Glucocorticoids induce gastroparesis in mice through depletion of l-arginine.

Glucocorticoids (GCs) constitute a highly pleiotropic class of drugs predominantly employed in the treatment of inflammatory diseases. In our search for new mechanisms of action, we identified a hitherto unknown effect of GCs in the gastrointestinal tract. We found that oral administration of dexamethasone (Dex) to mice caused an enlargement of the stomach due to the induction of gastroparesis and that this effect was abolished in GR(dim) mice carrying the A458T mutation in the GC receptor (GR). Gastroparesis was unrelated to the enhanced gastric acid secretion observed after Dex treatment, although both effects were mediated by the same molecular mechanism of the GR. Using conditional GR-knockout mice, we could further rule out that GC effects on enterocytes or myeloid cells were involved in the induction of gastroparesis. In contrast, we found that Dex upregulated arginase 2 (Arg2) in the stomach both at the mRNA and protein level. This suggests that GC treatment leads to a depletion of l-arginine thereby impeding the production of nitric oxide (NO), which is required for gastric motility. We tested this hypothesis by supplementing the drinking water of the mice with exogenous l-arginine to compensate for the presumed shortage of this major substrate of NO synthases. Importantly, this measure completely prevented both the enlargement of the stomach and the induction of gastroparesis after Dex treatment. Our findings raise considerations of combining orally applied GCs with l-arginine to improve tolerability of GC treatment and provide a possible explanation for the antiemetic effects of GCs widely exploited in chemotherapy.

An anti-inflammatory selective glucocorticoid receptor modulator preserves osteoblast differentiation.

Glucocorticoids (GCs) are in widespread use to treat inflammatory bone diseases, such as rheumatoid arthritis (RA). Their anti-inflammatory efficacy, however, is accompanied by deleterious effects on bone, leading to GC-induced osteoporosis (GIO). These effects include up-regulation of the receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratio to promote bone-resorbing osteoclasts and include inhibition of bone-forming osteoblasts. We previously identified suppression of osteoblast differentiation by the monomer glucocorticoid receptor (GR) via the inhibition of Il11 expression as a crucial mechanism for GIO. Here we show that the GR-modulating substance compound A (CpdA), which does not induce GR dimerization, still suppresses proinflammatory cytokines in fibroblast-like synovial cells from patients with RA and in osteoblasts. In contrast to the full GR agonist dexamethasone, it does not unfavorably alter the RANKL/OPG ratio and does not affect Il11 expression and subsequent STAT3 phosphorylation in these cells. Notably, while dexamethasone inhibits osteoblast differentiation, CpdA does not affect osteoblast differentiation in vitro and in vivo. We describe here for the first time that selective GR modulators can act against inflammation, while not impairing osteoblast differentiation.