Some receptors in the immune system use a signaling system in which the receptors associate with transmembrane adaptor proteins, which help activate appropriate signals in the cytoplasm. These adaptor proteins contain immunoreceptor tyrosine-based activation motifs (ITAMS). Koga et al. show that RANKL (receptor activator of nuclear factor NF-κB ligand), a receptor that promotes differentiation of osteoclasts in bone, requires a similar interaction with the two of the ITAM-containing adaptors known to function with receptors in the immune system, namely, DAP12 (DNAX-activating protein 12) and FcRγ (Fc receptor common γ subunit). DAP12 and FcRγ appear to substitute for one another, but in animals lacking both adaptors, osteoclast differentiation in response to a combination of RANKL and M-CSF (macrophage colony-stimulating factor) was strongly inhibited. Immunoprecipitation showed association of FcRγ with PIR-A (paired immunoglobulin-like receptor A), FcγRIII, and OSCAR (osteoclast-associated receptor), and stimulation of differentiation by RANKL required a signal from one of these other receptor complexes. Critical signals missing in cells from animals lacking DAP12 and FcRγ were the oscillation in the intracellular concentration of calcium and activation of the transcription factor NFATc1 (nuclear factor of activated T cells c1) that normally accompany RANKL-induced differentiation. Thus, development and homeostatic maintenance of bone requires a coincidence detector system similar to the so-called costimulatory signals that are required in immune regulation. The signals mediated by the adaptor proteins provide potential new targets for therapeutic intervention in skeletal disorders.
T. Koga, M. Inui, K. Inoue, S. Kim, A. Suematsu, E. Kobayashi, T. Iwata, H. Ohnishi, T. Matozaki, T. Kodama, T. Taniguchi, H. Takayanagi, T. Takai, Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758-763 (2004). [Online Journal]