Osteoporosis is a disease manifested in drastic bone loss resulting in osteopenia and high risk for fractures. This disease is generally divided into two subtypes. The first, post-menopausal (type I) osteoporosis, is primarily related to estrogen deficiency. The second, senile (type II) osteoporosis, is mostly related to aging. Decreased bone formation, as well as increased bone resorption and turnover, are thought to play roles in the pathophysiology of both types of osteoporosis. In this study, we demonstrate in murine models for both type I (estrogen deficiency) and type II (senile) osteopenia/osteoporosis that reduced bone formation is related to a decrease in adult mesenchymal stem cell (AMSC) number, osteogenic activity, and proliferation. Decreased proliferation is coupled with increased apoptosis in AMSC cultures obtained from osteopenic mice. Recombinant human bone morphogenetic protein (rhBMP-2) is a highly osteoinductive protein, promoting osteogenic differentiation of AMSCs. Systemic intra-peritoneal (i.p.) injections of rhBMP-2 into osteopenic mice were able to reverse this phenotype in the bones of these animals. Moreover, this change in bone mass was coupled to an increase in AMSCs numbers, osteogenic activity, and proliferation as well as a decrease in apoptosis. Bone formation activity was increased as well. However, the magnitude of this response to rhBMP-2 varied among different stains of mice. In old osteopenic BALB/c male mice (type II osteoporosis model), rhBMP-2 systemic treatment also restored both articular and epiphyseal cartilage width to the levels seen in young mice. In summary, our study shows that AMSCs are a good target for systemically active anabolic compounds like rhBMP-2.
A series of substituted 2-pyridinecarbothioamides was synthesized and evaluated for gastric mucosal protectant activity in the rat. Out of this investigation N-(3,5-difluorophenyl)-2- pyridinecarbothioamide (23, AY-31,574) was identified. This compound was much more potent than sucralfate and ranitidine against ethanol-induced lesions. Compound 23 was equipotent with ranitidine against gastric injury caused by stress. Unlike ranitidine, 23 was found to be devoid of antisecretory activity in the pylorus-ligated rat model, making it a selective mucosal protectant. Such a potent selective mucosal protectant may provide a novel clinical approach in treating ulcers.
A simple non-radioactive method for the simultaneous assessment of stomach emptying and intestinal propulsion in intact fasted conscious rats was developed employing Amberlite pellets. The Amberlite pellets were administered by gastric gavage and the rats were killed 20 or 120 min later. The number and percent of the pellets in the stomach and intestines and the distance travelled by each pellet in the small intestine were determined. The distance travelled by the leading pellet in the small intestine was employed as a parameter to determine effects on intestinal propulsion independent of the stomach emptying activity. Chlorisondamine (s.c), atropine (s.c), pentobarbital (i.p.) and sesame seed oil (p.o.) inhibited both stomach emtying and intestinal propulsion in a dose-related manner. All these agents also caused a dose-related displacement of the pellets in the small intestine which resulted in a more cephalad-oriented distribution of the pellets. Propantheline (s.c.) exerted a dose-related inhibition on the stomach emptying but not on intestinal propulsion. Carbachol (s.c.) increased both the rate of stomach emptying and that of propulsion in the small intestine.
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