Macrophage colony-stimulating factor

Structure

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.

Function

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 trophoblastic 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.

Clinical significance

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 kidney failure. The chronic activation of monocytes can lead to multiple metabolic, hematologic and immunologic abnormalities in patients with chronic kidney 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.

As a drug target

PD-0360324 and MCS110 are CSF1 inhibitors in clinical trials for some cancers. See also CSF1R inhibitors.

Interactions

Macrophage colony-stimulating factor has been shown to interact with PIK3R2.

References

References

1. (September 2006). "Distinct in vivo roles of colony-stimulating factor-1 isoforms in renal inflammation". Journal of Immunology.
2. "Entrez Gene: CSF1 colony stimulating factor 1 (macrophage)".
3. (January 1997). "Biology and action of colony--stimulating factor-1". Molecular Reproduction and Development.
4. (April 1993). "Macrophage function activating cytokines: potential clinical application". Critical Reviews in Oncology/Hematology.
5. (June 1997). "Macrophage colony-stimulating-factor (M-CSF or CSF-1) and its receptor: structure-function relationships". European Cytokine Network.
6. (2018). "Paracrine and endocrine actions of bone—the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts". Bone Research.
7. (January 2004). "The role of CSF-1 in normal physiology of mammary gland and breast cancer: an update". Experimental Biology and Medicine.
8. (June 1998). "Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice". The Journal of Clinical Investigation.
9. (2013-01-01). "Acute kidney injury: CSF-1 signalling is involved in repair following AKI". Nature Reviews Nephrology.
10. (September 1996). "Macrophage colony stimulating factor involvement in uremic patients". Kidney International.
11. (December 2012). "CSF-1 signaling mediates recovery from acute kidney injury". The Journal of Clinical Investigation.
12. (April 2014). "Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo". Kidney International.
13. [https://www.onclive.com/publications/oncology-live/2018/vol-19-no-7/interest-builds-in-csf1r-for-targeting-tumor-microenvironment?p=2 ''Interest Builds in CSF1R for Targeting Tumor Microenvironment'']
14. (December 1992). "Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 beta protein by using the baculovirus expression system". The Biochemical Journal.