Basic Research
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jul 28, 2006; 12(28): 4504-4510
Published online Jul 28, 2006. doi: 10.3748/wjg.v12.i28.4504
Effect of rapamycin on hepatic osteodystrophy in rats with portasystemic shunting
Schalk W van der Merwe, Maria M Conradie, Robert Bond, Brenda J Olivier, Elongo Fritz, Martin Nieuwoudt, Rhena Delport, Tomas Slavik, Gert Engelbrecht, Del Kahn, Enid G Shephard, Maritha J Kotze, Nico P de Villiers, Stephen Hough
Schalk W van der Merwe, Department of Internal Medicine and Gastroenterology, Immunology, Hepatology and GI- research laboratory, University of Pretoria, South Africa
Maria M Conradie, Stephen Hough, Department of Internal Medicine and Endocrinology, University of Stellenbosch, South Africa
Robert Bond, Department of Internal Medicine and Gastroenterology1, Hepatology and GI- research laboratory, University of Pretoria, South Africa
Brenda J Olivier, Elongo Fritz, Martin Nieuwoudt, Department of Hepatology and GI- research laboratory, University of Pretoria, South Africa
Rhena Delport, Department of Chemical Pathology, University of Pretoria, South Africa
Tomas Slavik, Department of Ampath pathology, Pretoria, South Africa
Gert Engelbrecht, Del Kahn, Department of Surgery, Grootte Schuur Hospital, University of Cape Town, South Africa
Enid G Shephard, MRC Liver Research Centre, Grootte Schuur Hospital, University of Cape Town, South Africa
Maritha J Kotze, Nico P de Villiers, Department of Genecare Molecular Genetics, Christiaan Barnard Memorial Hospital, Cape Town, South Africa
Correspondence to: Dr. Schalk W van der Merwe MBChB, MMed Internal Medicine, PhD, Department of Internal Medicine and Gastroenterology, Hepatology and GI- Research laboratory University of Pretoria, PO Box 1649, Faerie Glen, Pretoria 0043, South Africa. svdm@doctors.netcare.co.za
Telephone: +27-12-6640187 Fax: +27-12-6648167
Received: January 5, 2006
Revised: January 12, 2006
Accepted: January 24, 2006
Published online: July 28, 2006
Abstract

AIM: To study if T-cell activation related to portasystemic shunting causes osteoclast-mediated bone loss through RANKL-dependent pathways. We also investigated if T-cell inhibition using rapamycin would protect against bone loss in rats.

METHODS: Portasystemic shunting was performed in male Sprague-Dawley rats and rapamycin 0.1 mg/kg was administered for 15 wk by gavage. Rats received powderized chow and supplemental feeds to prevent the effects of malnutrition on bone composition. Weight gain and growth was restored after surgery in shunted animals. At termination, biochemical parameters of bone turnover and quantitative bone histology were assessed. Markers of T-cell activation, inflammatory cytokine production, and RANKL-dependent pathways were measured. In addition, the roles of IGF-1 and hypogonadism were investigated.

RESULTS: Portasystemic shunting caused low turnover osteoporosis that was RANKL independent. Bone resorbing cytokine levels, including IL-1, IL-6 and TNFα, were not increased in serum and TNFα and RANKL expression were not upregulated in PBMC. Portasystemic shunting increased the circulating CD8+ T-cell population. Rapamycin decreased the circulating CD8+ T-cell population, increased CD8+ CD25+ T-regulatory cell population and improved all parameters of bone turnover.

CONCLUSION: Osteoporosis caused by portasystemic shunting may be partially ameliorated by rapamycin in the rat model of hepatic osteodystrophy.

Keywords: Osteopenia, Liver disease, Portasystemic shunting, T-lymphocyte, Rapamycin