Ligands for Retinoic Acid Receptors Are Elevated in Osteoarthritis and May Contribute to Pathologic Processes in the Osteoarthritic Joint

AstraZeneca Pharmaceuticals, Cheshire, UK.
Arthritis & Rheumatology (Impact Factor: 7.76). 06/2009; 60(6):1722-32. DOI: 10.1002/art.24550
Source: PubMed


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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    • "Last, but not least, the retinoids display multiple effects relevant to the OA disease process. Davies and colleagues showed that components of the retinoid signaling pathways are upregulated during OA in humans and that all-trans-retinoic acid treatment of human explant cartilage samples led to significant increase of MMP-13 and aggrecanases, enzymes involved in two of the key proteolytic processes implicated in OA [66]. Taken together, many locally acting growth factors playing a crucial role in the regulation of chondrocyte proliferation and differentiation during EO also are involved in OA pathogenesis and disease progression, mainly by stimulation or activation of degradative enzymes (for example, MMP-13 or aggrecanases). "
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