Overexpression of the granulocyte colony-stimulating factor gene leads to osteoporosis in mice.
Although granulocyte colony-stimulating factor (G-CSF) was originally isolated as an activity for the growth and differentiation of cells in granulocytic lineage, it has been gradually accepted that G-CSF may have a function on a wide variety of cells besides granulocytes. To elucidate the function of G-CSF on bone cells in vivo, we examined the bone tissue of transgenic mice that overexpress G-CSF. Transgenic mice express human G-CSF at an elevated level (1041 +/- 242 pg/ml in sera) under the direction of SRalpha promoter. We performed radiographic, routine histologic, and histomorphometric analyses of the bone tissue and serum biochemical assay. Nontransgenic littermates were examined as age-matched, wild-type controls in all experiments. Radiographic analysis revealed cortical thinning accompanied by enlarged bone marrow cavities in both vertebral bodies and long bones. Histologically, a decreased number and thickness of trabecular bones and cortical thinning were observed in lumber vertebrae as well as in femur specimens. The enlarged bone marrow cavities exhibited an increased number of mature neutrophilic granulocytes without apparent changes in other types of cells. The static and dynamic parameters reflecting bone resorption were found to be significantly increased in the transgenic mice. By contrast, no significant differences were detected in the parameters reflecting bone formation. Transgenic mice and littermate controls had similar serum calcium, phosphorous, and alkaline phosphatase levels. However, the serum osteocalcin level was significantly higher in transgenic mice. These findings indicate that G-CSF-expressing transgenic mice developed osteoporosis because of increased osteoclastic activity. Collectively, G-CSF could have a negative influence on bone homeostasis in vivo.
Takahashi
T
T
Department of Orthopedic Surgery, Sapporo Medical University, School of Medicine, Japan.
Wada
T
T
Mori
M
M
Kokai
Y
Y
Ishii
S
S
D000818:Animals; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics* / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010024:Osteoporosis / Q000209:etiology*
D015850:Interleukin-6; D016179:Granulocyte Colony-Stimulating Factor