ROLE OF CSF-1 IN BONE AND BONE-MARROW DEVELOPMENT

There is a close interaction between the processes involved in osteoge nesis and hemopoiesis. In developing bone, the osteoclasts, cells of h emopoietic origin, resorb and invade the calcified cartilage rudiment. As a result, the primitive marrow cavity is formed and hemopoiesis in itiates. Osteogenic cells - osteoblasts and osteocytes - control the d evelopment and activity of the osteoclasts through the local release o f factors. One factor responsible for this osteoblast-osteoclast inter action is colony-stimulating factor-1 (CSF-1). Studies performed on th e osteopetrotic op/op mouse mutant have established that this factor i s essential for proliferation and differentiation of the osteoclasts. Expression of CSF-1 receptors by mature osteoclasts and osteoclast pre cursors strongly suggests that CSF-1 action is exerted directly on cel ls of this lineage. In vivo, CSF-1 synthesis by osteoblasts is tempora lly and spatially related to sites of osteoclast development, Thus CSF -1 may represent one of the factors responsible for coupling hemopoies is to osteogenesis. In vitro, osteoblasts express at least 4 transcrip ts encoding either a secreted or a membrane-bound form of CSF-1, At th e protein level, osteoblasts in vitro synthesize the membrane-bound fo rm and secrete the majority of CSF-1 as a proteoglycan, a small fracti on of which is integrated into the matrix. These different molecular f orms may locally restrict the biological action of this cytokine, Inde ed, injection of recombinant human CSF-1 in op/op mutants does not cor rect the osteoclast deficiency in the metaphyseal spongiosa of long bo nes, and sclerosis persists at this site. Similarly, the deficiency of some tissue macrophage populations in op/op mice is only partially or not at all corrected by injection of CSF-1, The expression of CSF-1 r eceptors by mature osteoclasts may imply that CSF-1 also influences th eir bone resorbing activity. Indeed, CSF-1 has been shown to induce os teoclast fusion, spreading, and survival. These findings suggest that CSF-1 is essential for the proliferation, differentiation, activity, a nd survival of tissue macrophages and osteoclasts, cells involved in t issue turnover. Furthermore, they corroborate the view that both osteo clasts and tissue macrophages stem from a CSF-l-dependent common precu rsor along the macrophage lineage. (C) 1997 Wiley-Liss, Inc.