Receptors and aging: structural selectivity of the rhamnose-receptor on fibroblasts as shown by Ca(2+)-mobilization and gene-expression profiles.

Qualitative and quantitative modifications of receptors were shown to play a key role in cell and tissue aging. We recently described the properties of a rhamnose-recognizing receptor on fibroblasts involved in the mediation of age-dependent functions of these cells. Using Ca(2+)-mobilization and DNA-microarrays we could show in the presence of rhamnose-rich oligo- and polysaccharides (RROPs) Ca(2+)-mobilization and changes in gene regulation. Here, we compared the effects of several RROPs, differing in their carbohydrate sequence and molecular weights, in normal human dermal fibroblasts (NHDFs). It appeared that different structural features were required for maximal effects on Ca(2+)-mobilization and gene-expression profiles. Maximal effect on Ca(2+) influx and intracellular free calcium regulation was exhibited by RROP-1, a 50 kDa average molecular weight polysaccharide, and RROP-3, a 5 kDa average molecular weight oligosaccharide with a different carbohydrate sequence. Maximal effect on gene-expression profiles was obtained with RROP-3. These results suggest the possibility of several different transmission pathways from the rhamnose-receptor to intracellular targets, differentially affecting these two intracellular functions, with potential consequences on aging. Although of only relative specificity, this receptor site exhibits a high affinity for rhamnose, absent from vertebrate glycoconjugates. The rhamnose-receptor might well represent an evolutionary conserved conformation of a prokaryote lectin.

The alpha-L-Rhamnose recognizing lectin site of human dermal fibroblasts functions as a signal transducer: modulation of Ca2+ fluxes and gene expression.

An alpha-l-Rhamnose specific lectin site was described on human skin keratinocytes and fibrobasts. The addition of Rhamnose-rich oligo- and polysaccharides (RROPs) to fibroblasts has been shown to stimulate cell proliferation and increase extracellular matrix biosynthesis, suggesting that this lectin site functions as a "true" receptor transmitting messages to the cell interior. It was confirmed here that addition of the Rhamnose-rich polysaccharide, RROP-1, to normal human dermal fibroblasts (NHDFs) and human endothelial cells produced a dose-dependent stimulation of the calcium-signaling pathway, inducing fast and transient increases in Ca2+ influx and intracellular free Ca2+ level. The Rhamnose-rich oligosaccharide RROP-3 as well as l-Rhamnose alone were also able to trigger similar intracellular free Ca2+ concentration increases in NHDFs. Moreover, the recording of the RROP-1-induced modification of the gene-expression profile in fibroblasts showed that this polysaccharide triggered a down-regulation of the expression of several growth factors, adhesion molecules and extracellular matrix proteins involved in pro-tumoral activity and/or fibrotic processes. These results further support the hypothesis of a receptor function for the Rhamnose-recognizing lectin site in fibroblasts. Anti-fibrotic and anti-tumoral potential of RROP-1 remains to be further explored.

Pharmacological properties of rhamnose-rich polysaccharides, potential interest in age-dependent alterations of connectives tissues.

Rhamnose-rich oligo- and polysaccharides (RROPs) were tested for their potential pharmacological properties using human skin fibroblasts in serial cultures. The substances tested were shown to stimulate cell proliferation, decrease elastase-type activity, stimulate collagen biosynthesis, and protect hyaluronan against free radical mediated degradation. These reactions appear to be triggered by the mediation of a specific alpha-L-rhamnose recognizing lectin-site acting as a receptor, transmitting signals to the cell-interior. The rapid increase of intracellular free calcium after addition of RROP-1 and preliminary data using micro arrays appear also to confirm this contention.

[Effectiveness of treatment during osteoarticular pain crises in drepanocytosis; based on the example of pentoxifylline]. / Evaluation de l'efficacité des traitements au cours des crises douloureuses ostéo-articulaires de la drépanocytose: exemple de la pentoxifylline.

Many drugs have been used for prevention and treatment of vaso-occlusive attacks in sickle cell anemia. Pentoxifylline is one of the most recent. It increases deformability and filtrability of normal or sickled red cells. In this double-blind study it is compared with a placebo for treatment of 20 osteoarticular crisis during SS or SC sickle cell anemia in Mali. Pentoxifylline did not decrease intensity nor duration of crisis. On the other hand the clinical assessment used for testing drugs efficiency over pain seemed effective and reproducible.