RBP‐Jκ–Dependent Notch Signaling Is Required for Murine Articular Cartilage and Joint Maintenance. Issue 10 (24th September 2013)

• Record Type: Journal Article
• Authors: Mirando, Anthony J.; Liu, Zhaoyang; Moore, Tyler; Lang, Alexandra; Kohn, Anat; Osinski, Alana M.; O'Keefe, Regis J.; Mooney, Robert A.; Zuscik, Michael J.; Hilton, Matthew J.
• Is Part Of: Arthritis and rheumatism. Volume 65:Issue 10(2013:Oct.)
• Page Start: 2623
• Page End: 2633
• Publication Date: 2013-09-24
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; Arthritis -- Periodicals; Rheumatic Diseases -- Periodicals; Rhumatisme -- Périodiques; Arthrite -- Périodiques; 616.72
• DOI: 10.1002/art.38076
• Languages: English
• ISSNs: 0004-3591

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art38076-sec-0001" sec-type="section"> <title>Objective</title> <p>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 tissue. This study was undertaken to investigate a novel role for Notch signaling in joint cartilage development, maintenance, and the pathogenesis of joint disease in a mouse model.</p> </sec> <sec id="art38076-sec-0002" sec-type="section"> <title>Methods</title> <p>We performed the first mouse gene study in which the core Notch signaling component, RBP‐Jκ, was tissue specifically deleted within joints. The <italic>Prx1Cre</italic> transgene removed <italic>Rbpjk</italic> loxP‐flanked alleles in mesenchymal joint precursor cells, while the <italic>Col2Cre</italic><sup><italic>ERT2</italic></sup> transgene specifically deleted <italic>Rbpjk</italic> in postnatal chondrocytes. Murine articular chondrocyte cultures were also used to examine Notch regulation of gene expression.</p> </sec> <sec id="art38076-sec-0003" sec-type="section"> <title>Results</title> <p>Loss of Notch signaling in mesenchymal joint precursor cells did not affect embryonic joint development in mice, but rather, resulted in an early, progressive OA‐like pathology. Additionally, partial loss of Notch signaling in murine postnatal cartilage resulted in progressive joint cartilage degeneration and an age‐related OA‐like pathology. Inhibition of Notch signaling altered the expression of the extracellular matrix (ECM)–related factors type II collagen (COL2A1), proteoglycan 4, COL10A1, matrix metalloproteinase 13, and ADAMTS.</p> </sec> <sec id="art38076-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Our findings indicate that the RBP‐Jκ–dependent Notch pathway is a novel pathway involved in joint maintenance and articular cartilage homeostasis, a critical regulator of articular cartilage ECM‐related molecules, and a potentially important therapeutic target for OA‐like joint disease.</p> </sec> </abstract>