Ligands for Retinoic Acid Receptors Are Elevated in Osteoarthritis and May Contribute to Pathologic Processes in the Osteoarthritic Joint
ABSTRACT Vitamin A derivatives, including all-trans-retinoic acid (ATRA), have a well-established role during skeletal development and limb formation and have been shown to have profound effects on chondrocyte phenotype. The aim of this study was to elucidate the effects of retinoids and components of the retinoid metabolic pathway on chondrocyte phenotype in the tibiofemoral joints of patients with osteoarthritis (OA), to show that the retinoids can have multiple effects relevant to the OA disease process.
Human explant tissue and a chondrocyte-like cell line were treated with ATRA, and the responses of 4 key markers of chondrocyte phenotype were analyzed. In addition, the effects of ATRA on a number of novel genes associated with OA were assessed using a low-density microarray containing 80 disease marker genes.
Vitamin A metabolite levels were elevated in synovial fluid, serum, and cartilage from patients with OA. Expression profiling of a retinoic acid receptor alpha coactivator protein, P/CAF, demonstrated elevated expression in patients with OA, suggesting the potential for increased signaling via the retinoid receptors in the disease. ATRA increased the levels of matrix metalloproteinase 13 and aggrecanase activity in human cartilage explants and in a human chondrocyte cell line. Furthermore, ATRA altered the expression of a wide range of relevant genes, including the types I, II, IX, and XI collagen genes, toward a nonchondrogenic and OA-like phenotype.
These results suggest that retinoid signaling could have a central role in OA, and that components of the pathway may provide potential disease biomarkers or targets for therapeutic intervention.
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ABSTRACT: Osteoarthritis (OA) is a degenerative joint disease for which there are no disease-modifying drugs. It is a leading cause of disability in the UK. Increasing age and obesity are both major risk factors for OA and the health and economic burden of this disease will increase in the future. Focusing on compounds from the habitual diet that may prevent the onset or slow the progression of OA is a strategy that has been under-investigated to date. An approach that relies on dietary modification is clearly attractive in terms of risk/benefit and more likely to be implementable at the population level. However, before undertaking a full clinical trial to examine potential efficacy, detailed molecular studies are required in order to optimise the design. This review focuses on potential dietary factors that may reduce the risk or progression of OA, including micronutrients, fatty acids, flavonoids and other phytochemicals. It therefore ignores data coming from classical inflammatory arthritides and nutraceuticals such as glucosamine and chondroitin. In conclusion, diet offers a route by which the health of the joint can be protected and OA incidence or progression decreased. In a chronic disease, with risk factors increasing in the population and with no pharmaceutical cure, an understanding of this will be crucial.Proceedings of The Nutrition Society 02/2014; DOI:10.1017/S0029665113003935 · 4.94 Impact Factor
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ABSTRACT: Objective: We evaluated the effect of a reduction in the systemic ratio of n-6:n-3 polyunsaturated fatty acids (PUFAs) on changes in inflammation, glucose metabolism, and the idiopathic development of knee osteoarthritis (OA) in mice. We hypothesized that a lower ratio of n-6:n-3 PUFAs would protect against OA markers in cartilage and synovium, but not bone. Design: Male and female fat-1 transgenic mice (Fat-1), which convert dietary n-6 to n-3 PUFAs endogenously, and their wild-type (WT) littermates were fed an n-6 PUFA enriched diet for 9-14 months. The effect of gender and genotype on serum PUFAs, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and glucose tolerance was tested by 2-factor analysis of variance (ANOVA). Cortical and trabecular subchondral bone changes were documented by micro-focal computed tomography (CT), and knee OA was assessed by semi-quantitative histomorphometry grading. Results: The n-6:n-3 ratio was reduced 12-fold and 7-fold in male and female Fat-1 mice, respectively, compared to WT littermates. IL-6 and TNF-alpha levels were reduced modestly in Fat-1 mice. However, these systemic changes did not reduce osteophyte development, synovial hyperplasia, or cartilage degeneration. Also the fat-1 transgene did not alter subchondral cortical or trabecular bone morphology or bone mineral density. Conclusions: Reducing the systemic n-6:n-3 ratio does not slow idiopathic changes in cartilage, synovium, or bone associated with early-stage knee OA in mice. The anti-inflammatory and anti-catabolic effects of n-3 PUFAs previously reported for cartilage may be more evident at later stages of disease or in post-traumatic and other inflammatory models of OA.Osteoarthritis and Cartilage 07/2014; 22(9). DOI:10.1016/j.joca.2014.06.033 · 4.66 Impact Factor
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ABSTRACT: Objective: Osteoarthritis (OA) is a serious disease of the entire joint, characterized by degeneration of articular cartilage, subchondral bone changes, osteophyte formation and synovial hyperplasia. Currently, there are no pharmaceutical treatments to slow 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 partially due to our incomplete understanding of the molecular mechanisms promoting disease initiation and progression. Here we identify the nuclear receptor PPARdelta as a promoter of cartilage degeneration in a mouse model of post-traumatic OA.Methods: Mouse chondrocytes and knee explants were treated with a pharmacological agonist of PPARdelta (GW501516) to evaluate changes in gene expression, histology and matrix glycosaminoglycan breakdown. In vivo, PPARdelta was specifically deleted in the cartilage of mice. Mutant and control mice were compared after destabilization of medial meniscus (DMM) surgery by histopathological scoring (OARSI) and immunohistochemistry.Results: In vitro, PPARdelta activation by GW501516 results in increased expression of several proteases in chondrocytes as well as aggrecan degradation and glycosaminoglycan release in knee joint explants. In vivo, cartilage specific Ppard knockout mice do not display any abnormalities of skeletal development, but show marked protection in the DMM model of post-traumatic OA (compared to control littermates). OARSI scoring and immunohistochemistry confirm strong protection of mutant mice from DMM-induced cartilage degeneration.Conclusion: These data demonstrate a catabolic role of endogenous PPARdelta in post-traumatic OA and suggest that pharmacological inhibition of PPARdelta is a promising therapeutic strategy. © 2014 American College of Rheumatology.10/2014; DOI:10.1002/art.38915