Submitted on July 25, 2008
Revised on December 30, 2008
Accepted on January 8, 2009
TARGETED OVER-EXPRESSION OF THE TWO COLONY STIMULATING FACTOR 1 ISOFORMS IN OSTEOBLASTS DIFFERENTIALLY AFFECTS BONE LOSS IN OVARIECTOMIZED MICE
Gang-Qing Yao1*, Jian-Jun Wu1, Shira Ovadia2, Nancy Troiano1, Ben Hua Sun1, and Karl Insogna1
1 Yale University School of Medicine
2 University of the Negev,
* To whom correspondence should be addressed. E-mail: gang-qing.yao{at}yale.edu.
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 non-redundant 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 alpha I collagen promoter. Bone density determined by pQCT was significantly reduced in mCSF1, sCSF1 and s/mCSF1 transgenic mice as compared to wild-type animals. When analyzed by sex, sCSF1 and m/sCSF1 female animals but not mCSF1 female mice were found to have lower 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 five-month-old animals. Interestingly, when compared to sham ovariectomized mice of the same genotype, ovariectomy in sCSF1op/op mice led to a greater loss of spinal BMD (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 non-redundant functions in bone and that sCSF1 may play a role in mediating estrogen-deficiency bone loss
