Targeting Fas in osteoresorptive disorders

Osteoblast differentiation is induced by several receptors, and leads to the activation of osteoblast transcription factors, including runt-related transcription factor 2 (Runx2), osterix, and Dlx5. Transforming growth factor-β (TGFβ) superfamily members (including bone morphogenetic proteins, BMPs) signal via serine/threonine receptor kinases and phosphorylation of Smad molecules. Phosphorylated Smads bind with the common Smad4 and forming a trimeric structure which is translocated to the nucleus, where they induce transcription of osteoblast genes. TGFβ superfamiliy receptors also signal through mitogen activated protein kinase (MAPK) pathways. Fibroblast growth factor (FGF) receptor signals through cytoplasmatic parts possessing tyrosine kinase domains, activated upon conformational changes induced by ligand binding. They phophorylate and activate MAPK and protein kinase C (PKC).Wnt ligand binds to a frizzled (FZZ)/low density lipoprotein receptor related protein (LRP) complex, activating the intracellular protein dishevelled (DSH). DSH inhibits the activity of complex protein structure which transports β-catenin to the proteasome, and results in β-catenin accumulation in the cytosol. β-catenin is then translocated to the nucleus where it regulates transcription.Ephrin (Eph) B4 is expressed on osteoblasts and signals through RhoA GTPase, while EphB2 expressed on osteoclasts signals through PDZ proteins. Interaction of EphB2 and EphB4 couples bone resorption to formation.Osteoclast differentiation is driven by several transcription factors, including nuclear factor of activated T-cells (NFATc1), Jun and Fos proteins, and NFκB. Receptor activator of nuclear factor (NF) κB (RANK) is a receptor from the tumor necrosis factor receptor (TNFR) superfamily, which is essential for osteoclastogenesis. Binding of its ligand (RANKL) activates various signaling pathways including NFκB, MAPK, c-Jun amino-terminal kinase (JNK), phospholipase Cγ (PLCγ), and phosphatidyl-inositol-3-kinase (PI3K). PI3K signaling links the RANK signaling pathway to the Akt proliferation and survival pathway. Binding of monocyte–colony stimulating factor (M-CSF) to its receptor (c-Fms) is essential for proliferation and survival of osteoclast precursors, and signals via PI3K/Akt and ERK. Additionally, signaling through the immunoglobulin (Ig)-like receptor, involving DAP12 protein or FcRγ activates PLCγ, and induces calcium release, and transcription of osteoclast genes via calmodulin (CaM) and calcineurin.Yellow arrows point to the components of osteoblast and osteoclast differentiation pathways, which are proposed to be regulated by Fas signaling.

Publication

Targeting Fas in osteoresorptive disorders. () Natasa Kovacic, et al. Expert Opin Ther Targets. ;14(10):1121-1134. Figure: F2. All organisms Mus musculus Homo sapiens Drosophila melanogaster Danio rerio

Disease mentions