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. 1993 Nov 1;178(5):1733–1744. doi: 10.1084/jem.178.5.1733

Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts

PMCID: PMC2191238  PMID: 8228819

Abstract

Macrophage colony-stimulating factor (M-CSF) is known to play an important role in osteoclast formation. However, its actions on mature cells have not been fully characterized. We now report that M-CSF dramatically stimulates osteoclastic motility and spreading; osteoclasts responded to a gradient of M-CSF with orientation, and random cell polarization occurred after isotropic exposure. M-CSF also supported the survival of osteoclasts by preventing apoptosis. Paradoxically, M-CSF inhibits bone resorption by isolated osteoclasts. We found that this was effected predominantly by reduction in the number of excavations. Thus, M-CSF showed a propensity to suppress resorption through a reduction in the proportion of cells that were resorbing bone. Our data suggest that apart from the established role of M-CSF in the provision of precursors for osteoclastic induction, a major role for M-CSF in bone resorption is to enhance osteoclastic survival, migration, and chemotaxis. It seems appropriate that during these processes resorptive functions should be suppressed. We suggest that M-CSF continues to modulate osteoclastic activity once osteoclasts are on resorptive sites, through regulation of the balance between resorption and migration, such that not only the quantity, but the spatial pattern of resorption can be controlled by adjacent M-CSF- secreting cells of osteoblastic lineage.

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Selected References

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  1. Abe K., Kanno T., Kitao K., Schneider G. B. Sex differences in bone resorption: a scanning electron microscopic study of mouse parietal bones. Arch Histol Jpn. 1984 Oct;47(4):429–440. [PubMed] [Google Scholar]
  2. Arends M. J., Morris R. G., Wyllie A. H. Apoptosis. The role of the endonuclease. Am J Pathol. 1990 Mar;136(3):593–608. [PMC free article] [PubMed] [Google Scholar]
  3. Begg S. K., Radley J. M., Pollard J. W., Chisholm O. T., Stanley E. R., Bertoncello I. Delayed hematopoietic development in osteopetrotic (op/op) mice. J Exp Med. 1993 Jan 1;177(1):237–242. doi: 10.1084/jem.177.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chambers J. J., Horton M. A. Osteoclasts: putative, surrogate and authentic. J Pathol. 1984 Dec;144(4):295–296. doi: 10.1002/path.1711440411. [DOI] [PubMed] [Google Scholar]
  5. Chambers T. J., Hall T. J. Cellular and molecular mechanisms in the regulation and function of osteoclasts. Vitam Horm. 1991;46:41–86. doi: 10.1016/s0083-6729(08)60682-2. [DOI] [PubMed] [Google Scholar]
  6. Chambers T. J., Magnus C. J. Calcitonin alters behaviour of isolated osteoclasts. J Pathol. 1982 Jan;136(1):27–39. doi: 10.1002/path.1711360104. [DOI] [PubMed] [Google Scholar]
  7. Chambers T. J., McSheehy P. M., Thomson B. M., Fuller K. The effect of calcium-regulating hormones and prostaglandins on bone resorption by osteoclasts disaggregated from neonatal rabbit bones. Endocrinology. 1985 Jan;116(1):234–239. doi: 10.1210/endo-116-1-234. [DOI] [PubMed] [Google Scholar]
  8. Chambers T. J. Osteoblasts release osteoclasts from calcitonin-induced quiescence. J Cell Sci. 1982 Oct;57:247–260. doi: 10.1242/jcs.57.1.247. [DOI] [PubMed] [Google Scholar]
  9. Chambers T. J., Owens J. M., Hattersley G., Jat P. S., Noble M. D. Generation of osteoclast-inductive and osteoclastogenic cell lines from the H-2KbtsA58 transgenic mouse. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5578–5582. doi: 10.1073/pnas.90.12.5578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chambers T. J., Thomson B. M., Fuller K. Effect of substrate composition on bone resorption by rabbit osteoclasts. J Cell Sci. 1984 Aug;70:61–71. doi: 10.1242/jcs.70.1.61. [DOI] [PubMed] [Google Scholar]
  11. Chow J., Chambers T. J. An assessment of the prevalence of organic material on bone surfaces. Calcif Tissue Int. 1992 Feb;50(2):118–122. doi: 10.1007/BF00298787. [DOI] [PubMed] [Google Scholar]
  12. Davies J., Warwick J., Totty N., Philp R., Helfrich M., Horton M. The osteoclast functional antigen, implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor. J Cell Biol. 1989 Oct;109(4 Pt 1):1817–1826. doi: 10.1083/jcb.109.4.1817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Delaisse J. M., Boyde A., Maconnachie E., Ali N. N., Sear C. H., Eeckhout Y., Vaes G., Jones S. J. The effects of inhibitors of cysteine-proteinases and collagenase on the resorptive activity of isolated osteoclasts. Bone. 1987;8(5):305–313. doi: 10.1016/8756-3282(87)90007-x. [DOI] [PubMed] [Google Scholar]
  14. Dempster D. W., Elder H. Y., Smith D. A. Scanning electron microscopy of rachitic rat bone. Scan Electron Microsc. 1979;(2):513–520. [PubMed] [Google Scholar]
  15. Devreotes P. N., Zigmond S. H. Chemotaxis in eukaryotic cells: a focus on leukocytes and Dictyostelium. Annu Rev Cell Biol. 1988;4:649–686. doi: 10.1146/annurev.cb.04.110188.003245. [DOI] [PubMed] [Google Scholar]
  16. Elford P. R., Felix R., Cecchini M., Trechsel U., Fleisch H. Murine osteoblastlike cells and the osteogenic cell MC3T3-E1 release a macrophage colony-stimulating activity in culture. Calcif Tissue Int. 1987 Sep;41(3):151–156. doi: 10.1007/BF02563795. [DOI] [PubMed] [Google Scholar]
  17. Felix R., Cecchini M. G., Fleisch H. Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology. 1990 Nov;127(5):2592–2594. doi: 10.1210/endo-127-5-2592. [DOI] [PubMed] [Google Scholar]
  18. Ferrier J., Ross S. M., Kanehisa J., Aubin J. E. Osteoclasts and osteoblasts migrate in opposite directions in response to a constant electrical field. J Cell Physiol. 1986 Dec;129(3):283–288. doi: 10.1002/jcp.1041290303. [DOI] [PubMed] [Google Scholar]
  19. Filderman A. E., Bruckner A., Kacinski B. M., Deng N., Remold H. G. Macrophage colony-stimulating factor (CSF-1) enhances invasiveness in CSF-1 receptor-positive carcinoma cell lines. Cancer Res. 1992 Jul 1;52(13):3661–3666. [PubMed] [Google Scholar]
  20. Grills B. L., Gallagher J. A., Allan E. H., Yumita S., Martin T. J. Identification of plasminogen activator in osteoclasts. J Bone Miner Res. 1990 May;5(5):499–505. doi: 10.1002/jbmr.5650050512. [DOI] [PubMed] [Google Scholar]
  21. Hamilton J. A., Stanley E. R., Burgess A. W., Shadduck R. K. Stimulation of macrophage plasminogen activator activity by colony-stimulating factors. J Cell Physiol. 1980 Jun;103(3):435–445. doi: 10.1002/jcp.1041030309. [DOI] [PubMed] [Google Scholar]
  22. Hattersley G., Chambers T. J. Calcitonin receptors as markers for osteoclastic differentiation: correlation between generation of bone-resorptive cells and cells that express calcitonin receptors in mouse bone marrow cultures. Endocrinology. 1989 Sep;125(3):1606–1612. doi: 10.1210/endo-125-3-1606. [DOI] [PubMed] [Google Scholar]
  23. Hattersley G., Chambers T. J. Generation of osteoclasts from hemopoietic cells and a multipotential cell line in vitro. J Cell Physiol. 1989 Sep;140(3):478–482. doi: 10.1002/jcp.1041400311. [DOI] [PubMed] [Google Scholar]
  24. Hattersley G., Dorey E., Horton M. A., Chambers T. J. Human macrophage colony-stimulating factor inhibits bone resorption by osteoclasts disaggregated from rat bone. J Cell Physiol. 1988 Oct;137(1):199–203. doi: 10.1002/jcp.1041370125. [DOI] [PubMed] [Google Scholar]
  25. Hattersley G., Owens J., Flanagan A. M., Chambers T. J. Macrophage colony stimulating factor (M-CSF) is essential for osteoclast formation in vitro. Biochem Biophys Res Commun. 1991 May 31;177(1):526–531. doi: 10.1016/0006-291x(91)92015-c. [DOI] [PubMed] [Google Scholar]
  26. Hofstetter W., Wetterwald A., Cecchini M. C., Felix R., Fleisch H., Mueller C. Detection of transcripts for the receptor for macrophage colony-stimulating factor, c-fms, in murine osteoclasts. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9637–9641. doi: 10.1073/pnas.89.20.9637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hume D. A., Loutit J. F., Gordon S. The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80: macrophages of bone and associated connective tissue. J Cell Sci. 1984 Mar;66:189–194. doi: 10.1242/jcs.66.1.189. [DOI] [PubMed] [Google Scholar]
  28. Kerby J. A., Hattersley G., Collins D. A., Chambers T. J. Derivation of osteoclasts from hematopoietic colony-forming cells in culture. J Bone Miner Res. 1992 Mar;7(3):353–362. doi: 10.1002/jbmr.5650070316. [DOI] [PubMed] [Google Scholar]
  29. Kodama H., Yamasaki A., Abe M., Niida S., Hakeda Y., Kawashima H. Transient recruitment of osteoclasts and expression of their function in osteopetrotic (op/op) mice by a single injection of macrophage colony-stimulating factor. J Bone Miner Res. 1993 Jan;8(1):45–50. doi: 10.1002/jbmr.5650080107. [DOI] [PubMed] [Google Scholar]
  30. Kodama H., Yamasaki A., Nose M., Niida S., Ohgame Y., Abe M., Kumegawa M., Suda T. Congenital osteoclast deficiency in osteopetrotic (op/op) mice is cured by injections of macrophage colony-stimulating factor. J Exp Med. 1991 Jan 1;173(1):269–272. doi: 10.1084/jem.173.1.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Moore R. N., Oppenheim J. J., Farrar J. J., Carter C. S., Jr, Waheed A., Shadduck R. K. Production of lymphocyte-activating factor (Interleukin 1) by macrophages activated with colony-stimulating factors. J Immunol. 1980 Sep;125(3):1302–1305. [PubMed] [Google Scholar]
  32. Nicholson G. C., Moseley J. M., Sexton P. M., Mendelsohn F. A., Martin T. J. Abundant calcitonin receptors in isolated rat osteoclasts. Biochemical and autoradiographic characterization. J Clin Invest. 1986 Aug;78(2):355–360. doi: 10.1172/JCI112584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Okamura T., Shimokawa H., Takagi Y., Ono H., Sasaki S. Detection of collagenase mRNA in odontoclasts of bovine root-resorbing tissue by in situ hybridization. Calcif Tissue Int. 1993 Apr;52(4):325–330. doi: 10.1007/BF00296659. [DOI] [PubMed] [Google Scholar]
  34. Phillips W. A., Hamilton J. A. Colony stimulating factor-1 is a negative regulator of the macrophage respiratory burst. J Cell Physiol. 1990 Aug;144(2):190–196. doi: 10.1002/jcp.1041440203. [DOI] [PubMed] [Google Scholar]
  35. Pierce J. H., Di Marco E., Cox G. W., Lombardi D., Ruggiero M., Varesio L., Wang L. M., Choudhury G. G., Sakaguchi A. Y., Di Fiore P. P. Macrophage-colony-stimulating factor (CSF-1) induces proliferation, chemotaxis, and reversible monocytic differentiation in myeloid progenitor cells transfected with the human c-fms/CSF-1 receptor cDNA. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5613–5617. doi: 10.1073/pnas.87.15.5613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rodan G. A., Martin T. J. Role of osteoblasts in hormonal control of bone resorption--a hypothesis. Calcif Tissue Int. 1981;33(4):349–351. doi: 10.1007/BF02409454. [DOI] [PubMed] [Google Scholar]
  37. Sieff C. A. Hematopoietic growth factors. J Clin Invest. 1987 Jun;79(6):1549–1557. doi: 10.1172/JCI112988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Takahashi N., Udagawa N., Akatsu T., Tanaka H., Isogai Y., Suda T. Deficiency of osteoclasts in osteopetrotic mice is due to a defect in the local microenvironment provided by osteoblastic cells. Endocrinology. 1991 Apr;128(4):1792–1796. doi: 10.1210/endo-128-4-1792. [DOI] [PubMed] [Google Scholar]
  39. Tushinski R. J., Oliver I. T., Guilbert L. J., Tynan P. W., Warner J. R., Stanley E. R. Survival of mononuclear phagocytes depends on a lineage-specific growth factor that the differentiated cells selectively destroy. Cell. 1982 Jan;28(1):71–81. doi: 10.1016/0092-8674(82)90376-2. [DOI] [PubMed] [Google Scholar]
  40. Udagawa N., Takahashi N., Akatsu T., Sasaki T., Yamaguchi A., Kodama H., Martin T. J., Suda T. The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. Endocrinology. 1989 Oct;125(4):1805–1813. doi: 10.1210/endo-125-4-1805. [DOI] [PubMed] [Google Scholar]
  41. Udagawa N., Takahashi N., Akatsu T., Tanaka H., Sasaki T., Nishihara T., Koga T., Martin T. J., Suda T. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7260–7264. doi: 10.1073/pnas.87.18.7260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wang J. M., Griffin J. D., Rambaldi A., Chen Z. G., Mantovani A. Induction of monocyte migration by recombinant macrophage colony-stimulating factor. J Immunol. 1988 Jul 15;141(2):575–579. [PubMed] [Google Scholar]
  43. Warren M. K., Ralph P. Macrophage growth factor CSF-1 stimulates human monocyte production of interferon, tumor necrosis factor, and colony stimulating activity. J Immunol. 1986 Oct 1;137(7):2281–2285. [PubMed] [Google Scholar]
  44. Wiktor-Jedrzejczak W., Bartocci A., Ferrante A. W., Jr, Ahmed-Ansari A., Sell K. W., Pollard J. W., Stanley E. R. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4828–4832. doi: 10.1073/pnas.87.12.4828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wilkinson P. C. Leucocyte locomotion: behavioural mechanisms for accumulation. J Cell Sci Suppl. 1987;8:103–119. doi: 10.1242/jcs.1987.supplement_8.6. [DOI] [PubMed] [Google Scholar]
  46. Wood G. W., De M., Sanford T., Choudhuri R. Macrophage colony stimulating factor controls macrophage recruitment to the cycling mouse uterus. Dev Biol. 1992 Aug;152(2):336–343. doi: 10.1016/0012-1606(92)90140-c. [DOI] [PubMed] [Google Scholar]
  47. Yoshida H., Hayashi S., Kunisada T., Ogawa M., Nishikawa S., Okamura H., Sudo T., Shultz L. D., Nishikawa S. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature. 1990 May 31;345(6274):442–444. doi: 10.1038/345442a0. [DOI] [PubMed] [Google Scholar]
  48. Zigmond S. H. Ability of polymorphonuclear leukocytes to orient in gradients of chemotactic factors. J Cell Biol. 1977 Nov;75(2 Pt 1):606–616. doi: 10.1083/jcb.75.2.606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Zigmond S. H., Sullivan S. J. Sensory adaptation of leukocytes to chemotactic peptides. J Cell Biol. 1979 Aug;82(2):517–527. doi: 10.1083/jcb.82.2.517. [DOI] [PMC free article] [PubMed] [Google Scholar]

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