OVEREXPRESSION OF THE PTHrP RECEPTOR IN TRANSGENIC MICE (PTHRP-R-TG) ACCELERATES GASTROINTESTINAL TRANSIT

Abstract

68 Parathyroid hormone-related protein (PTHrP) and its receptor (PTHrP-R) are expressed in visceral smooth muscle. Binding of PTHrP to PTHRP-R has been shown to relax intestinal smooth muscle strip preparations in vitro. We tested the hypothesis that selective overexpression of PTHrP-R in smooth muscle (confirmed by in situ hybridization) would alter small intestinal (SI) transit. Radiographic screening following a barium gavage indicated faster SI transit in PTHrP-R-TG mice compared to their wild type littermates. No apparent differences were noted in the pattern of intestinal contraction or segmentation in the two groups of mice. We next assessed SI transit in intact animals by measuring the distance traveled by a charcoal-resin meal in 20 minutes, as a ratio of the length of the small intestine. SI transit was significantly faster in the PTHrP-R-TG than control mice (p=0.0002, N=8), even though the former had significantly longer small intestines than controls. A detailed histological study of the SI revealed significantly taller villi and deeper crypts in the proximal duodenum of PTHrP-R-TG mice compared to controls. These anatomical changes may represent a compensatory response to increase the effective absorptive area of the small intestine. PTHrP-R- TG mice had significantly lower body weights in early life, which tended to normalize by about 10-12 weeks of age. Absorption studies using radioactive triolein-labeled lipid meal showed evidence of decreased lipid absorption in PTHrP-R-TG mice and also confirmed faster SI transit using the principle of geometric center of mean. We attribute the accelerated gastrointestinal transit in TG mice to a paracrine or autocrine effect of PTHrP on the intestinal pacemaker cells, enteric neurons, or smooth muscle cells. The precise mechanisms accounting for this effect remain to be determined.