Bone malformations in interleukin-18 transgenic mice.
The in vivo effects of IL-18 on bone metabolism were investigated by histopathology in IL-18 transgenic mice. Deformed cortical bone and decreased turnover rate of lumbar trabecular bone are consistent with increased expression of IFN-gamma and IL-18 in the bone marrow. Interleukin (IL)-18 has been demonstrated to inhibit osteoclastogenesis in an in vitro co-culture system. We investigated the effects of IL-18 overexpression on bone metabolism by comparing bone characteristics in male IL-18 transgenic (TG) mice, which secrete mature murine IL-18 from their B- and T-cells, and their wildtype littermates (WT). Histopathological analysis revealed that the cortical bone of the femur was thinner and more deformed in IL-18 TG mice. Bone histomorphometry showed that the cortical bone area of the mid-diaphysis of the femur and the trabecular bone volume of the lumbar vertebrae were significantly reduced in IL-18 TG mice. IL-18 TG mice also exhibited significantly fewer osteoclasts and a reduced bone formation rate in the trabecular bones of their lumbar vertebrae. Real-time reverse transcriptase-polymerase chain reaction amplification of bone marrow cell mRNA revealed that interferon (IFN)-gamma mRNA expression was significantly increased, whereas IL-4 mRNA expression was significantly reduced, in IL-18 TG mice. However, the expression ratio of receptor activator of NFkappaB ligand and osteoprotegerin mRNA was not significantly altered. Thus, deformed cortical bone and a decreased turnover rate of lumbar trabecular bone are characteristic of IL-18 TG mice, and these features might be associated with the increased expression of IFN-gamma and IL-18 in the bone marrow.
Kawase
Yusuke
Y
R&D Laboratories, Nippon Organon K.K., Osaka, Japan.
Hoshino
Tomoaki
T
Yokota
Koichi
K
Kuzuhara
Akemi
A
Nakamura
Masanori
M
Maeda
Yu
Y
Nishiwaki
Eiji
E
Zenmyo
Michihisa
M
Hiraoka
Koji
K
Aizawa
Hisamichi
H
Yoshino
Kohichiro
K
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D015519:Bone Density; D001842:Bone and Bones / Q000002:abnormalities*; D003433:Crosses, Genetic; D017931:DNA Primers; D005269:Femur / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D020382:Interleukin-18 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D053244:Osteoprotegerin; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic
D017931:DNA Primers; D006023:Glycoproteins; D020382:Interleukin-18; D053244:Osteoprotegerin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D007371:Interferon-gamma