LXR modulation blocks prostaglandin E^sub 2^ production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-02, Vol.107 (8), p.3734
• Main Authors: Li, Ning, Rivéra-Bermúdez, Moisés A, Zhang, Mei, Tejada, Julio, Glasson, Sonya S, Collins-Racie, Lisa A, LaVallie, Edward R, Wang, Yihe, Chang, Ken C N, Nagpal, Sunil, Morris, Elisabeth A, Flannery, Carl R, Yang, Zhiyong
• Format: Article
• Language: English
• Subjects: Cartilage; Cytokines; Effects; Gene expression; Liver; Rodents; Tissues
• ISSN: 0027-8424; 1091-6490

Osteoarthritis (OA), the most common arthritic condition in humans, is characterized by the progressive degeneration of articular cartilage accompanied by chronic joint pain. Inflammatory mediators, such as cytokines and prostaglandin E... (PGE...) that are elevated in OA joints, play important roles in the progression of cartilage degradation and pain-associated nociceptor sensitivity. We have found that the nuclear receptor family transcription factors Liver X Receptors (LXRα and -β) are expressed in cartilage, with LXRβ being the predominant isoform. Here we show that genetic disruption of Lxrβ gene expression in mice results in significantly increased proteoglycan (aggrecan) degradation and PGE... production in articular cartilage treated with IL-1β, indicating a protective role of LXRβ in cartilage. Using human cartilage explants, we found that activation of LXRs by the synthetic ligand GW3965 significantly reduced cytokine-induced degradation and loss of aggrecan from the tissue. Furthermore, LXR activation dramatically inhibited cytokine-induced PGE... production by human osteoarthritic cartilage as well as by a synovial sarcoma cell line. These effects were achieved at least partly by repression of the expression of ADAMTS4, a physiological cartilage aggrecanase, and of cyclooxygenase-2 and microsomal prostaglandin E synthase-1, key enzymes in the PGE... synthesis pathway. Consistent with our in vitro observations, oral administration of GW3965 potently alleviated joint pain in a rat meniscal tear model of osteoarthritis. (ProQuest: ... denotes formulae/symbols omitted.)