TNF (Tumor Necrosis Factor) and TNFR (Tumor Necrosis Factor Receptor) family proteins play important roles in the control of cell death, proliferation, autoimmunity, the function of immune cells, and the organogenesis of lymphoid organs. Recently, novel members of this large family have been identified that have critical functions in immunity and that couple lymphoid cells with other organ systems, such as bone remodeling and mammary gland formation in pregnancy. Bone remodeling results from the coordinate action of bone resorption by osteoclasts and the formation of new bone by osteoblasts. Regulation of bone remodeling occurs through multiple mechanisms that ultimately converge on the interaction of osteoclasts or their precursors with osteoblasts and bone marrow stromal cells. Osteoblasts and osteoclasts arise from distinct cell lineages and maturation processes, i.e., osteoblasts arise from mesenchymal stem cells, whereas osteoclasts differentiate from hematopoietic monocyte/macrophage precursors .
The TNF-family molecule RANKL (Receptor Activator of NF-kappaB Ligand; also known as OPGL, TRANCE, ODF and TNFSF11) and its receptor RANK (TNFRSF11A) are key regulators of bone remodeling, and they are essential for the development and activation of osteoclasts . RANKL induces the differentiation of osteoclast precursor cells and stimulates the resorption function and survival of mature osteoclasts. The TRAF (TNF Receptor-Associated Factor) adaptor proteins play an important role in the initial event of the signal transduction pathway induced by RANK. TRAFs 1, 2, 3, 5 and 6 bind through the conserved TRAF domain to RANK . Among the TRAF proteins, TRAF6 is critical for RANK signaling in osteoclasts. TRAF proteins may act by transmitting the RANK signal to downstream targets that include NF-kappaB (Nuclear Factor-kappa B) and JNK (c-Jun N-terminal kinase). NF-kappaB is retained in the cytoplasm as a complex with the inhibitory I-KappaB (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells) protein in unstimulated cells. Stimuli that activate NF-kappaB induce the activation of IKKs (I-KappaB Kinases), resulting in the phosphorylation and subsequent proteasome-mediated degradation of I-KappaB. The liberated NF-kappaB then enters the nucleus where it binds to DNA target sites. Events that occur after RANK stimulation in differentiated osteoclasts or osteoclast precursor cells include the phosphorylation and degradation of I-kappaB-Alpha and the nuclear translocation and DNA binding of the NF-kappaB proteins p50, p52, and p65 . Other intracellular adaptor proteins that interact with TRAF proteins and regulate the function of TRAF in osteoclasts are TAK1 (TGF-Beta Activated Kinase) and NIK (NF-KappaB-Inducing Kinase). XIAP (Xenopus Inhibitor of Apoptosis) and cIAP are downstream targets of NF-kappaB in osteoclast survival pathway. Members of all three MAPK (Mitogen Activated Protein kinase) families, ERK (Extracellular signal Regulated Kinase), JNK, and p38, are activated by RANK in osteoclasts or osteoclast precursors . JNK1, and not JNK2, is important for efficient osteoclast differentiation. The upstream targets of JNK in RANK signaling include MKK7. The dominant-negative MKK6 regulates p38 activity and osteoclastogenesis. Raf is implicated in the activation of ERK via signal transduction involving CD40, a TNFR family receptor that shares similar signaling characteristics as RANK . The TAK1/TAB2 activity that induces JNK and p38 activation is downstream of TRAF6 in the RANK-signaling pathway. The downstream targets of ERKs and JNKs include the transcription factor Activating Protein-1, a dimmer composed of c-Fos and c-Jun protein. ERK induce and activate c-Fos and NFAT (Nuclear Factor of Activated T-Cells) by phosphorylating Elk1, which is a part of a TCF (Ternary Complex Factor), while JNK increase Activating Protein-1 transcriptional activity through the phosphorylation of c-Jun. Another transcription factor MITF (Microphthalmia-Associated Transcription Factor) is a target of p38 in the RANK-signaling pathway in osteoclasts .
Src act as a mediator of the RANK to PI3K (Phosphatidylinositol-3 Kinase)/Akt1 signal in osteoclasts. Among the many molecules downstream of Src, PYK2 (Protein Tyrosine Kinase-2) and c-Cbl are implicated in osteoclast adhesion signaling and bone resorption function. Additionally, the association of the actin-binding protein gelsolin with PI3K is important in actin filament formation in osteoclasts. Src and PI3K function at the point where RANK and adhesion signals converge, transmitting the signals for proper actin cytoskeletal organization that facilitates resorption activity of osteoclasts . Increased osteoclast activity is seen in many osteopenic disorders, including postmenopausal osteoporosis, Paget's Disease, lytic bone metastases, and rheumatoid arthritis, leading to increased bone resorption and crippling bone damage. 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, and bone loss, as well as pain associated with bone metastases. 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 .
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