RANK Pathway

RANKL is expressed on osteoblasts and bone marrow stromal cells, while its receptor RANK is expressed on osteoclast progenitors or mature osteoclasts. RANKL interacts with RANK via direct cell-cell contact, thereby promoting the differentiation, survival, and bone-resorbing capability of osteoclasts [3]. Signaling through RANK involves the recruitment of cytosolic TRAFs (Tumor Necrosis Factor Receptor Associated Factors) TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6, which in turn activate multiple signaling pathways. The association of RANK with TRAF2 induces activation of MAPK (Mitogen-Activated Protein Kinase), NF-KappaB, and JNK (c-Jun N-Terminal Kinase), which leads to phosphorylation of c-Jun and activation of transcription factor, Activating Protein-1. Activation of NF-KappaB-inducing kinase leads to activation of IKKs (I-KappaB kinases), which in turn phosphorylate serine residues on I-KappaBs (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells), targeting it for degradation in the proteasome. I-kappaB degradation exposes the NF-KappaB nuclear localization sequence, permitting its nuclear import. Within the nucleus, NF-KappaB acts in concert with other transcription factors to regulate gene expression [3]. The RANK cytoplasmic tail associates with c-Src kinase, which activates the anti-apoptotic serine/threonine kinase Akt/PKB (Protein Kinase-B) through a signaling complex involving c-Src and TRAF6 [4]. Moreover, RANK recruits c-Cbl family scaffolding proteins, and PI3K (Phosphatidylinositol-3 Kinase) in a ligand and Src-dependent manner. c-Src and TRAF6 interact with each other and with RANK following receptor engagement, and a deficiency in c-Src or the addition of Src family kinase inhibitors blocks RANK-mediated Akt/PKB activation in osteoclasts. TRAF6 enhances the kinase activity of c-Src, leading to tyrosine phosphorylation of downstream signaling molecules such as c-Cbl, NF-KappaB, and c-Fos, which is an important mediator of osteoclast differentiation [5].

RANKL and its receptor RANK are key regulators of bone remodeling, and are essential for the development and activation of osteoclasts. RANKL/RANK interactions regulate T-cell/dendritic cell communications, dendritic cell survival, and lymph node formation. T-cell–derived RANKL mediate autoimmune diseases, cancers, leukemia, asthma, chronic viral infections, and periodontal disease, which result in systemic and local bone loss and cartilage destruction in arthritis. RANKL and RANK are expressed in mammary gland epithelial cells, and they control the development of a lactating mammary gland during pregnancy. Inhibition of RANKL function via the natural decoy receptor OPG prevents bone loss in postmenopausal osteoporosis and cancer metastases and is useful to treat osteoporosis, crippling arthritis, osteopenic disorders, such as Paget's disease, and bone loss and pain associated with bone metastases [6]. This system provides an unexpected molecular paradigm that links bone morphogenesis, T-cell activation, and the organization of lymphoid tissues with mammary gland formation required for the survival of mammalian species. Modulation of these systems provides a unique opportunity to design novel therapeutics to inhibit bone loss in arthritis, periodontal disease, and osteoporosis [5].