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Peroxisome proliferator-activated receptor δ promotes the progression of posttraumatic osteoarthritis in a mouse model
Arthritis and Rheumatology
  • A. Ratneswaran, The University of Western Ontario
  • E. A. LeBlanc, The University of Western Ontario
  • E. Walser, The University of Western Ontario
  • I. Welch, The University of Western Ontario
  • J. S. Mort, Université McGill
  • N. Borradaile, The University of Western Ontario
  • F. Beier, The University of Western Ontario
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Objective. Osteoarthritis (OA) is a serious disease of the entire joint, characterized by articular cartilage degeneration, subchondral bone changes, osteophyte formation, and synovial hyperplasia. Currently, there are no pharmaceutical treatments that can slow the disease progression, resulting in greatly reduced quality of life for patients and the need for joint replacement surgeries in many cases. The lack of available treatments for OA is partly due to our incomplete understanding of the molecular mechanisms that promote disease initiation and progression. The purpose of the present study was to examine the role of the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) as a promoter of cartilage degeneration in a mouse model of posttraumatic OA. Methods. Mouse chondrocytes and knee explants were treated with a pharmacologic agonist of PPARδ (GW501516) to evaluate changes in gene expression, histologic features, and matrix glycosaminoglycan breakdown. In vivo, PPARδ was specifically deleted from the cartilage of mice. Histopathologic scoring according to the Osteoarthritis Research Society International (OARSI) system and immunohistochemical analysis were used to compare mutant and control mice subjected to surgical destabilization of the medial meniscus (DMM). Results. In vitro, PPARδ activation by GW501516 resulted in increased expression of several proteases in chondrocytes, as well as aggrecan degradation and glycosaminoglycan release in knee joint explants. In vivo, cartilage-specific PPARδ-knockout mice did not display any abnormalities of skeletal development but showed marked protection in the DMM model of posttraumatic OA (as compared to control littermates). OARSI scoring and immunohistochemical analyses confirmed strong protection of mutant mice from DMM-induced cartilage degeneration. Conclusion. These data demonstrate a catabolic role of endogenous PPARδ in posttraumatic OA and suggest that pharmacologic inhibition of PPARδ is a promising therapeutic strategy.

Citation Information
A. Ratneswaran, E. A. LeBlanc, E. Walser, I. Welch, et al.. "Peroxisome proliferator-activated receptor δ promotes the progression of posttraumatic osteoarthritis in a mouse model" Arthritis and Rheumatology Vol. 67 Iss. 2 (2015) p. 454 - 464
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