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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/E714    most recent 90631.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yao, G.-Q. Articles by Insogna, K. Search for Related Content PubMed PubMed Citation Articles by Yao, G.-Q. Articles by Insogna, K.

Targeted overexpression of the two colony-stimulating factor-1 isoforms in osteoblasts differentially affects bone loss in ovariectomized mice

¹Section of Comparative Medicine and Departments of ²Internal Medicine and ³Orthopaedics, Yale University School of Medicine, New Haven, Connecticut

Submitted 7 November 2008 ; accepted in final form 5 January 2009

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 I-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 (sCSF1^op/op and mCSF1^op/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 sCSF1^op/op mice led to a greater loss of spinal bone mineral density (22.1%) than was seen in either mCSF1^op/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.

osteoclastogenesis; estrogen deficiency; membrane-bound colony-stimulating factor