathology. This study investigated the targeted cell population within the knee joint in which Notch signaling is required for normal cartilage and joint integrity.
  
  
  METHODS
  Two loss-of-function mouse models were generated with tissue-specific knockout of the core Notch signaling component, RBPjκ. The AcanCre(ERT2) transgene specifically removed Rbpjκ floxed alleles in postnatal joint chondrocytes, while the Col1Cre(2.3kb) transgene deleted Rbpjκ in osteoblast populations, including subchondral osteoblasts. Mutant and control mice were analyzed via histology, immunohistochemistry (IHC), real-time quantitative polymerase chain reaction (qPCR), X-ray, and microCT imaging at multiple time-points.
  
  
  RESULTS
  Loss of Notch signaling in postnatal joint chondrocytes results in a progressive OA-like pathology, and triggered the recruitment of non-targeted fibrotic cells into the articular cartilage potentially due to mis-regulated chemokine expression from within the cartilage. Upon recruitment, these fibrotic cells produced degenerative enzymes that may lead to the observed cartilage degradation and contribute to a significant portion of the age-related OA-like pathology. On the contrary, loss of Notch signaling in subchondral osteoblasts did not affect normal cartilage development or joint maintenance.
  
  
  CONCLUSIONS
  RBPjκ-dependent Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance.
authors.affiliation: Department of Orthopaedics and Rehabilitation, The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Biology, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, Duke Orthopaedic Cellular, Developmental, and Genome Laboratories, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Y
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: A 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, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics and Rehabilitation, The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Zuscik
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, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: O'Keefe
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. Electronic address: matthew.hilton@dm.duke.edu.
authors.forename: M J
authors.initials: MJ
authors.lastname: Hilton
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002358:Cartilage, Articular / Q000254:growth & development / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019902:Chondrocytes / Q000378:metabolism*; D018450:Disease Progression; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010006:Osteoblasts / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051880:Receptors, Notch
keywords: Cartilage; Chondrocytes; Notch signaling; Osteoarthritis; Subchondral bone; Synovium