Impairment of gastric ulcer healing by alendronate, a nitrogen-containing bisphosphonate, in rats.
Bisphosphonates such as alendronate have been developed as antiresorptive agents capable of treating diseases related to bone remodeling. In the present study, we examined the effect of alendronate on the healing of acetic acid-induced gastric ulcers in rats and investigated the mechanism involved in this action both in vivo and in vitro using the rat gastric epithelial cell line (RGM1). Acetic acid-induced gastric ulcers healed spontaneously, with up-regulation of COX-2/prostaglandin E2 production as well as expression of vascular endothelium-derived growth factor (VEGF) and basic fibroblast growth factor (bFGF) in ulcerated mucosa. The healing of ulcers was impaired by indomethacin (2 mg/kg, s.c.) or alendronate (60 mg/kg, p.o.) given once daily for 7 days, starting 3 days after acid application. Indomethacin, but not alendronate, inhibited mucosal prostaglandin E2 production. Alendronate as well as indomethacin decreased the protein expression of both VEGF and bFGF in ulcerated mucosa, resulting in a reduction of angiogenesis in the ulcer base. Supplementation of recombinant bFGF significantly reverted the delay in ulcer healing caused by alendronate. On the other hand, the size of cell-free areas in RGM1 cells in vitro decreased with time after wound induction, and this process was promoted by epidermal growth factor (EGF; 10 ng/ml). Co-incubation with alendronate (1 mM) did not affect the spontaneous healing but significantly suppressed the accelerated wound healing caused by EGF. These results suggest that alendronate impairs the healing of gastric ulcers in rats, and this effect may be related to down-regulation of VEGF and bFGF, the important growth factors for vascularization/granulation, as well as suppression of the stimulatory action of EGF on epithelial proliferation/migration.
Amagase
Kikuko
K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
Hayashi
Shusaku
S
Nishikawa
Kaoru
K
Aihara
Eitaro
E
Takeuchi
Koji
K
D019342:Acetic Acid; D019386:Alendronate / Q000009:adverse effects*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000009:adverse effects*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000032:analysis; D015232:Dinoprostone / Q000096:biosynthesis; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D014945:Wound Healing / Q000187:drug effects
D050071:Bone Density Conservation Agents; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D019342:Acetic Acid; D019386:Alendronate; D007213:Indomethacin