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NEW MOLECULES IN THE TUMOR NECROSIS FACTOR LIGAND AND RECEPTOR SUPERFAMILIES WITH IMPORTANCE FOR PHYSIOLOGICAL AND PATHOLOGICAL BONE RESORPTION

Department of Oral Cell Biology, Umeå University, 901 87 Umeå, Sweden; ulf.lerner{at}odont.umu.se

View larger version (21K): [in a new window]   Figure 1. Osteoclast progenitor cells are closely related to monocytes/macrophages, and initial proliferation/differentiation is controlled by common signaling pathways. However, several extra- and intracellular signaling molecules are specifically involved in differentiation, fusion, polarization, and activation of the osteoclast-specific lineage. Some of these molecules are expressed in osteoclasts or their progenitor cells (in italic) and some in stromal cells/osteoblasts (underscored).

View larger version (24K): [in a new window]   Figure 2. Osteoclasts are derived from hematopoietic stem cells. The osteoclast progenitor cells are closely related to the monocyte/macrophage progenitor cells. Osteoclastogenesis requires initial expansion of the number of progenitor cells induced by activation of c-fms, the receptor for M-CSF. The commitment to the osteoclastic lineage is dependent on activation of the receptor RANK, which is activated by RANKL expressed by stromal cells in bone marrow and osteoblasts in the periosteum. RANK activation results in differentiation of the mononuclear progenitor cells and subsequent fusion to multinucleated latent osteoclasts. Activation of RANK in these cells is required for polarization and activation to mature bone-resorbing osteoclasts. The activation of RANK by RANKL can be inhibited by the RANK-related soluble receptor OPG, released by stromal cells/osteoblasts. Thus, the relative expression of RANKL/OPG is rate-limiting for the osteoclastogenic process. The expression of these molecules is controlled by a variety of hormones and cytokines stimulating bone resorption, e.g., PTH, D3, the IL-6 family of cytokines. Stimulators like PTH and D3 are particularly effective for bone resorption, since activation of their receptors leads to increased RANKL and decreased OPG, whereas members of the IL-6 family of cytokines are less effective, since both RANKL and OPG expression are induced by their receptors.

View larger version (43K): [in a new window]   Figure 3. RANKL activates the receptor RANK on osteoclast progenitor cells and mature osteoclasts in a trimeric symmetric complex. (A) The downstream intracellular signaling pathways include TRAF6-dependent activation of IKK and NF-B, as well as TRAF6-dependent activation of MKK and subsequent stimulation of p38 MAPK, ERK, and JNK. Activation of the MAPKs leads to activation and nuclear translocation of the transcription factors ATF2, c-Fos, c-Jun, and NFATc1, resulting in transcription of genes, mostly unknown, required for osteoclast differentiation and activation. (B) RANKL-RANK-TRAF6 signaling in osteoclasts also results in activation of c-src required for polarization of mature osteoclasts. The c-src-dependent activation of PI3K results in increased PtdIns(3,4,5)P3 and subsequent activation of Akt, which then inactivates Bad. Inhibition of Akt/Bad-dependent apoptosis is involved in the anti-apoptotic pathway induced by RANKL-RANK signaling. This pathway can be inactivated by PTEN and SHIP, expressed by osteoclasts and their progenitor cells, which gives rise to decreased numbers of osteoclasts.

View larger version (17K): [in a new window]   Figure 4. In periodontitis, osteoclast formation can be due either to activation of RANKL expressed by infiltrating T-cells or to RANKL induced in resident fibroblasts, periodontal ligament (PDL) cells, or osteoblasts.