The Cell Surface Form of Colony-Stimulating Factor-1 Is Biologically Active in Bone in Vivo

Abstract

The specific biological function of the cell surface or membrane-bound isoform of colony-stimulating factor-1 (mCSF-1) is not well understood. To help define the role of this isoform in bone, we developed a transgenic mouse in which targeted expression of human mCSF-1 in osteoblasts was achieved under the control of the 2.4-kb rat collagen type I alpha promoter. Bone density, determined by peripheral quantitative computed tomography, was reduced 7% in mCSF-1 transgenic compared with that in wild-type mice. Histomorphometric analyses indicated that the number of osteoclasts in bone (NOc/BPm, NOc/TAR, OcS/BS) was significantly increased in transgenic mice (1.7- to 1.8-fold; P < 0.05 to P < 0.01) compared with that in wild-type animals. Interestingly, the osteoblast-restricted isoform transgene corrected the osteopetrosis seen in CSF-1-deficient op/op mice. Skeletal growth and bone density in op/op mice expressing mCSF-1 in osteoblasts were similar to those in wild-type mice and were dramatically different from those in the unmanipulated op/op animals. The op/op mice expressing mCSF-1 in bone had normal incisor and molar tooth eruption, whereas the op/op mice evidenced the expected failure of tooth eruption. These findings directly support the conclusion that mCSF-1 is functionally active in bone in vivo and is probably an important local source of CSF-1.

Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1–deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1

“…29,39,40 Recently, a csCSF-1 transgene driven by the collagen I␣ promoter has been shown to correct the bone density and tooth eruption defects of Csf1 op / Csf1 op mice. 41 In previous studies, we identified a 3.13-kb promoter and first intron fragment of mouse CSF-1 gene that conferred an essentially normal tissue-specific and developmental CSF-1 expression pattern. This fragment was successfully used to drive the transgenic expression of the full-length CSF-1 gene (TgC), which encodes CSF-1 proteoglycan, glycoprotein, and some csCSF-1, in Csf1 op / Csf1 op mice.…”

“…18,[24][25][26][27][28][29]36,37 It has been shown to support macrophage proliferation 25,38 and the formation of multinucleated osteoclastlike cells in vitro 37,39,40 and in vivo. 41 csCSF-1 was proposed to play adhesion molecule-like roles in its interaction with the CSF-1 receptor (CSF-1R) on leukemic cells in a culture system. 42 When expressed on tumor cells, csCSF-1, but not secreted CSF-1, can induce tumor cell cytotoxicity by macrophages and also activate systemic immunity to the tumor cell.…”

Microglia Overexpressing the Macrophage Colony-Stimulating Factor Receptor Are Neuroprotective in a Microglial-Hippocampal Organotypic Coculture System

“…Furthermore, in addition to a soluble form, M-CSF exists as a membrane-bound glycoprotein and extracellular matrix-bound proteoglycan that are biologically active (Fixe and Praloran, 1997). These M-CSF forms participate in cell adhesion and activation (Uemura et al, 1993;Yao et al, 2003) and could be important in neuroprotection. Membrane-or extracellular-bound M-CSF would not affect neurons or other cells in the slice culture in the two-level system, resulting in loss of neuroprotection.…”

Targeted expression of csCSF-1 in op/op mice ameliorates tooth defects

“…16 csCSF-1 has been reported to either completely or partially correct osteopetrosis and induce eruption; however, bone histomorphometry and tooth morphology were not examined. 17,18 Whether dental cells in vivo also express csCSF-1 or CSF-1R has not been described. As previously stated, cell-cell contact mediates csCSF-1 action.…”