Targeted overexpression of the two colony-stimulating factor-1 isoforms in osteoblasts differentially affects bone loss in ovariectomized mice.
Colony-stimulating factor-1 (CSF1) is one of two cytokines required for normal osteoclastogenesis. There are two major isoforms of CSF1, the cell-surface or membrane-bound isoform (mCSF1) and soluble CSF1 (sCSF1). Whether these isoforms serve nonredundant functions in bone is unclear. To explore this question, we generated transgenic mice expressing human sCSF1, human mCSF1, or both (s/mCSF1) in osteoblasts using the 2.3-kb rat alphaI-collagen promoter. Bone density determined by peripheral quantitative computed tomography was significantly reduced in mCSF1, sCSF1, and s/mCSF1 transgenic mice compared with wild-type animals. When analyzed by sex, sCSF1, and s/mCSF1, female animals but not mCSF1 female mice were found to have greater bone loss than their male littermates (-20 vs. -9.2%; P<0.05 for sCSF1 and -21.6 vs. -11.2% for s/mCSF1; P<0.01). By breeding CSF1 isoform-selective transgenic mice to an op/op background, mice were generated in which a single CSF1 isoform was the only source of the cytokine (sCSF1op/op and mCSF1op/op). Unlike osteoblast-targeted overexpression of mCSF1, selective transgenic expression of sCSF1 did not completely correct the op/op phenotype in 5-mo-old animals. Interestingly, compared with sham-ovariectomized mice of the same genotype, ovariectomy in sCSF1op/op mice led to a greater loss of spinal bone mineral density (22.1%) than was seen in either mCSF1op/op mice (12.9%) or in wild-type animals (10.9%). Our findings support the conclusion that sCSF1 and mCSF1 serve nonredundant functions in bone and that sCSF1 may play a role in mediating estrogen-deficiency bone loss.
Yao
Gang-Qing
GQ
Department of Internal Medicine, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520-8016, USA. gang-qing.yao@yale.edu
Wu
Jian-Jun
JJ
Ovadia
Shira
S
Troiano
Nancy
N
Sun
Ben Hua
BH
Insogna
Karl
K
D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density / Q000187:drug effects / Q000235:genetics; D001862:Bone Resorption / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D018390:Gene Targeting / Q000379:methods; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D010006:Osteoblasts / Q000378:metabolism*; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism; D010052:Ovariectomy / Q000662:veterinary; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000502:physiology
D020033:Protein Isoforms; D004958:Estradiol; D016173:Macrophage Colony-Stimulating Factor