Osteoblast-specific targeting of soluble colony-stimulating factor-1 increases cortical bone thickness in mice.
The soluble and membrane-bound forms of CSF-1 are synthesized by osteoblasts and stromal cells in the bone microenvironment. Transgenic mice, generated to selectively express sCSF-1 in bone, showed increased cortical thickness in the femoral diaphysis caused by new bone formation along the endosteal surface. The ability of sCSF-1 to enhance bone cell activity in vivo is potentially relevant for increasing cortical bone in a variety of disorders.


BACKGROUND
The soluble form of colony-stimulating factor-1 (sCSF-1) and the membrane-bound form of CSF-1 (mCSF-1) have been shown to support osteoclastogenesis in vitro; however, the effect of each peptide on bone remodeling in vivo is unclear. To determine the effect of sCSF-1, selectively expressed in bone, the skeletal phenotype of transgenic mice harboring the human sCSF-1 cDNA under the control of the osteocalcin promoter was assessed.


METHODS
At 5 and 14 weeks, mice were analyzed for CSF-1 protein levels, weighed, and X-rayed, and femurs were removed for peripheral quantitative computed tomography, histology, and histomorphometry.


RESULTS
High levels of human sCSF-1 were detected in bone extracts and, to a lesser extent, in plasma. Adult transgenic mice showed normal body weight and increased circulating monocytic cells. At 5 weeks, the femoral diaphysis was similar in CSF-1T and wt/wt littermates. However, by 14 weeks, the femoral diaphysis in CSF-1T mice showed increased cortical thickness and bone mineral density. In contrast to the diaphysis, the femoral metaphysis of CSF-1T mice showed normal cancellous bone comparable with wt/wt littermates at each time point. Histological sections demonstrated increased woven bone along the endosteal surface of the diaphysis and intracortical remodeling. Fluorochrome-labeling analysis confirmed endocortical bone formation in CSF-1T, with a 3.1-fold increase in the percentage of double-labeled surfaces and a 3.6-fold increase in the bone formation rate compared with wt/wt mice. Although remodeling resulted in a slightly porous cortex, sCSF-1 preferentially stimulated endocortical bone formation, leading to increased cortical thickness.


CONCLUSIONS
These findings indicate that sCSF-1 is a key determinant of bone cell activity in the corticoendosteal envelope.
Abboud
S L
SL
Audie L. Murphy Division, The South Texas Veteran's Health Care System, San Antonio, Texas, USA. abbouds@uthscsa.edu
Ghosh-Choudhury
N
N
Liu
L C
LC
Shen
V
V
Woodruff
K
K
D000818:Animals; D015519:Bone Density / Q000502:physiology*; D005269:Femur / Q000166:cytology* / Q000000981:diagnostic imaging / Q000378:metabolism*; D015316:Genetic Therapy; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D011859:Radiography; D012995:Solubility; D013997:Time Factors; D019076:Transgenes / Q000235:genetics
D016173:Macrophage Colony-Stimulating Factor