A bone to pick with Fc gamma receptors

Bone formation is a dynamic process, in which the bone structure is constantly remodeled. Osteoclasts and osteoblasts play critical but opposing roles in bone formation and resorption. While osteoclasts promote bone resorption, osteoblasts drive bone formation. Both processes are intertwined and tightly regulated to ensure the integrity of the bony skeleton. In particular, bone mass, strength and mineral homeostasis depend on balanced osteoclast and osteoblast function. Enhanced osteoclast activity leads to massive bone loss as exemplified in autoimmune diseases like rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Osteoclasts and osteoblasts originate from different precursors. Whereas osteoblasts derive from mesenchymal stem cells, osteoclasts originate from multinucleated progenitors of the monocyte/ macrophage family. Two critical factors that regulate osteoclastogenesis are macrophage colony-stimulating factor (M-CSF) and receptor for activation of nuclear factor kappa B (NF-κB) (RANK) ligand (RANKL). RANKL is expressed by T cells, endothelial cells and osteoblasts. Although activation of the RANKL pathway is essential to initiate osteoclastogenesis, an immunoreceptor tyrosin based activation motif (ITAM) co-stimulatory pathway is required for calcium-mediated activation of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), which serves as an important factor in osteoclast differentiation. The ITAM co-stimulatory pathway is activated in response to ligation of immunoglobulin-like receptors such as osteoclast-associated receptor (OSCAR), triggering receptor expressed on myeloid cells (TREM-2) or paired Ig-like receptor A (PIR-A), and the phosphorylation of the adaptor molecules containing ITAM motifs. Such ITAM motif-containing proteins are DNAX activation protein of 12 kDa (DAP12) and the Fc-receptor γ subunit (FcRγ) Importantly, the γ-chain not only facilitates FcγR signaling but is also required for the transport of IgG Fc receptors to the cell surface. The critical role of FcRγ and DAP12 for osteoclast activation was first demonstrated in mice suffering from severe osteopetrosis when both factors were lacking. Importantly, the phenotype was less pronounced in mice lacking only DAP12, whereas FcRγ-deficient mice showed no disease phenotype. These data suggest that FcRγ plays an important role in osteoclastogenesis in concert with DAP12.