Rapamycin retards growth and causes marked alterations in the growth plate of young rats.
Rapamycin is a potent immunosuppressant with antitumoral properties widely used in the field of renal transplantation. To test the hypothesis that the antiproliferative and antiangiogenic activity of rapamycin interferes with the normal structure and function of growth plate and impairs longitudinal growth, 4-week-old male rats (n = 10/group) receiving 2 mg/kg per day of intraperitoneal rapamycin (RAPA) or vehicle (C) for 14 days were compared. Rapamycin markedly decreased bone longitudinal growth rate (94 +/- 3 vs. 182 +/- 3 microm/day), body weight gain (60.2 +/- 1.4 vs. 113.6 +/- 1.9 g), food intake (227.8 +/- 2.6 vs. 287.5 +/- 3.4 g), and food efficiency (0.26 +/- 0.00 vs. 0.40 +/- 0.01 g/g). Signs of altered cartilage formation such as reduced chondrocyte proliferation (bromodeoxiuridine-labeled cells 32.9 +/- 1.4 vs. 45.2 +/- 1.1%), disturbed maturation and hypertrophy (height of terminal chondrocytes 26 +/- 0 vs. 29 +/- 0 microm), and decreased cartilage resorption (18.7 +/- 0.5 vs. 31.0 +/- 0.8 tartrate-resistant phosphatase alkaline reactive cells per 100 terminal chondrocytes), together with morphological evidence of altered vascular invasion, were seen in the growth plate of RAPA animals. This study indicates that rapamycin can severely impair body growth in fast-growing rats and distort growth-plate structure and dynamics. These undesirable effects must be kept in mind when rapamycin is administered to children.
Alvarez-Garcia
Oscar
O
Universidad de Oviedo, Oviedo, Spain.
Carbajo-Pérez
Eduardo
E
Garcia
Enrique
E
Gil
Helena
H
Molinos
Ines
I
Rodriguez
Julian
J
Ordoñez
Flor A
FA
Santos
Fernando
F
D000135:Acid Phosphatase / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000378:metabolism / Q000502:physiology; D004435:Eating / Q000187:drug effects; D006128:Growth / Q000187:drug effects*; D006132:Growth Plate / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000097:blood / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000097:blood / Q000494:pharmacology*; D000071681:Tartrate-Resistant Acid Phosphatase; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007166:Immunosuppressive Agents; D007527:Isoenzymes; D042461:Vascular Endothelial Growth Factor A; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D020123:Sirolimus