Macrophage colony-stimulating factor induces substantial osteoclast generation and bone resorption in human bone marrow cultures.
Macrophage colony-stimulating factor (M-CSF) is essential for murine osteoclast formation and its role in human hematopoiesis in vitro is not fully defined. Therefore, we have investigated the effect of M-CSF on the formation of human osteoclasts in vitro. M-CSF was found to induce substantial bone resorption and osteoclast formation in a dose-responsive and time-dependent manner above that induced by 1,25 dihydroxyvitamin D3 (1,25 vitamin D3) in cultures of human bone marrow (BM) stromal cells sedimented onto devitalized bone. By day 14 there was a mean of approximately 50% of the surfaces of the bone slices resorbed compared with only 6% in cultures treated with 1,25 vitamin D3 alone. Osteoclasts were identified as 23c6+ cells (an antibody that recognizes the vitronectin receptor), 87.5% of which coexpressed the calcitonin receptor. The number of 23c6+ cells correlated strongly with bone resorption spatially, and in a dose-responsive and time-dependent manner; the correlation coefficient in cultures treated with 1,25 vitamin D3 alone was 0.856 and those treated with both M-CSF and 1,25 vitamin D3 was 0.880. Granulocyte-macrophage colony-stimulating factor, IL-1 beta, IL-3, IL-6, tumor necrosis factor-alpha, transforming growth factor-beta, leukemia inhibitory factor, and IL-11 did not increase bone resorption above that in 1,25 vitamin D3-treated cultures. We also found that 1,25 vitamin D3 increased, to a minor but significant degree, both bone resorption and the concentration of M-CSF in the culture supernatants above that in vehicle-treated cultures, indicating that M-CSF is present in our BM cultures, but that there is insufficient to induce substantial osteoclast formation. These results define a critical role for M-CSF in the formation of human osteoclasts.
Sarma
U
U
Department of Histopathology, Imperial College School of Medicine at St. Mary's, London, UK.
Flanagan
A M
AM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D001862:Bone Resorption / Q000139:chemically induced*; D002117:Calcitriol / Q000494:pharmacology; D002467:Cell Nucleus / Q000648:ultrastructure; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D018003:Receptors, Calcitonin / Q000032:analysis; D019030:Receptors, Vitronectin / Q000032:analysis; D013268:Stimulation, Chemical
D015415:Biomarkers; D016207:Cytokines; D016298:Hematopoietic Cell Growth Factors; D018003:Receptors, Calcitonin; D019030:Receptors, Vitronectin; D016173:Macrophage Colony-Stimulating Factor; D002117:Calcitriol