PPARdelta promotes the progression of post-traumatic osteoarthritis

Abstract

s / Osteoarthritis and Cartilage 22 (2014) S57–S489 S370 micro computed tomography (mCT, Skyscan 1172, 4.5 um resolution) of the knee at 3, 7, 14, 28, 56, 84, 112 days (n 8 per group). Changes in subchondral bone at 28 days post DMM (n 1⁄4 6) were measured separating the subchondral plate from the subchondral tabecular structures. Results: Osteophytes were identified in 70% of mice by day 7 post DMM and in all mice by day 14. At day 7 most samples had 1 or 2 osteophytes, with somehavingup to 4 osteophytes by day 14. Fromday 28onwards the osteophytes fused and formed into one or two large osteophytes. Osteophytes increased in size and bone content with time, plateauing by day 112. The trabeculae of the subchondral bone at day 28 showed a significant (p<0.03) decrease in trabecular number on the medial side of both theDMMand shamoperatedmicewhen compared to the respective contralateral leg. In the sham samples, the reduction of trabecular number translated to a significant increase in trabecular space, whereas in the DMM mice an increase in trabecular thickness occurred, eliminating the increase in trabecular space. Although bone changes occurred within a week of DMM induction, cartilage damage scores were not significant until day 56 (p<0.05), compared to earlier time points. Conclusions:We herein charachterised differential bone changes in the DMM murine model of OA: there was accelerated osteophyte development within the first week, whereas subchondral bone changes were not evident until day 28. Interestingly sham operated animals showed subchondral trabecular bone loss in the ipsilateral knee, highlighting the need to use the contralateral knee as an internal control. The early bone changes in this OA model significantly preceded cartilage degradation, consistent with altered bone biology being an important driver of OA pathogenesis.Supported By Arthritis Research UK (20199). 651 PPARDELTA PROMOTES THE PROGRESSION OF POST-TRAUMATIC OSTEOARTHRITIS A. Ratneswaran y, E. LeBlanc y, E. Walser y, I. Welch y, J.S. Mort zx, N. Borradaile y, F. Beier yk. yWestern Univ., London, ON, Canada; zMcGill Univ., Montreal, QC, Canada; x Shriner’s Hosp. for Children, Montreal, ON, Canada; k Children’s Hlth.Res. Inst., London, ON, Canada Background: Osteoarthritis (OA) is a degenerative joint disorder, characterized by the breakdown of articular cartilage, subchondral bone thickening, osteophyte formation and synovial inflammation. The human burden of this disease influences both the independence and quality of life of those afflicted. Currently, there are no pharmaceutical treatments to slow, stop or reverse disease progression, resulting in greatly reduced quality of life for OA patients and the need for joint replacement surgeries in many cases. The lack of available treatments for OA is partially due to our incomplete understanding of themolecular mechanisms promoting disease initiation and progression. Recent findings from our laboratory indicate that activation of the transcription factor PPARdelta induces the expression of enzymes involved in proteoglycan breakdown and can lead to cartilage degeneration in OA, prompting us to speculate whether inhibition of PPARdelta, can protect from cartilage breakdown in OA. Purpose:We aimed to characterize the role of PPARdelta in OA through in-vitro, ex-vivo, and in-vivo studies to determine whether it is a feasible target for OA therapy. Hypothesis: We hypothesize that inhibition of PPARdelta will slow the progression of OA in animal models. Methods: Primary mouse chondrocytes and cartilage explants were treated with a pharmacological PPARdelta agonist (GW501516) to evaluate changes in gene expression (qPCR), and histology (Safranin-O, immunohistochemistry) consistent with OA development. In order to examine the role of PPARdelta in-vivo, cartilage-specific knockout mice and wild-type littermate controls were subjected to destabilization of medial meniscus surgery (DMM) at 20 weeks of age. 8 weeks postsurgery mice were compared through classical histological and biochemical measures of OA progression including Safranin-O staining with OARSI scoring, immunohistochemistry for cartilage matrix breakdown products, and picrosirius red staining for collagen fiber structure and orientation. Results: In vitro, PPARdelta agonism (by GW501516) results in the upregulation of expression of proteases implicated in cartilage degeneration (including MMPs, and ADAMTS genes). Activation of PPARdelta also results in proteoglycan breakdown in the cartilage matrix of an explant culture system. Mice with cartilage-specific deletion of PPARdelta do not demonstrate any abnormalities in skeletal growth or development, but do show significant chondroprotection in comparison to wild-type littermate controls after surgical induction of OA. OARSI scoring and immunohistochemistry confirm strong protection of mutant mice against cartilage matrix breakdown, and decreased breakdown products in the cartilage of PPARdelta knockout mice. Conclusion: This study provides strong evidence for catabolic roles of endogenous PPARdelta in post-traumatic OA and suggests that pharmacological inhibition of PPARdelta is a promising therapeutic strategy. 652 DKK3 PREVENTS MATRIX LOSS INDUCED BY PRO-INFLAMMATORY CYTOKINES IN HUMAN CARTILAGE EXPLANTS S.M. Walzer, D. Bieder, B. Simon, R. Windhager, S. Toegel. Karl Chiari Lab for Orthopaedic Biology, Dept. of Orthopaedics, Med. Univ. of Vienna,