IGF binding protein-3 treatment alters intestinal cell proliferation but not body weight of adult cystic fibrosis transmembrane conductance regulator deficient mice.
The intestinal phenotype of cystic fibrosis (CF) transmembrane conductance regulator deficient mice includes altered cell homeostasis and a distended crypt-villus axis, which, in previous work, was inversely proportional to body weight. To investigate this correlation, herein, we treated CF mice with IGF binding protein-3 (IGFBP-3), a protein which, as it has potent effects on cell proliferation and apoptosis, we hypothesized would alter the intestinal cell homeostasis, and assessed body weight. Six-week-old C57BL/6JxBALB F2 CF and WT mice received recombinant human IGFBP-3 (rhIGFBP-3, 20 mg/kg) or vehicle treatment, and weight gain, serum protein levels, and intestinal histology were assessed. Administration of rhIGFBP-3 to CF mice significantly increased the number of Igfbp-3 positive cells in the intestine and partially reversed the hyperproliferative phenotype of intestinal crypts and muscularis externa, while not affecting apoptosis. Serum Igfbp-3 levels were increased, and Igf-I, albumin, and triglycerides measures were decreased in CF compared with WT mice. rhIGFBP-3 treatment significantly increased serum albumin and triglycerides but did not affect weight gain in CF mice. We have identified rhIGFBP-3 treatment to reduce intestinal cell proliferation, resulting in decreases in crypt depth and muscularis externa thickness in CF mice.
Department of Human Genetics, Meakins-Christie Laboratories, McGill University, Montreal, Quebec H2X 2P2, Canada.
Juan Carlos
JC
Canale-Zambrano
Christina K
CK
Haston
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000008:administration & dosage* / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D018181:Mice, Inbred CFTR; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D012709:Serum Albumin / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012709:Serum Albumin; D014280:Triglycerides; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I