Peroxisome Proliferator Activated Receptor Delta in Osteoarthritis

Osteoarthritis (OA) affects 1 in 10 Canadians and is a leading cause of mobility disability worldwide. This condition is characterized by cartilage degeneration, subchondral bone damage and inflammation of the synovium, resulting in pain and joint failure. No treatments exist to stop the progression of this disease, and its underlying molecular mechanisms remain largely unknown. We previously identified the peroxisome proliferator activated receptor (PPAR) nuclear receptor pathway as altered in OA cartilage. In-vitro studies identified PPARd as a promoter of catabolic activity in chondrocytes, providing the foundation for my overarching hypothesis that PPARd inhibition is protective in OA. I commenced my thesis by generating Ppard cartilage-specific knockout mice to investigate the role of this gene in skeletal development. I evaluated the anatomy, morphology, and cellular organization of the skeleton, long bones and growth plate through histological techniques and concluded that there were no congenital abnormalities predisposing these mice to OA. I next compared the progression of disease severity between Ppard KO mice and WT controls after destabilization of medial meniscus surgery to induce post-traumatic osteoarthritis (PTOA). After histopathological assessment, I found that mice lacking PPARd were significantly protected from cartilage damage and displayed decreased cartilage matrix breakdown in lesioned areas. Subsequently, I evaluated pharmacological inhibition of PPARd in PTOA in rats. I discovered that PPARd inhibitors prevent behavioural modifications associated with OA development and pain. However, their effects on structural progression of OA remains inconclusive and more stringent quantitative methods are needed to assess these differences. Lastly, I examined global gene expression through microarray analysis of chondrocytes treated with a PPARd agonist. I discovered that genes induced were primarily involved in lipid metabolism, which translated into functional changes in lipid metabolism, such as significantly decreased cellular triglycerides. Mediators of oxidative stress were also identified, and Txnip, an inhibitor of anti-oxidant thioredoxin, was significantly elevated in response to PPARd activation. Immunohistochemistry revealed increased TXNIP staining in OA cartilage, but substantially less in cartilage of Ppard KO mice. Overall, these data demonstrate a novel role for PPARd in Osteoarthritis. My data support my hypothesis that PPARd inhibition is protective in OA

A top-notch dilemma: The complex role of NOTCH signaling in osteoarthritis

A study by Liu et al. in the current issue of Science Signaling explores the complex dual role of NOTCH in the etiology of osteoarthritis by comparing gain-offunction mouse models representing aberrant pathological signaling and transient physiological signaling

Nuclear receptors as potential drug targets in osteoarthritis

Osteoarthritis is amongst the major causes of disability worldwide, but no medications that can slow or stop progression of this disorder have been identified. Recent evidence suggests roles for a variety of members of the nuclear receptor family of ligand-activated transcription factors in various forms of osteoarthritis. Since nuclear receptors are amongst the major classes of drug targets, these studies suggest that modulators of nuclear receptor activity might provide novel strategies to treat osteoarthritis. This review focuses on recent advances in our understanding of the role of nuclear receptors in osteoarthritis onset and progression, as well as their therapeutic implications. Future studies should continue to examine the possible roles of additional nuclear receptors in the pathophysiology of different types of osteoarthritis

Contribution of microRNA-27b-3p to synovial fibrotic responses in knee osteoarthritis

OBJECTIVES: Synovial fibrosis contributes to osteoarthritis (OA) pathology but the underlying mechanisms remain unknown. We have observed increased microRNA (miR)-27b-3p levels in synovial fluid of late-stage radiographic knee OA patients. Here, we determined the contribution of miR-27b-3p to synovial fibrosis. METHODS: Synovium sections obtained from Kellgren-Lawrence-graded knee OA patients and a mouse model of knee OA (destabilization of medial meniscus; DMM) were stained for miR-27b-3p using in situ hybridization. Effects of intra-articular injections of miR-27b-3p mimic into naïve mouse knee joints, and miR-27b-3p inhibitor in the DMM model were also examined. MiR-27b-3p mimic or inhibitor transfection experiments were performed on human OA fibroblast-like synoviocytes (FLS) using RT-qPCR array, RNA sequencing, RT-qPCR, Western blotting, immunofluorescence and migration assays. RESULTS: MiR-27b-3p expression increased in the synovium of knee OA patients and after DMM surgery in mice. Intra-articular injections of miR-27b-3p mimic injected in mouse knee joints induced a synovial fibrosis-like phenotype with increased synovitis scores and increased COL1A1 and α-SMA expression. In the DMM model, miR-27b-3p inhibitor decreased α-SMA with unchanged COL1A1 expression and synovitis scores. MiR-27b-3p mimic treatment of human OA FLS induced pro-fibrotic responses including increased migration and expression of key extracellular matrix (ECM) genes, while inhibitor transfection had opposite effects. RNA-sequencing identified a PPARG/ADAMTS8 signaling axis regulated by miR-27b-3p in OA FLS. MiR-27b-3p mimic-transfected OA FLS treated with the PPARG agonist rosiglitazone or ADAMTS8-siRNA exhibited altered expression of select ECM genes. CONCLUSIONS: This study demonstrates a key role of miR-27b-3p in ECM regulation associated with synovial fibrosis during OA