A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts

Abstract

Osteoclasts require coordinated co-stimulation by several signaling pathways to initiate and regulate their cellular differentiation. RANKL (Receptor Activator for NFkB ligand or TNFSF25), a TNF (tumor necrosis factor) superfamily member, is the master cytokine required for osteoclastogenesis with essential co-stimulatory signals mediated by ITAM (immunoreceptor tyrosine-based activation motif)-signaling adaptors, DAP12 (DNAX associated protein 12kD size) and FcRγ (FcεR1 gamma chain). The ITAM-signaling adaptors do not have an extracellular ligand-binding domain, and therefore must pair with ligand-binding immunoreceptors to interact with their extracellular environment. DAP12 pairs with a number of different immunoreceptors including TREM-2 (Triggering Receptor Expressed on Myeloid Cells 2), MDL-1 (Myeloid Dap-12 associated Lectin) and Siglec-15 (Sialic acid-binding immunoglobulin-type lectin15), while FcRγ pairs with a different set of receptors including OSCAR (Osteoclast Specific Activating Receptor), PIR-A (Paired Immunoglobulin Receptor A), and Fc Receptors. The ligands for many of these receptor in the bone microenvironment remain unknown. Here we will review immunoreceptors known to pair with either DAP12 or FcRγ that have been shown to regulate osteoclastogenesis, However, co-stimulation and the effects of ITAM-signaling have turned out to be complex including paradoxical findings that ITAM-signaling adaptor-associated receptors can inhibit osteoclastogenesis and ITIM (immunoreceptor tyrosine-based inhibitory motif) receptors can promote osteoclastogenesis. Thus, co-stimulation of osteoclastogenesis continues to reveal additional complexities that are important in the regulatory mechanisms that seek to maintain bone homeostasis.

TREM2, Microglia, and Neurodegenerative Diseases

“…As previously discussed, the TREM2 gene is highly expressed in a subset of myeloid cell typesnamely, microglia in the CNS, osteoclasts in the bone, and other tissue-specific macrophages, including Kupffer cells, as well as alveolar, intestinal, and peritoneal macrophages [58,73,[90][91][92][93][94][95]. Bone marrow cells and blood monocytes express low to undetectable levels of TREM2, although expression can be induced upon differentiation of the former into macrophages or dendritic cells in vitro [50,87,91].…”

“…Osteoclasts are giant, multinucleated syncytial cells involved in bone resorption that can be derived in vitro when human blood monocytes are cultured with colony stimulating factor 1 [ 5 5 4 _ T D $ D I F F ] (CSF1) and receptor activator of nuclear factor kappa B ligand (RANKL) proteins, but this differentiation is impaired in cultures from TYROBP-deficient or TREM2-deficient NHD patients [70,71]. For details on TREM2 function in bone maintenance the reader is referred to recent reviews [72][73][74]. The regulation of osteoclast differentiation and bone remodeling by TREM2 could give rise to unwanted side effects for therapeutics intended to boost TREM2 signaling in AD or other neurodegenerative settings.…”

The many ways of osteoclast activation

“…These include TNF receptor-associated factor 6 (TRAF6), NF-κB, MAPK, and activator protein 1 (AP-1) (10), all of which are costimulated by immunoreceptor tyrosine-based activation motif (ITAM) signaling (11). These factors downstream of RANKL/RANK are thought to influence osteoclasts through their effects on a common transcription factor, nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) (12,13).…”

C/EBPα and PU.1 exhibit different responses to RANK signaling for osteoclastogenesis

“…Mechanistically, we demonstrated that C/EBPα or PU.1 overexpression failed to control the deregulated RBP-J expression from the IVVY-motif inactivation, leading to repression of osteoclast genes and inhibition of osteoclast differentiation. Osteoclastogenesis requires two essential cross-talk signaling induced by RANK activation and the ITAM-associated receptors (DAP12 and FcRγ) (48,49,58). Our finding is consistent with a recent study indicating that RBP-J suppresses the ITAM-mediated costimulatory signaling and limits the cross-talk between the ITAM and RANK signaling during osteoclastogenesis.…”