The M-CSF receptor in osteoclasts and beyond

Abstract

Colony-stimulating factor 1 receptor (CSF1R, also known as c-FMS) is a receptor tyrosine kinase. Macrophage colony-stimulating factor (M-CSF) and IL-34 are ligands of CSF1R. CSF1R-mediated signaling is crucial for the survival, function, proliferation, and differentiation of myeloid lineage cells, including osteoclasts, monocytes/macrophages, microglia, Langerhans cells in the skin, and Paneth cells in the intestine. CSF1R also plays an important role in oocytes and trophoblastic cells in the female reproductive tract and in the maintenance and maturation of neural progenitor cells. Given that CSF1R is expressed in a wide range of myeloid cells, altered CSF1R signaling is implicated in inflammatory, neoplastic, and neurodegenerative diseases. Inhibiting CSF1R signaling through an inhibitory anti-CSF1R antibody or small molecule inhibitors that target the kinase activity of CSF1R has thus been a promising therapeutic strategy for those diseases. In this review, we cover the recent progress in our understanding of the various roles of CSF1R in osteoclasts and other myeloid cells, highlighting the therapeutic applications of CSF1R inhibitors in disease conditions.

Fig. 1. Genomic structure of the mouse Csf1r locus.

Both human and mouse Csf1r genes consist of 22 exons and 21 introns (upper panel). Exon 1 is only expressed in trophoblasts through activation of the trophoblast-specific promoter. The human trophoblast-specific promoter is located 20 kb upstream of exon 1. Csf1r transcription in macrophages starts from the promoter that is upstream of exon 2. Neither promoter has a TATA box. The Fms-intronic regulatory element (FIRE) is a highly conserved regulatory element that produces antisense transcripts to overcome the unknown repressive elements in intron 2. Several transcription factors known to bind to the FIRE have been characterized (lower panel).

Fig. 2. Structure of CSF1R protein.

The left panel shows the structure of CSF1R. The extracellular regions have five Ig-like domains; D2 and D3 are ligand binding domains. The intracellular domains consist of the transmembrane domain, the juxtamembrane domain, two-kinase domains, a kinase insert, and cytoplasmic domains. CSF1R is a receptor tyrosine kinase and has 6 tyrosine residues that are phosphorylated upon ligand binding (purple circle). Green square: phosphorylated tyrosine in the v-FMS oncogenic receptor. Ligand engagement of CSF1R induces dimerization and phosphorylation of tyrosine residues. Phosphorylated tyrosines serve as docking sites for Src homology domain 2-containing signaling molecules to promote osteoclast differentiation, proliferation, cytoskeletal reorganization, and motility.