Regulatory roles and molecular signaling of TNF family members in osteoclasts. [Review] [133 refs]

Department of Pathology, University of Alabama at Birmingham, 1670 University BLVD, VH G046B, Birmingham, AL 35294, USA.
Gene (Impact Factor: 2.14). 05/2005; 350(1):1-13. DOI: 10.1016/j.gene.2005.01.014
Source: PubMed


The tumor necrosis factor (TNF) family has been one of the most intensively studied families of proteins in the past two decades. The TNF family constitutes 19 members that mediate diverse biological functions in a variety of cellular systems. The TNF family members regulate cellular functions through binding to membrane-bound receptors belonging to the TNF receptor (TNFR) family. Members of the TNFR family lack intrinsic kinase activity and thus they initiate signaling by interacting intracellular signaling molecules such as TNFR associated factor (TRAF), TNFR associated death domain (TRADD) and Fas-associated death domain (FADD). In bone metabolism, it has been shown that numerous TNF family members including receptor activator of nuclear factor kappaB ligand (RANKL), TNF-alpha, Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) play pivotal roles in the differentiation, function, survival and/or apoptosis of osteoclasts, the principal bone-resorbing cells. These TNF family members not only regulate physiological bone remodeling but they are also implicated in the pathogenesis of various bone diseases such as osteoporosis and bone loss in inflammatory conditions. This review will focus on our current understanding of the regulatory roles and molecular signaling of these TNF family members in osteoclasts.

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    • "Whereas M-CSF mainly stimulates proliferation and survival of bone marrow macrophages (BMMs, namely, osteoclast precursors), RANKL primarily drives osteoclast differentiation. RANKL binds to its receptor RANK, a member of the TNF receptor superfamily, to activate numerous signaling pathways (NF-κB, JNK, ERK, p38 and Akt) [35], [36]. RANKL also up-regulates the expression of nuclear factor of activated T-cells c1 (NFATc1), which plays an essential role in osteoclastogenesis [37]. "
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    ABSTRACT: Thiazolidinediones are synthetic peroxisome proliferator-activated receptor γ agonists used to treat type 2 diabetes mellitus. Clinical evidence indicates that thiazolidinediones increase fracture risks in type 2 diabetes mellitus patients, but the mechanism by which thiazolidinediones augment fracture risks is not fully understood. Several groups recently demonstrated that thiazolidinediones stimulate osteoclast formation, thus proposing that thiazolidinediones induce bone loss in part by prompting osteoclastogenesis. However, numerous other studies showed that thiazolidinediones inhibit osteoclast formation. Moreover, the molecular mechanism by which thiazolidinediones modulate osteoclastogenesis is not fully understood. Here we independently address the role of thiazolidinediones in osteoclastogenesis in vitro and furthermore investigate the molecular mechanism underlying the in vitro effects of thiazolidinediones on osteoclastogenesis. Our in vitro data indicate that thiazolidinediones dose-dependently inhibit osteoclastogenesis from bone marrow macrophages, but the inhibitory effect is considerably reduced when bone marrow macrophages are pretreated with RANKL. In vitro mechanistic studies reveal that thiazolidinediones inhibit osteoclastogenesis not by impairing RANKL-induced activation of the NF-κB, JNK, p38 and ERK pathways in bone marrow macrophages. Nonetheless, thiazolidinediones inhibit osteoclastogenesis by suppressing RANKL-induced expression of NFATc1 and c-Fos, two key transcriptional regulators of osteoclastogenesis, in bone marrow macrophages. In addition, thiazolidinediones inhibit the RANKL-induced expression of osteoclast genes encoding matrix metalloproteinase 9, cathepsin K, tartrate-resistant acid phosphatase and carbonic anhydrase II in bone marrow macrophages. However, the ability of thiazolidinediones to inhibit the expression of NFATc1, c-Fos and the four osteoclast genes is notably weakened in RANKL-pretreated bone marrow macrophages. These in vitro studies have not only independently demonstrated that thiazolidinediones exert inhibitory effects on osteoclastogenesis but have also revealed crucial new insights into the molecular mechanism by which thiazolidinediones inhibit osteoclastogenesis.
    PLoS ONE 07/2014; 9(7):e102706. DOI:10.1371/journal.pone.0102706 · 3.23 Impact Factor
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    • "Osteoclasts, the bone-resorbing cells, play an important role in skeletal development and adult bone remodeling [1] [2]. Osteoclasts differentiate from hematopoietic cells of the monocyte/macrophage lineage involving several different stages [3]. Hematopoietic stem cells (HSC) give rise to common myeloid progenitors (CMP) with stimulation of various factors including stem cell factor (SCF), IL-3 and interleukin 6 (IL-6). "
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    ABSTRACT: Interleukin (IL)-3, a multilineage hematopoietic growth factor, is implicated in the regulation of osteoclastogenesis. However, the role of IL-3 in osteoclastogenesis remains controversial; whereas early studies showed that IL-3 stimulates osteoclastogenesis, recent investigations demonstrated that IL-3 inhibits osteoclast formation. The objective of this work is to further address the role of IL-3 in osteoclastogenesis. We found that IL-3 treatment of bone marrow cells generated a population of cells capable of differentiating into osteoclasts in tissue culture dishes in response to the stimulation of the monocyte/macrophage-colony stimulating factor (M-CSF) and the receptor activator of nuclear factor kappa B ligand (RANKL). The IL-3-dependent hematopoietic cells were able to further proliferate and differentiate in response to M-CSF stimulation and the resulting cells were also capable of forming osteoclasts with M-CSF and RANKL treatment. Interestingly, IL-3 inhibits M-CSF-/RANKL-induced differentiation of the IL-3-dependent hematopoietic cells into osteoclasts. The flow cytometry analysis indicates that while IL-3 treatment of bone marrow cells slightly affected the percentage of osteoclast precursors in the surviving populations, it considerably increased the percentage of osteoclast precursors in the populations after subsequent M-CSF treatment. Moreover, osteoclasts derived from IL-3-dependent hematopoietic cells were fully functional. Thus, we conclude that IL-3 plays dual roles in osteoclastogenesis by promoting the development of osteoclast progenitors but inhibiting the osteoclastogenic process. These findings provide a better understanding of the role of IL-3 in osteoclastogenesis.
    Biochemical and Biophysical Research Communications 10/2013; 440(4). DOI:10.1016/j.bbrc.2013.09.098 · 2.30 Impact Factor
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    • "RANKL and M-CSF are expressed in osteoblasts/stromal cells, which is essential for osteoclastogenesis [21]. RANK is expressed in osteoclast precursors and stimulates osteoclast maturation [10]. In the present study, TRAP-positive multinucleated cells were observed among duck embryo bone marrow cells treated with M-CSF and RANKL. "
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    ABSTRACT: The aim of this study was to determine whether osteoprotegerin (OPG) could affect differentiation and activation of osteoclast in serum-free conditions. Both duck embryo bone marrow cells and RAW264.7 cells were incubated with M-CSF + RANKL in serum-free medium for osteoclastogenesis. In the cultivation of the cells, 0, 10, 20, 50, and 100ng/mL OPG were added to various groups. Osteoclast differentiation and activation were estimated via TRAP staining study, F-actin rings analysis, and bone resorption assay. Furthermore, expression levels of osteoclast related genes, such as TRAP and RANK, which were influenced by OPG, were examined using real-time PCR with RAW264.7 cells. In summary, these findings suggested that M-CSF + RANKL could promote the differentiation and activation of osteoclast, enhance the expression of TRAP mRNA and RANK mRNA in osteoclast, whereas OPG inhibited them in serum-free conditions.
    Journal of veterinary science (Suwŏn-si, Korea) 06/2013; 14(4). DOI:10.4142/jvs.2013.14.4.405 · 1.16 Impact Factor
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