title: A dual role for NOTCH signaling in joint cartilage maintenance and osteoarthritis.
abstract: Loss of NOTCH signaling in postnatal murine joints results in osteoarthritis, indicating a requirement for NOTCH during maintenance of joint cartilage. However, NOTCH signaling components are substantially increased in abundance in posttraumatic osteoarthritis in humans and mice, suggesting either a reparative or a pathological role for NOTCH activation in osteoarthritis. We investigated a potential dual role for NOTCH in joint maintenance and osteoarthritis by generating two mouse models overexpressing the NOTCH1 intracellular domain (NICD) within postnatal joint cartilage. The first mouse model exhibited sustained NOTCH activation to resemble pathological NOTCH signaling, whereas the second model had transient NOTCH activation, which more closely reflected physiological NOTCH signaling. Sustained NOTCH signaling in joint cartilage led to an early and progressive osteoarthritic-like pathology, whereas transient NOTCH activation enhanced the synthesis of cartilage matrix and promoted joint maintenance under normal physiological conditions. Through RNA-sequencing, immunohistochemical, and biochemical approaches, we identified several targets that could be responsible for NOTCH-mediated cartilage degradation, fibrosis, and osteoarthritis progression. These targets included components of the interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase signaling pathways, which may also contribute to the posttraumatic development of osteoarthritis. Together, these data suggest a dual role for the NOTCH pathway in joint cartilage, and they identify downstream effectors of NOTCH signaling as potential targets for disease-modifying osteoarthritis drugs.
authors.affiliation: Department of Orthopaedics and Rehabilitation, 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: Zhaoyang
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: Jianquan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics and Rehabilitation, 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, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA. Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics and Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zuscik
authors.affiliation: Department of Orthopaedics and Rehabilitation, 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: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
authors.affiliation: Department of Orthopaedics and Rehabilitation, 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. matthew.hilton@dm.duke.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hilton
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse