sRANKL and OPG in serum and synovial fluid of patients with rheumatoid arthritis in comparison to non-destructive chronic arthritis.

The aim of this study was to investigate sRANKL and OPG levels in serum and synovial fluid (SF) and to evaluate their relations in patients with RA in comparison to those with non-erosive arthritis (NEA). The study included 45 unselected RA patients with knee joint effusions and 27 patients with knee joint effusions because of NEA. Serum and SF samples were investigated isochronously. OPG and sRANKL were measured by ELISA assays. In RA, sRANKL levels were higher in serum than in SF (P = 0.007). In contrast, the NEA revealed higher sRANKL in SF compared to the serum (P = 0.001). Though in RA the average levels of sRANKL(ser) were 5.6 times and of sRANKL(syn) 1.5 times higher than in NEA, the differences were not significant. The free (unbound) OPG in SF was not significantly different in RA compared to NEA. Also in serum, the measured free OPG was only slightly higher in RA. There were no significant differences between RA and NEA concerning ESR and CRP. Significant correlations could be found between sRANKL(syn )and CRP (r = 0.453; P = 0.005) as well as ESR (r = 0.362; P = 0.033) in RA. Nearly a positive correlation was evident also between sRANKL(syn) and CRP in NEA (r = 0.520; P = 0.08). RA and NEA differ in particular concerning their power and intensity to destruct the juxtaarticular bone. This is the most remarkable finding of this study, that in RA a high part of sRANKL seems to be OPG bound and cleared by the blood stream, but the sRANKL neutralizing capacity of produced OPG in opposite to NEA is not sufficient to prevent osteoclast activation and bone destruction in the RA joint.

Glycation endproducts in osteoporosis--is there a pathophysiologic importance?

Advanced glycation endproducts (AGEs) are chemical modifications of proteins by carbohydrates including those metabolic intermediates formed during the Maillard reaction. The generation of AGEs is an inevitable process in vivo. AGEs constitute a heterogeneous class of compounds characterized by brown color, fluorescence and a tendency to polymerize. These unique compounds are specifically recognized by AGE receptors (RAGE) present on different cell types. A remarkable feature of AGE-mediated cross-linked proteins is decreased solubility and resistance to proteolytic digestion. This effect results in altered biomechanical properties in affected tissues including increased stiffness and rigidity. The AGE-RAGE interaction additionally induces activation of nuclear factor kB (NF-kB) in RAGE bearing cells (e.g., cells participating in bone turnover). This interaction results e.g. in increased expression of cytokines, growth factors and adhesion molecules. Recent findings provide important evidence that bone proteins are also affected by AGE modification. Investigations conducted by other groups, as well as ours, support the hypothesis that bone protein glycation influences osteoclasts (bone resorption) and osteoblasts (bone formation).

The advanced glycation end product pentosidine correlates to IL-6 and other relevant inflammatory markers in rheumatoid arthritis.

OBJECTIVE: Oxidative stress and inflammatory processes accelerate the formation of advanced glycation end products (AGE), e.g. of pentosidine. The aim of this study was to investigate the relationships between levels of pentosidine in serum and synovial fluid, proinflammatory cytokines, other markers of inflammatory activity, and the state of radiologically visible bone destruction in patients with rheumatoid arthritis (RA). OBJECTIVES: One hundred thirty-three nondiabetic RA patients and 56 age-matched, healthy subjects were included. Serum and synovial fluid pentosidine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and rheumatoid factor levels were determined. In 30 patients, the proinflammatory cytokines interleukin (IL)-1beta, IL-6, and TNF-alpha and the soluble receptors sIL-2R, sIL-6R, sTNF-alpha, and RI/RII were also measured. RESULTS: Serum levels of pentosidine were on average significantly higher in RA patients than in healthy subjects and correlated significantly to ESR, CRP, and serum levels of IL-6. Serum and synovial fluid pentosidine did not show any differences. Rheumatoid factor-positive RA patients had higher pentosidine levels in the synovial fluid than rheumatoid factor-negative patients. Correlations could not be found between pentosidine and the other cytokines or cytokine receptors measured. CONCLUSION: The binding of AGE on cell receptors induces activation of nuclear factor kappa B, resulting in enhanced synthesis of proinflammatory cytokines. Moreover, AGE generation may also lead to the formation of new, immunologically relevant epitopes at synovial proteins. Both mechanisms could contribute to initiation and perpetuation of the inflammatory and destructive processes in RA.