Effect of rapamycin on hepatic osteodystrophy in rats with portasystemic shunting.
OBJECTIVE
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 TNFalpha, were not increased in serum and TNFalpha 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.


CONCLUSIONS
Osteoporosis caused by portasystemic shunting may be partially ameliorated by rapamycin in the rat model of hepatic osteodystrophy.
van der Merwe
Schalk W
SW
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
Conradie
Maria M
MM
Bond
Robert
R
Olivier
Brenda J
BJ
Fritz
Elongo
E
Nieuwoudt
Martin
M
Delport
Rhena
R
Slavik
Tomas
T
Engelbrecht
Gert
G
Kahn
Del
D
Shephard
Enid G
EG
Kotze
Maritha J
MJ
de Villiers
Nico P
NP
Hough
Stephen
S
D000818:Animals; D015992:Body Mass Index; D015519:Bone Density / Q000502:physiology; D001862:Bone Resorption / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004435:Eating / Q000502:physiology; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D010024:Osteoporosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D011170:Portasystemic Shunt, Surgical / Q000009:adverse effects*; D053245:RANK Ligand; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D016207:Cytokines; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha; D020123:Sirolimus