Rescue of the osteopetrotic defect in op/op mice by osteoblast-specific targeting of soluble colony-stimulating factor-1

• Published in: Endocrinology (Philadelphia) Vol. 143; no. 5; pp. 1942 - 1949
• Main Authors: Abboud, S L, Woodruff, K, Liu, C, Shen, V, Ghosh-Choudhury, N
• Format: Journal Article
• Language: English
• Published: United States 01.05.2002
• Subjects: Acid Phosphatase; Animals; Body Weight - physiology; Bone Density; Femur - pathology; Genetic Therapy; Humans; Isoenzymes; Macrophage Colony-Stimulating Factor - biosynthesis; Macrophage Colony-Stimulating Factor - genetics; Mice; Mice, Transgenic; Osteoblasts - pathology; Osteoblasts - physiology; Osteocalcin - genetics; Osteopetrosis - genetics; Osteopetrosis - pathology; Osteopetrosis - prevention & control; Promoter Regions, Genetic - genetics; Reverse Transcriptase Polymerase Chain Reaction; Tartrate-Resistant Acid Phosphatase; Tomography, X-Ray Computed; Transgenes
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.143.5.1942

Soluble colony-stimulating factor-1 (sCSF-1) and membrane bound CSF-1 are synthesized by osteoblasts and stromal cells. However, the precise role of each form in osteoclastogenesis is unclear. In the op/op mouse, absence of osteoblast-derived CSF-1 leads to decreased osteoclasts and osteopetrosis. To determine whether sCSF-1 gene replacement can cure the osteopetrotic defect, we took advantage of the osteoblast specificity of the osteocalcin promoter to selectively express sCSF-1 in the bone of op/op mice. Transgenic mice harboring the human sCSF-1 cDNA under the control of the osteocalcin promoter were generated and cross-bred with heterozygous op/wt mice to establish op/op mutants expressing the transgene (op/opT). The op/op genotype and transgene expression were confirmed by PCR and Southern blot analysis, respectively. High levels of human sCSF-1 protein were selectively expressed in bone. At 2(1/2) wk, op/opT mice showed normal growth and tooth eruption. Femurs removed at 5 and 14 wk were analyzed by peripheral quantitative computed tomography and histomorphometry. The abnormal bone mineral density, cancellous bone volume, and growth plate width observed in op/op mice was completely reversed in op/opT mice by 5 wk, and this effect persisted at 14 wk, with measurements comparable with wt/wt mice at each time point. Correction of the skeletal abnormalities in the 5-wk-old op/opT mice correlated with a marked increase in the total osteoclast number, and their number per millimeter of bone surface compared with that of op/op mutants. Osteoclast number was maintained at 14 wk in op/opT mice and morphologically resembled wt/wt osteoclasts. These results indicate that sCSF-1 is sufficient to drive normal osteoclast development and that the osteocalcin promoter provides an efficient tool for delivery of exogenous genes to the bone. Moreover, targeting sCSF-1 to osteoblasts in the bone microenvironment may be a potentially useful therapeutic modality for treating bone disorders.