M-CSF is a cytokine, being a smaller protein involved in cell signaling. The active form of the protein is found extracellularly as a disulfide-linked homodimer, and is thought to be produced by proteolytic cleavage of membrane-bound precursors.
Four transcript variants encoding three different isoforms (a proteoglycan, glycoprotein and cell surface protein) have been found for this gene.
M-CSF (or CSF-1) is a hematopoietic growth factor that is involved in the proliferation, differentiation, and survival of monocytes, macrophages, and bone marrow progenitor cells. M-CSF affects macrophages and monocytes in several ways, including stimulating increased phagocytic and chemotactic activity, and increased tumour cell cytotoxicity.
The role of M-CSF is not only restricted to the monocyte/macrophage cell lineage. By interacting with its membrane receptor (CSF1R or M-CSF-R encoded by the c-fms proto-oncogene), M-CSF also modulates the proliferation of earlier hematopoietic progenitors and influence numerous physiological processes involved in immunology, metabolism, fertility and pregnancy.
M-CSF released by osteoblasts (as a result of endocrine stimulation by parathyroid hormone) exerts paracrine effects on osteoclasts. M-CSF binds to receptors on osteoclasts inducing differentiation, and ultimately leading to increased plasma calcium levels—through the resorption (breakdown) of bone. Additionally, high levels of CSF-1 expression are observed in the endometrial epithelium of the pregnant uterus as well as high levels of its receptor CSF1R in the placental trophoblast. Studies have shown that activation of trophoblasitc CSF1R by local high levels of CSF-1 is essential for normal embryonic implantation and placental development. More recently, it was discovered that CSF-1 and its receptor CSF1R are implicated in the mammary gland during normal development and neoplastic growth.
Locally produced M-CSF in the vessel wall contributes to the development and progression of atherosclerosis.
M-CSF has been described to play a role in renal pathology including acute kidney injury and chronic renal failure. The chronic activation of monocytes can lead to multiple metabolic, hematologic and immunologic abnormalities in patients with chronic renal failure. In the context of acute kidney injury, M-CSF has been implicated in promoting repair following injury, but also been described in an opposing role, driving proliferation of a pro-inflammatory macrophage phenotype.
^Jang MH, Herber DM, Jiang X, Nandi S, Dai XM, Zeller G, Stanley ER, Kelley VR (September 2006). "Distinct in vivo roles of colony-stimulating factor-1 isoforms in renal inflammation". Journal of Immunology. 177 (6): 4055–63. doi:10.4049/jimmunol.177.6.4055. PMID16951369.
^Cao Q, Wang Y, Zheng D, Sun Y, Wang C, Wang XM, Lee VW, Wang Y, Zheng G, Tan TK, Wang YM, Alexander SI, Harris DC (April 2014). "Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo". Kidney International. 85 (4): 794–806. doi:10.1038/ki.2013.341. PMID24048378.
Suzu S, Ohtsuki T, Yanai N, Takatsu Z, Kawashima T, Takaku F, Nagata N, Motoyoshi K (March 1992). "Identification of a high molecular weight macrophage colony-stimulating factor as a glycosaminoglycan-containing species". The Journal of Biological Chemistry. 267 (7): 4345–8. PMID1531650.
Saltman DL, Dolganov GM, Hinton LM, Lovett M (February 1992). "Reassignment of the human macrophage colony stimulating factor gene to chromosome 1p13-21". Biochemical and Biophysical Research Communications. 182 (3): 1139–43. doi:10.1016/0006-291X(92)91850-P. PMID1540160.
Praloran V, Chevalier S, Gascan H (May 1992). "Macrophage colony-stimulating factor is produced by activated T lymphocytes in vitro and is detected in vivo in T cells from reactive lymph nodes". Blood. 79 (9): 2500–1. PMID1571567.
Price LK, Choi HU, Rosenberg L, Stanley ER (February 1992). "The predominant form of secreted colony stimulating factor-1 is a proteoglycan". The Journal of Biological Chemistry. 267 (4): 2190–9. PMID1733926.
Pampfer S, Tabibzadeh S, Chuan FC, Pollard JW (December 1991). "Expression of colony-stimulating factor-1 (CSF-1) messenger RNA in human endometrial glands during the menstrual cycle: molecular cloning of a novel transcript that predicts a cell surface form of CSF-1". Molecular Endocrinology. 5 (12): 1931–8. doi:10.1210/mend-5-12-1931. PMID1791839.
Stein J, Borzillo GV, Rettenmier CW (October 1990). "Direct stimulation of cells expressing receptors for macrophage colony-stimulating factor (CSF-1) by a plasma membrane-bound precursor of human CSF-1". Blood. 76 (7): 1308–14. PMID2145044.
Sherr CJ, Rettenmier CW, Sacca R, Roussel MF, Look AT, Stanley ER (July 1985). "The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1". Cell. 41 (3): 665–76. doi:10.1016/S0092-8674(85)80047-7. PMID2408759.
Cerretti DP, Wignall J, Anderson D, Tushinski RJ, Gallis BM, Stya M, Gillis S, Urdal DL, Cosman D (August 1988). "Human macrophage-colony stimulating factor: alternative RNA and protein processing from a single gene". Molecular Immunology. 25 (8): 761–70. doi:10.1016/0161-5890(88)90112-5. PMID2460758.
Takahashi M, Hirato T, Takano M, Nishida T, Nagamura K, Kamogashira T, Nakai S, Hirai Y (June 1989). "Amino-terminal region of human macrophage colony-stimulating factor (M-CSF) is sufficient for its in vitro biological activity: molecular cloning and expression of carboxyl-terminal deletion mutants of human M-CSF". Biochemical and Biophysical Research Communications. 161 (2): 892–901. doi:10.1016/0006-291X(89)92683-1. PMID2660794.
Kawasaki ES, Ladner MB, Wang AM, Van Arsdell J, Warren MK, Coyne MY, Schweickart VL, Lee MT, Wilson KJ, Boosman A (October 1985). "Molecular cloning of a complementary DNA encoding human macrophage-specific colony-stimulating factor (CSF-1)". Science. 230 (4723): 291–6. doi:10.1126/science.2996129. PMID2996129.
Takahashi M, Hong YM, Yasuda S, Takano M, Kawai K, Nakai S, Hirai Y (May 1988). "Macrophage colony-stimulating factor is produced by human T lymphoblastoid cell line, CEM-ON: identification by amino-terminal amino acid sequence analysis". Biochemical and Biophysical Research Communications. 152 (3): 1401–9. doi:10.1016/S0006-291X(88)80441-8. PMID3259875.