RBP-J and ITAM crosstalk

Osteoclasts, multinucleated giant cells derived from the monocyte/macrophage lineage, are the exclusive specialized bone-resorbing cells that are indispensable for skeletal development, bone remodeling and repair and mineral homeostasis. Increased osteoclastogenesis leads to excessive bone resorption in osteoporosis and in inflammatory diseases with bone destruction, such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), juvenile chronic arthritis (JCA) and periodontitis [1]. As bone is one of the major metastatic sites for tumorigenesis of the breast, prostate, lung as well as multiple myeloma, abnormal generation and activation of osteoclasts facilitate skeletal metastasis and tumor growth in bone tissue [2]. Thus, appropriate control of osteoclastogenesis will be a direct and highly effective approach in the prevention and treatment of osteolysis in pathological conditions. The immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling pathways play important roles in various cellular activities, including immune response and cancer activation. The main ITAM-containing adaptors expressed by myeloid osteoclast precursors are DNAX-activating protein 12 (DAP12) and Fc receptor common γ subunit (FcRγ). These adaptors associate with and mediate signaling by various receptors, including DAP12-associated triggering receptor expressed in myeloid cells 2 (TREM2) and signal-regulatory protein β 1 (SIRPβ1), FcRγ-associated osteoclast-associated receptor (OSCAR), paired immunoglobulin-like receptor-A (PIR-A) and FcRs. Osteoclasts require ITAM-mediated costimulation of RANK signaling for their appropriate differentiation during bone homeostasis [3]. Osteoclastogenesis is delicately modulated at various levels, but little is known about the mechanisms that regulate ITAM-mediated costimulation. Recombinant recognition sequence binding protein at the J κ, site (RBP-J, also named RBP-J κ, , CSL or CBF1) functions as a central transcription factor that receives inputs from several signaling pathways, such as the canonical Notch pathway, Wnt-β-catenin, NF-κB pathway, TLR and TNF signaling pathways. We recently identified RBP-J as a key negative regulator that imposes the requirement for ITAM-mediated costimulation of osteoclastogenesis, homeostatic bone remodeling and inflammatory bone resorption, and discovered the signaling pathways and mechanisms by which RBP-J regulates ITAM-mediated costimulation [4, 5]. Loss of DAP12 or both DAP12 and FcRγ in mice leads to severe osteopetrosis due to impaired osteoclastogenesis and resorptive function. To investigate the role of RBP-J in ITAM-mediated bone remodeling, we generated DAP12 and RBP-J double knockout (KO) mice (R-DKO) and DAP12, FcRγ and RBP-J triple KO mice (TKO) [5]. Strikingly, we found that RBP-J deficiency almost completely reversed the defects of osteoclast differentiation program and significantly rescued the osteopetrotic bone phenotype of Dap12 KO or Dap12/ Fcrg double knockout (DKO) mice by …