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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: 2.08). 05/2005; 350(1):1-13. DOI: 10.1016/j.gene.2005.01.014
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ABSTRACT 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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    • "Osteoclasts are formed from hematopoietic precursors of the monocyte/macrophage lineage. Receptor activator of nuclear factor jB (RANK) ligand (RANKL), a member of the tumor necrosis factor family, plays crucial roles in osteoclast differentiation, function and survival (Boyle et al. 2003; Feng 2005; Takahashi et al. 1999; Suda et al. 1999). Osteoclast precursors express RANK, which recognizes RANKL expressed Midori Asai and Ji-Won Lee contributed equally to this work. "
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    ABSTRACT: The dried flower buds of Magnolia sp. are widely used as herbal medicines because of their anti-inflammatory, anti-malarial and anti-platelet activities. Here, we found that veraguensin and galgravin, lignan compounds derived from Magnolia sp., dose-dependently inhibited osteoclast formation in co-cultures of bone marrow cells and osteoblastic cells. These compounds also inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in RAW264.7 cells and bone marrow macrophages. In the RANKL-induced signaling pathway, veraguensin and galgravin reduced p38 phosphorylation and suppressed the expression of c-Fos, a key transcription factor for osteoclastogenesis. Veraguensin and galgravin also inhibited osteoclastic pit formation, which was accompanied by decreased mature osteoclast viability. In conclusion, these results indicate that veraguensin and galgravin can inhibit bone resorption and may offer novel compounds for the development of drugs to treat bone-destructive diseases such as osteoporosis.
    Cytotechnology 04/2012; 64(3):315-22. DOI:10.1007/s10616-011-9416-z · 1.45 Impact Factor
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    • "RANKL is a member of the tumor necrosis factor (TNF) family and interacts with the receptor RANK, which recruits adaptor molecules such as TNF receptor-associated factors (TRAFs) (Asagiri and Takayanagi, 2007), and is involved in the downstream activation of the mitogen-activated protein (MAP) kinases, nuclear factor κB (NF-κB), and activator protein- 1 (AP-1) (Walsh et al., 2006). RANKL plays a role in bone metabolism by mediating osteoclast formation and activation and calcium homeostasis (Dempsey et al., 2003; Feng, 2005). Among the TRAFs, TRAF6 is the most important adaptor molecule for RANKL-mediated signaling because it activates various kinases via its multiple domains (Bharti and Aggarwal, 2004; Lamothe et al., 2007; Wada et al., 2006). "
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    ABSTRACT: Osteoclasts, multinucleated bone-resorbing cells, are closely associated with bone diseases such as rheumatoid arthritis and osteoporosis. Osteoclasts are derived from hematopoietic precursor cells, and their differentiation is mediated by two cytokines, including macrophage colony stimulating factor and receptor activator of nuclear factor κB ligand (RANKL). Previous studies have shown that arctigenin exhibits an anti-inflammatory effect. However, the effect of arctigenin on osteoclast differentiation is yet to be elucidated. In this study, we found that arctigenin inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages in a dose-dependent manner and suppressed RANKL-mediated bone resorption. Additionally, the expression of typical marker proteins, such as NFATc1, c-Fos, TRAF6, c-Src, and cathepsin K, were significantly inhibited. Arctigenin inhibited the phosphorylation of Erk1/2, but not p38 and JNK, in a dose-dependent manner. Arctigenin also dramatically suppressed immunoreceptor tyrosine-based activation motif-mediated costimulatory signaling molecules, including Syk and PLCγ2, and Gab2. Notably, arctigenin inhibited the activation of Syk through RANKL stimulation. Furthermore, arctigenin prevented osteoclast differentiation in the calvarial bone of mice following stimulation with lipopolysaccharide. Our results show that arctigenin inhibits osteoclast differentiation in vitro and in vivo. Therefore, arctigenin may be useful for treating rheumatoid arthritis and osteoporosis.
    European journal of pharmacology 02/2012; 682(1-3):29-36. DOI:10.1016/j.ejphar.2012.02.026 · 2.68 Impact Factor
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    • "In bone, RANKL is primarily expressed in osteoblasts and stromal cells (Yasuda and others 1998) and regulates osteoclast differentiation, function, and survival by activating its receptor RANK, a member of the TNF receptor (TNFR) superfamily , in osteoclast precursors and mature osteoclasts. RANK employs 3 TNFR-associated factor (TRAF)-binding sites in its cytoplasmic tail (PFQEP 369–373 , PVQEET 559–564 , and PVEQG 604–609 ) (Armstrong and others 2002; Liu and others 2004) to recruit various TRAFs to activate the nuclear factor-kB (NF-kB) and 3 mitogen-activated protein kinase pathways ( JNK, c-Jun N-terminal kinase; extracellular signalregulated kinase; and p38) in osteoclast precursors (Boyle and others 2003; Liu and others 2004; Feng 2005). In particular, PFQEP 369–373 has been previously shown to interact with TRAF6 (Ye and others 2002), which plays a crucial role in osteoclast formation and/or function (Lomaga and others 1999; Naito and others 1999). "
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    ABSTRACT: Although interferon-γ (IFN-γ) potently inhibits osteoclastogenesis, the suppressive effect is significantly reduced when osteoclast precursors are pre-exposed to the receptor activator of NF-κB (RANK) ligand (RANKL). However, the molecular mechanism underlying the biphasic effects of IFN-γ on osteoclastogenesis remains elusive. Here, we recapitulate the biphasic functions of IFN-γ in osteoclastogenesis in both tissue culture dishes and on bone slices. We further demonstrate that IFN-γ markedly suppresses the RANKL-induced expression of nuclear factor of activated T-cells c1 (NFATc1) in normal, but not RANKL-pretreated bone marrow macrophages (BMMs). Similarly, IFN-γ impairs the activation of the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways in normal, but not RANKL-pretreated, BMMs. These findings indicate that IFN-γ inhibits osteoclastogenesis partially by suppressing the expression of NFATc1 and the activation of the NF-κB and JNK pathways. Moreover, IFN-γ inhibits the RANKL-induced expression of osteoclast genes, but RANKL pretreatment reprograms osteoclast genes into a state in which they can no longer be suppressed by IFN-γ, indicating that IFN-γ inhibits osteoclastogenesis by blocking the expression of osteoclast genes. Finally, the IVVY(535-538) motif in the cytoplasmic domain of RANK is responsible for rendering BMMs refractory to the inhibitory effect of IFN-γ. Taken together, these findings provide important mechanistic insights into the biphasic effects of IFN-γ on osteoclastogenesis.
    Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 12/2011; 32(1):34-45. DOI:10.1089/jir.2011.0019 · 3.90 Impact Factor
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