Few signaling molecules or extracellular matrix (ECM) genes have been identified as critical regulators of joint cartilage maintenance in the pathogenesis of osteoarthritis (OA) in mice or humans. Recently, we have identified the Notch signaling pathway as a novel and critical regulator of skeletal progenitor cell differentiation during early limb development, as well as, an integral mediator of chondrocyte proliferation and maturation during endochondral bone development. Here we present additional breakthrough discoveries identifying the Notch signaling effector, RBPjk, as a novel and critical regulator of normal articular cartilage and joint maintenance. Specifically, we have discovered that loss of RBPjk in nearly all cells of the joints (Prx1Cre;RBPjkf/f) results in 1) fibrosis and degenerationof the articular cartilage with a significant loss in ECM components, 2) meniscus fibrosis and degeneration, 3) subchondral bone sclerosis, 4) osteophyte formation, and 5) a progressive loss of the Prg4 (lubricin) expressing superficial articular cartilage. Based on these novel findings, w hypothesize that chondrocyte-specific RBPjk-dependent Notch signaling is required for articular cartilage and joint maintenance via regulation of ECM-related molecules, which ultimately controls PRG4 (LUBRICIN) expression, localization, and function within the articular cartilage. To test this hypothesis we have developed three specific aims geared at uncovering the cellular and molecular mechanisms by which RBPjk- dependent Notch signaling maintains articular cartilage. We will generate several mouse genetic models and in vitro articular chondrocyte culture or explant models to test whether: A) cartilage-specific RBPjk-dependent Notch signaling controls articular cartilage maintenance, B) RBPjk-dependent Notch signaling is required to maintain normal PRG4 expression, localization, and function, C) RBPjk and PRG4 genetically and functionally interact during articular cartilage maintenance, D) PRG4 overexpression can rescue the OA phenotype of Prx1Cre;RBPjkf/f mutant mice, E) RBPjk haploinsufficiency accelerates OA progression following traumatic joint injury, and F) transient Notch activation can suppress OA progression following traumatic joint injury. Data generated by this proposal wil likely identify the RBPjk-dependent Notch pathway as a potential target for developing disease modifying osteoarthritis drugs (DMOADs).

Public Health Relevance

We have identified the RBPJk-dependent Notch pathway as an important regulator of articular cartilage and joint maintenance. Our proposal will determine the exact Notch signaling mechanisms responsible for maintaining the articular cartilage phenotype and joint integrity. Data generated by this proposal wil likely implicate RBPjk-dependent Notch signaling in the regulation of specific cartilage-related extracellular matrix molecules, including TENASCIN-C and PRG4, and will likely identify the Notch pathway as a potential target for developing disease modifying osteoarthritis drugs (DMOADs).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
7R01AR063071-03
Application #
8664814
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Tyree, Bernadette
Project Start
2012-07-02
Project End
2017-05-31
Budget Start
2014-07-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
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Qiu, Tao; Xian, Lingling; Crane, Janet et al. (2015) PTH receptor signaling in osteoblasts regulates endochondral vascularization in maintenance of postnatal growth plate. J Bone Miner Res 30:309-17
Kohn, Anat; Rutkowski, Timothy P; Liu, Zhaoyang et al. (2015) Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9. Bone Res 3:15021

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