Relationship of serum markers of cartilage metabolism to imaging and clinical outcome measures of knee joint structure.

BACKGROUND: Biomarkers of cartilage metabolism have prognostic potential. OBJECTIVE: To examine whether serum cartilage biomarkers, cartilage oligomeric matrix protein (COMP), N-propeptide of type IIA procollagen (PIIANP), type II collagen breakdown product (collagen type-II cleavage (C2C)) predict cartilage volume loss and knee joint replacement. METHODS: 117 subjects with knee osteoarthritis (OA) had MRI at baseline and 2 years. Cartilage biomarkers were measured at baseline. Change in knee cartilage volume over 2 years and knee joint replacement over 4 years was determined. The population was divided into subgroups with high or low cartilage biomarkers (based on biomarker levels greater than or equal to, or less than, the mean, respectively). The relationships between biomarkers and outcome measures were examined in the whole population, and separately in marker subgroups. RESULTS: The relationship between cartilage biomarkers and cartilage volume loss was not linear across the whole population. In the low (regression coefficient B=-9.7, 95% CI -0.01 to 0.003, p=0.01), but not high (B=-0.46, 95% CI -8.9 to 8.0, p=0.92) COMP subgroup, COMP was significantly associated with a reduced rate of medial cartilage volume loss (p for difference between groups=0.05). Similarly, in the low (B=-8.2, 95% CI -12.9 to -3.5, p=0.001) but not high (B=2.6, 95% CI -3.3 to 8.5, p=0.38) PIIANP subgroup, PIIANP was associated with a significantly reduced rate of medial volume cartilage loss (p for difference=0.003). C2C was not significantly associated with rate of cartilage volume loss. PIIANP was associated with a reduced risk of joint replacement (odds ratio (OR)=0.28, 95% CI 0.10 to 0.93, p=0.04). CONCLUSION: Cartilage biomarkers may be used to identify subgroups among those with clinical knee OA in whom disease progresses at different rates. This may facilitate our understanding of the pathogenesis of disease and allow us to differentiate phenotypes of disease within a heterogeneous knee OA population.

Ligands for retinoic acid receptors are elevated in osteoarthritis and may contribute to pathologic processes in the osteoarthritic joint.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Nurr1 dependent regulation of pro-inflammatory mediators in immortalised synovial fibroblasts.

BACKGROUND: Nurr1 is an orphan member of the nuclear receptor superfamily; these orphan receptors are a group for which a ligand has yet to be identified. Nurr1 has been shown to regulate the expression of a small number of genes as a monomeric, constitutively active receptor. These Nurr1 regulated genes are primarily associated with dopamine cell maturation and survival. However, previous reports have shown an increased expression of Nurr1 in the synovium of patients with rheumatoid arthritis (RA) suggesting a pro-inflammatory role for Nurr1 in RA. In this study we investigate the potential pro-inflammatory role of Nurr1 by monitoring Nurr1 dependent gene expression in an immortalised synoviocyte cell line, K4IM. METHODS: We overexpressed the wild type and a dominant negative form of the orphan nuclear receptor Nurr1, in a model synoviocyte cell line. Using the Affymetrix HG-U133 Genechips we demonstrate the effects on the transcriptome by the receptor. Further evidence of gene expression change was demonstrated using quantitative RT-PCR and ELISA analysis. RESULTS: We show that Nurr1 regulates transcription of a small number of genes for pro-inflammatory modulators of which the most significant is interleukin-8 (IL-8). We also demonstrate increased synthesis and secretion of IL-8 further supporting a role for Nurr1 in inflammatory signalling pathways. CONCLUSION: Using microarray analysis we show that elevated levels of Nurr1 leads to increased gene expression of pro-inflammatory genes: IL-8, Amphiregulin and Kit ligand in a model cell line. This data provides further evidence for an additional role for Nurr1 in inflammation and may play a role in the pathogenesis of rheumatoid arthritis.