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.

Macrophages Derived From Human Induced Pluripotent Stem Cells: The Diversity of Protocols, Future Prospects, and Outstanding Questions

“…Mφ colony-stimulating factor is a lineage-specific hematopoietic factor essential for the differentiation, survival, and functioning of mononuclear phagocytes, including monocyte/Mφs, dendritic cells, and osteoclasts (reviewed in Jones and Ricardo, 2013 ; Stanley and Chitu, 2014 ; Mun et al, 2020 ). M-CSF is produced by mesenchymal and epithelial cells located in different tissues ( Ryan et al, 2001 ).…”

18F-Sodium Fluoride PET as a Diagnostic Modality for Metabolic, Autoimmune, and Osteogenic Bone Disorders: Cellular Mechanisms and Clinical Applications

“…Osteoclasts, the multinucleated bone-resorbing cells of the body, originate from the myeloid lineage of the hematopoietic stem cells in the marrow. Proliferation and differentiation of osteoclast precursor cells are regulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κ B ligand (RANKL), respectively [ 24 , 25 ]. Under pathological conditions, osteoclasts can also become activated by various inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6 [ 24 ].…”

Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption

“…While this compound binds the active site of SIKs, it also engages a number of tyrosine kinases including the receptor tyrosine kinase CSF1R (FMS, the M-CSF receptor) (Figure 7A). Given the essential role of M-CSF action in osteoclast development (17,37), this raised the possibility that YKL-05-099 might block osteoclast differentiation via effects on CSF1R. Most proteins within the human kinome share a highly conserved catalytic domain (38).…”

“…While YKL-05–099 potently blocked osteoclast differentiation in vitro, deletion of SIK2/3 or SIK1/2/3 showed no obvious effects on differentiation or function of isolated osteoclast precursors. YKL-05–099 also potently inhibited CSF1R, the receptor for the key osteoclastogenic cytokine M-CSF ( Mun et al, 2020 ). Modeling revealed that YKL-05–099 prefers a common conformation of both CSF1R and SIK2.…”