RBP‐Jκ–Dependent Notch Signaling Is Required for Murine Articular Cartilage and Joint Maintenance

Abstract

Objective Osteoarthritis (OA) is a degenerative disease resulting in severe joint cartilage destruction and disability. While the mechanisms underlying the development and progression of OA are poorly understood, gene mutations have been identified within cartilage-related signaling molecules implicating impaired cell signaling in OA and joint disease. The Notch pathway has recently been identified as a crucial regulator of growth plate cartilage development and components are expressed in joint tissues. Therefore, we set out to investigate a novel role for Notch signaling in joint cartilage development, maintenance, and the pathogenesis of joint disease. Methods We performed the first mouse genetic studies in which the core Notch signaling component, RBPjκ, was tissue-specifically deleted within joints. The Prx1Cre transgene removed Rbpjκ floxed alleles in mesenchymal joint precursor cells, while the Col2CreERT2 transgene specifically deleted Rbpjκ in postnatal chondrocytes. Articular chondrocyte cultures were also utilized to examine Notch regulation of gene expression. Results Loss of Notch signaling in mesenchymal joint precursor cells does not affect embryonic joint development, but rather results in an early, progressive OA-like pathology. Additionally, partial loss of Notch signaling in postnatal cartilage results in progressive joint cartilage degeneration and an age-related OA-like pathology. Inhibition of Notch signaling alters expression of the ECM-related factors: COL2A1, PRG4, COL10A1, MMP13, and ADAMTSs. Conclusions These data have identified the RBPjκ-dependent Notch pathway as: 1) a novel pathway involved in joint maintenance and articular cartilage homeostasis, 2) a critical regulator of articular cartilage ECM-related molecules, and 3) a potentially important therapeutic target for OA-like joint disease.

Knockdown MiR-302b Alleviates LPS-Induced Injury by Targeting Smad3 in C28/I2 Chondrocytic Cells

“…Recent evidence have revealed that the Notch pathway function as a potential regulator of both catabolic and anabolic molecules in the cartilage extracellular matrix during development [27]. Activation of Notch pathway is crucial for OA development [28, 29].…”

HES factors regulate specific aspects of chondrogenesis and chondrocyte hypertrophy during cartilage development

“…AOS is an autosomal dominant disorder caused by mutations in RBPJ and/or NOTCH1 genes resulting in Notch LOF, although no additional molecular mechanisms underlying this disease are known (Hassed et al, 2012;Stittrich et al, 2014). Notch signaling defects, either GOF or LOF, have also been implicated in osteoarthritis (Mahjoub et al, 2012;Hosaka et al, 2013;Mirando et al, 2013;Sassi et al, 2014;Liu et al, 2015), rheumatoid arthritis (Nakazawa et al, 2001;Park et al, 2015) and osteoporosis (Engin et al, 2008;Hilton et al, 2008;Majewski et al, 2011;Simpson et al, 2011), and have been associated with a predisposition to pathologic fractures (Kung et al, 2010). Studies like the one presented here further our understanding of the molecular players and events that Notch signaling might control during normal skeletal development, as well as our understanding of how they contribute to the pathology of certain skeletal diseases and injury processes.…”

Cartilage damage in osteoarthritis and rheumatoid arthritis—two unequal siblings

“…57 In a further illustration of the complexity of Notch signalling, the early loss of RBPJκ in the limbbud mesenchyme does not affect joint development during embryogenesis, but leads to an early and progressive OAlike pathology. 60 As with the adult inactivation of RBPJκ, knockout of Sdc4 (the gene encoding syndecan4) in mice leads to nearly complete protection from development of OA fol lowing surgical destabilization of the knees. 61 However, the loss of SYND4 has only minimal effects on embry onic skeletal development, although it clearly affects bone regeneration through endochondral ossification, result ing in impaired fracture healing in adults.…”