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Naoyuki Takahashi - One of the best experts on this subject based on the ideXlab platform.
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regulatory mechanisms of osteoblast and Osteoclast differentiation
Oral Diseases, 2002Co-Authors: Takenobu Katagiri, Naoyuki TakahashiAbstract:Bone is continuously destroyed and reformed to maintain constant bone volume and calcium homeostasis in vertebrates throughout their lives. Osteoblasts and Osteoclasts are specialized cells responsible for bone formation and resorption, respectively. Recent developments in bone cell biology have greatly changed our conceptions of the regulatory mechanisms of the differentiation of osteoblasts and Osteoclasts. Bone morphogenetic proteins (BMPs) play critical roles in osteoblast differentiation. The discovery of Smad-mediated signals revealed the precise functions of BMPs in osteoblast differentiation. Transcription factors, Runx2 and Osterix, are found to be essential molecules for inducing osteoblast differentiation, as indicated by the fact that both Runx2-null mice and Osterix-null mice have neither bone tissue nor osteoblasts. Smad transcriptional factors are shown to interact with other transcription regulators, including Runx2. Also, the recent discovery of receptor activator of NF-κB ligand (RANKL)–RANK interaction confirms the well-known hypothesis that osteoblasts play an essential role in Osteoclast differentiation. Osteoblasts express RANKL as a membrane-associated factor. Osteoclast precursors that express RANK, a receptor for RANKL, recognize RANKL through the cell–cell interaction and differentiate into Osteoclasts. Recent studies have shown that lipopolysaccharide and inflammatory cytokines such as tumor necrosis factor receptor-α and interleukin 1 directly regulate Osteoclast differentiation and function through a mechanism independent of the RANKL–RANK interaction. Transforming growth factor-β super family members and interferon-γ are also shown to be important regulators in Osteoclastogenesis. These findings have opened new areas for exploring the molecular mechanisms of osteoblast and Osteoclast differentiation.
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tumor necrosis factor α stimulates Osteoclast differentiation by a mechanism independent of the odf rankl rank interaction
Journal of Experimental Medicine, 2000Co-Authors: Kanichiro Kobayashi, Nobuaki Nakagawa, Eijiro Jimi, Nobuyuki Udagawa, Naoyuki Takahashi, Shigeru Kotake, Masamichi Takami, Masahiko Kinosaki, Kyoji Yamaguchi, Nobuyuki ShimaAbstract:Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of Osteoclast progenitors of the monocyte/macrophage lineage into Osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF–dependent bone marrow macrophages (M-BMMφ) appeared within 3 d. Tartrate-resistant acid phosphatase–positive Osteoclasts were also formed when M-BMMφ were further cultured for 3 d with mouse tumor necrosis factor α (TNF-α) in the presence of M-CSF. Osteoclast formation induced by TNF-α was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by Osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti–RANK (ODF/RANKL receptor) antibody. Experiments using M-BMMφ prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for Osteoclast formation induced by TNF-α. Osteoclasts induced by TNF-α formed resorption pits on dentine slices only in the presence of IL-1α. These results demonstrate that TNF-α stimulates Osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL–RANK system. TNF-α together with IL-1α may play an important role in bone resorption of inflammatory bone diseases.
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osteoblasts stromal cells stimulate Osteoclast activation through expression of Osteoclast differentiation factor rankl but not macrophage colony stimulating factor
Bone, 1999Co-Authors: Nobuyuki Udagawa, Kenichiro Matsuzaki, Taro Tsurukai, Nobuaki Nakagawa, Eijiro Jimi, Naoyuki Takahashi, Hisataka Yasuda, Kanami Itoh, Masaaki Goto, E TsudaAbstract:We previously reported that osteoblasts/stromal cells are essentially involved in the activation as well as differentiation of Osteoclasts through a mechanism involving cell-to-cell contact between osteoblasts/stromal cells and Osteoclast precursors/Osteoclasts. Osteoclast differentiation factor (ODF, also called RANKL/OPGL/TRANCE) and macrophage colony-stimulating factor (M-CSF, also called CSF-1) are two essential factors produced by osteoblasts/stromal cells for Osteoclastogenesis. In other words, osteoblasts/stromal cells were not necessary to generate Osteoclasts from spleen cells in the presence of both ODF/RANKL and M-CSF. In the present study, we examined the precise roles of ODF/RANKL and M-CSF in the activation of Osteoclasts induced by calvarial osteoblasts. Osteoclasts were formed in mouse bone marrow cultures on collagen gel-coated dishes in response to a soluble form of ODF/RANKL (sODF/sRANKL) and M-CSF, and recovered by collagenase digestion. When recovered Osteoclasts were further cultured on plastic dishes, most of the Osteoclasts spontaneously died within 24 h. Osteoclasts cultured for 24 h on dentine slices could not form resorption pits. Addition of sODF/sRANKL to the recovered Osteoclasts markedly enhanced their survival and pit-forming activity. M-CSF similarly stimulated the survival of Osteoclasts, but did not induce their pit-forming activity. When primary mouse osteoblasts were added to the recovered Osteoclasts, resorption pits were formed on dentine slices. Bone-resorbing factors such as 1alpha,25-dihydroxyvitamin D3, parathyroid hormone, or prostaglandin E2 enhanced pit-forming activity of Osteoclasts only in the presence of osteoblasts. M-CSF-deficient osteoblasts prepared from op/op mice similarly enhanced pit-forming activity of Osteoclasts. The pit-forming activity of Osteoclasts induced by sODF/sRANKL or osteoblasts was completely inhibited by simultaneous addition of osteoprotegerin/Osteoclastogenesis inhibitory factor, a decoy receptor of ODF/RANKL. Primary osteoblasts constitutively expressed ODF/RANKL mRNA, and its level was upregulated by treatment with 1alpha,25-dihydroxyvitamin D3, parathyroid hormone, and prostaglandin E2. These results, obtained by using an assay system that unequivocally assesses Osteoclast activation, suggest that ODF/RANKL but not M-CSF mediates osteoblast-induced pit-forming activity of Osteoclasts, and that bone-resorbing factors stimulate Osteoclast activation through upregulation of ODF/RANKL by osteoblasts/stromal cells.
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modulation of Osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families
Endocrine Reviews, 1999Co-Authors: Tatsuo Suda, Eijiro Jimi, Nobuyuki Udagawa, Naoyuki Takahashi, Matthew T Gillespie, T J MartinAbstract:I. Introduction II. Role of Osteoblasts/Stromal Cells in Osteoclast Differentiation and Function A. Origin of Osteoclasts B. Stimulation of Osteoclast differentiation by osteoblasts/stromal cells C. Stimulation of Osteoclast function by osteoblasts/stromal cells III. New Members of the Tumor Necrosis Factor (TNF) Receptor and Ligand Families A. Osteoprotegerin (OPG) B. Osteoclast differentiation factor (ODF) and stromal Osteoclast-forming activity (SOFA) IV. Regulatory Mechanism in Osteoclast Development and Function A. Regulatory mechanism of Osteoclast differentiation by RANKL B. Regulatory mechanism of RANKL action on Osteoclast function C. Signals induced by interleukin-1 (IL-1) and RANKL in Osteoclasts V. Regulation of Human Osteoclast Development VI. Summary and Conclusion
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il 17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of Osteoclastogenesis
Journal of Clinical Investigation, 1999Co-Authors: Shigeru Kotake, Kenichiro Matsuzaki, Nobuyuki Udagawa, Naoyuki Takahashi, Kanami Itoh, Shigeru Ishiyama, Seiji Saito, Kazuhiko Inoue, Naoyuki Kamatani, Matthew T GillespieAbstract:IL-17 is a newly discovered T cell–derived cytokine whose role in Osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of Osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between Osteoclast progenitors and osteoblasts was required for IL-17–induced Osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E2 (PGE2) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of Osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to Osteoclast progenitors for differentiation into Osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17–induced Osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti–IL-17 antibody significantly inhibited Osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2–dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of Osteoclast progenitors into mature Osteoclasts, and that IL-17 is a crucial cytokine for Osteoclastic bone resorption in RA patients.
Nobuyuki Udagawa - One of the best experts on this subject based on the ideXlab platform.
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tks5 dependent formation of circumferential podosomes invadopodia mediates cell cell fusion
Journal of Cell Biology, 2012Co-Authors: Tsukasa Oikawa, Nobuyuki Udagawa, Masaaki Oyama, Hiroko Kozukahata, Shunsuke Uehara, Hideyuki Saya, Koichi MatsuoAbstract:Osteoclasts fuse to form multinucleated cells during Osteoclastogenesis. This process is mediated by dynamic rearrangement of the plasma membrane and cytoskeleton, and it requires numerous factors, many of which have been identified. The underlying mechanism remains obscure, however. In this paper, we show that Tks5, a master regulator of invadopodia in cancer cells, is crucial for Osteoclast fusion downstream of phosphoinositide 3-kinase and Src. Expression of Tks5 was induced during Osteoclastogenesis, and prevention of this induction impaired both the formation of circumferential podosomes and Osteoclast fusion without affecting cell differentiation. Tyrosine phosphorylation of Tks5 was attenuated in Src−/− Osteoclasts, likely accounting for defects in podosome organization and multinucleation in these cells. Circumferential invadopodia formation in B16F0 melanoma cells was also accompanied by Tks5 phosphorylation. Co-culture of B16F0 cells with Osteoclasts in an inflammatory milieu promoted the formation of melanoma–Osteoclast hybrid cells. Our results thus reveal an unexpected link between circumferential podosome/invadopodium formation and cell–cell fusion in and beyond Osteoclasts.
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wnt5a ror2 signaling between osteoblast lineage cells and Osteoclast precursors enhances Osteoclastogenesis
Nature Medicine, 2012Co-Authors: Kazuhiro Maeda, Nobuyuki Udagawa, Shunsuke Uehara, Yasuhiro Kobayashi, Akihiro Ishihara, Toshihide Mizoguchi, Yuichiro Kikuchi, Ichiro Takada, Shigeaki Kato, Shuichi KaniAbstract:The signaling molecule Wnt regulates bone homeostasis through β-catenin-dependent canonical and β-catenin-independent noncanonical pathways. Impairment of canonical Wnt signaling causes bone loss in arthritis and osteoporosis; however, it is unclear how noncanonical Wnt signaling regulates bone resorption. Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor (Ror) proteins. We showed that Wnt5a-Ror2 signaling between osteoblast-lineage cells and Osteoclast precursors enhanced Osteoclastogenesis. Osteoblast-lineage cells expressed Wnt5a, whereas Osteoclast precursors expressed Ror2. Mice deficient in either Wnt5a or Ror2, and those with either Osteoclast precursor-specific Ror2 deficiency or osteoblast-lineage cell-specific Wnt5a deficiency showed impaired Osteoclastogenesis. Wnt5a-Ror2 signals enhanced receptor activator of nuclear factor-κB (RANK) expression in Osteoclast precursors by activating JNK and recruiting c-Jun on the promoter of the gene encoding RANK, thereby enhancing RANK ligand (RANKL)-induced Osteoclastogenesis. A soluble form of Ror2 acted as a decoy receptor of Wnt5a and abrogated bone destruction in mouse arthritis models. Our results suggest that the Wnt5a-Ror2 pathway is crucial for Osteoclastogenesis in physiological and pathological environments and represents a therapeutic target for bone diseases, including arthritis.
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tumor necrosis factor α stimulates Osteoclast differentiation by a mechanism independent of the odf rankl rank interaction
Journal of Experimental Medicine, 2000Co-Authors: Kanichiro Kobayashi, Nobuaki Nakagawa, Eijiro Jimi, Nobuyuki Udagawa, Naoyuki Takahashi, Shigeru Kotake, Masamichi Takami, Masahiko Kinosaki, Kyoji Yamaguchi, Nobuyuki ShimaAbstract:Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of Osteoclast progenitors of the monocyte/macrophage lineage into Osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF–dependent bone marrow macrophages (M-BMMφ) appeared within 3 d. Tartrate-resistant acid phosphatase–positive Osteoclasts were also formed when M-BMMφ were further cultured for 3 d with mouse tumor necrosis factor α (TNF-α) in the presence of M-CSF. Osteoclast formation induced by TNF-α was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by Osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti–RANK (ODF/RANKL receptor) antibody. Experiments using M-BMMφ prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for Osteoclast formation induced by TNF-α. Osteoclasts induced by TNF-α formed resorption pits on dentine slices only in the presence of IL-1α. These results demonstrate that TNF-α stimulates Osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL–RANK system. TNF-α together with IL-1α may play an important role in bone resorption of inflammatory bone diseases.
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osteoblasts stromal cells stimulate Osteoclast activation through expression of Osteoclast differentiation factor rankl but not macrophage colony stimulating factor
Bone, 1999Co-Authors: Nobuyuki Udagawa, Kenichiro Matsuzaki, Taro Tsurukai, Nobuaki Nakagawa, Eijiro Jimi, Naoyuki Takahashi, Hisataka Yasuda, Kanami Itoh, Masaaki Goto, E TsudaAbstract:We previously reported that osteoblasts/stromal cells are essentially involved in the activation as well as differentiation of Osteoclasts through a mechanism involving cell-to-cell contact between osteoblasts/stromal cells and Osteoclast precursors/Osteoclasts. Osteoclast differentiation factor (ODF, also called RANKL/OPGL/TRANCE) and macrophage colony-stimulating factor (M-CSF, also called CSF-1) are two essential factors produced by osteoblasts/stromal cells for Osteoclastogenesis. In other words, osteoblasts/stromal cells were not necessary to generate Osteoclasts from spleen cells in the presence of both ODF/RANKL and M-CSF. In the present study, we examined the precise roles of ODF/RANKL and M-CSF in the activation of Osteoclasts induced by calvarial osteoblasts. Osteoclasts were formed in mouse bone marrow cultures on collagen gel-coated dishes in response to a soluble form of ODF/RANKL (sODF/sRANKL) and M-CSF, and recovered by collagenase digestion. When recovered Osteoclasts were further cultured on plastic dishes, most of the Osteoclasts spontaneously died within 24 h. Osteoclasts cultured for 24 h on dentine slices could not form resorption pits. Addition of sODF/sRANKL to the recovered Osteoclasts markedly enhanced their survival and pit-forming activity. M-CSF similarly stimulated the survival of Osteoclasts, but did not induce their pit-forming activity. When primary mouse osteoblasts were added to the recovered Osteoclasts, resorption pits were formed on dentine slices. Bone-resorbing factors such as 1alpha,25-dihydroxyvitamin D3, parathyroid hormone, or prostaglandin E2 enhanced pit-forming activity of Osteoclasts only in the presence of osteoblasts. M-CSF-deficient osteoblasts prepared from op/op mice similarly enhanced pit-forming activity of Osteoclasts. The pit-forming activity of Osteoclasts induced by sODF/sRANKL or osteoblasts was completely inhibited by simultaneous addition of osteoprotegerin/Osteoclastogenesis inhibitory factor, a decoy receptor of ODF/RANKL. Primary osteoblasts constitutively expressed ODF/RANKL mRNA, and its level was upregulated by treatment with 1alpha,25-dihydroxyvitamin D3, parathyroid hormone, and prostaglandin E2. These results, obtained by using an assay system that unequivocally assesses Osteoclast activation, suggest that ODF/RANKL but not M-CSF mediates osteoblast-induced pit-forming activity of Osteoclasts, and that bone-resorbing factors stimulate Osteoclast activation through upregulation of ODF/RANKL by osteoblasts/stromal cells.
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modulation of Osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families
Endocrine Reviews, 1999Co-Authors: Tatsuo Suda, Eijiro Jimi, Nobuyuki Udagawa, Naoyuki Takahashi, Matthew T Gillespie, T J MartinAbstract:I. Introduction II. Role of Osteoblasts/Stromal Cells in Osteoclast Differentiation and Function A. Origin of Osteoclasts B. Stimulation of Osteoclast differentiation by osteoblasts/stromal cells C. Stimulation of Osteoclast function by osteoblasts/stromal cells III. New Members of the Tumor Necrosis Factor (TNF) Receptor and Ligand Families A. Osteoprotegerin (OPG) B. Osteoclast differentiation factor (ODF) and stromal Osteoclast-forming activity (SOFA) IV. Regulatory Mechanism in Osteoclast Development and Function A. Regulatory mechanism of Osteoclast differentiation by RANKL B. Regulatory mechanism of RANKL action on Osteoclast function C. Signals induced by interleukin-1 (IL-1) and RANKL in Osteoclasts V. Regulation of Human Osteoclast Development VI. Summary and Conclusion
Masaki Noda - One of the best experts on this subject based on the ideXlab platform.
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leptin regulation of bone resorption by the sympathetic nervous system and cart
Nature, 2005Co-Authors: Florent Elefteriou, Michael Starbuck, Hisataka Kondo, Tony W. Bannon, Xiangli Yang, Masaki Noda, William G. Richards, Shu Takeda, Karine Clement, Christian VaisseAbstract:Bone structure and function are maintained by bone remodelling, a balance of bone resorption by Osteoclasts and bone formation by osteoblasts. New work in mice suggests that leptin, best known as a hormone regulating body weight, may play a major role in striking this balance. In one pathway, leptin stimulation of sympathetic neurons promotes differentiation of Osteoclasts (and resorption) and in the other, a neuropeptide called CART inhibits Osteoclast differentiation. Blockade of the leptin-regulated neural pathway might help prevent bone loss in osteoporosis. Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by Osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling Osteoclast differentiation. Sympathetic signalling via β2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin1. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the Osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function2. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse3. This discrepancy is explained, in part, by the fact that CART (‘cocaine amphetamine regulated transcript’), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice4, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.
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Leptin regulation of bone resorption by the sympathetic nervous system and CART
Nature, 2005Co-Authors: Florent Elefteriou, Jong Deok Ahn, Michael Starbuck, Hisataka Kondo, Tony W. Bannon, Xiuyun Liu, Xiangli Yang, William G. Richards, Shu Takeda, Masaki NodaAbstract:Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by Osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling Osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the Osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.
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mice lacking osteopontin show normal development and bone structure but display altered Osteoclast formation in vitro
Journal of Bone and Mineral Research, 1998Co-Authors: Susa R Rittling, Masaki Noda, Hiroko Matsumoto, Marc D Mckee, Antonio Nanci, Xiaorong A, Kristine E Novick, Aaro J Kowalski, David T DenhardAbstract:We have used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of the osteopontin (Opn, or Spp1, for secreted phosphoprotein 1) gene. Mice homozygous for this disruption fail to express osteopontin (OPN) as assessed at both the mRNA and protein level, although an N-terminal fragment of OPN is detectable at extremely low levels in the bones of -/- animals. The Opn -/- mice are fertile, their litter size is normal, and they develop normally. The bones and teeth of animals not expressing OPN are morphologically normal at the level of light and electron microscopy, and the skeletal structure of young animals is normal as assessed by radiography. Ultrastructurally, proteinaceous structures normally rich in OPN, such as cement lines, persist in the bones of the Opn-/- animals. Osteoclastogenesis was assessed in vitro in cocultures with a feeder layer of calvarial osteoblast cells from wild-type mice. Spleen cells from Opn-/- mice cells formed Osteoclasts 3- to 13-fold more frequently than did control Opn+/+ cells, while the extent of Osteoclast development from Opn -/- bone marrow cells was about 2- to 4-fold more than from the corresponding wild-type cells. Osteoclast development occurred when Opn-/- spleen cells were differentiated in the presence of Opn-/-osteoblasts, indicating that endogenous OPN is not required for this process. These results suggest that OPN is not essential for normal mouse development and osteogenesis, but can modulate Osteoclast differentiation.
Matthew T Gillespie - One of the best experts on this subject based on the ideXlab platform.
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glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways
Journal of Clinical Investigation, 2004Co-Authors: Natalie A Sims, Markus Glatt, Brendan J. Jenkins, Matthias Ernst, Julian M. W. Quinn, Matthew T Gillespie, John T Martin, Akira NakamuraAbstract:The gp130-dependent cytokines, which signal through at least two intracellular pathways, regulate Osteoclast and osteoblast formation. To define their roles in regulating bone mass, we analyzed mice in which gp130 signaling via either the signal transducer and activator of transcription (STAT) 1/3 (gp130ΔSTAT/ΔSTAT) or SHP2/ras/MAPK (gp130Y757F/Y757F) pathway was attenuated. In gp130ΔSTAT/ΔSTAT mice, trabecular bone volume (BV/TV) and turnover were normal, but bone length was reduced by premature growth plate closure, indicating an essential role for gp130-STAT1/3 signaling in chondrocyte differentiation. In contrast, while bone size was normal in gp130Y757F/Y757F mice, BV/TV was reduced due to high bone turnover, indicated by high Osteoclast surface/bone surface (OcS/BS) and osteoblast surface/bone surface (ObS/BS). Furthermore, generation of functional Osteoclasts from bone marrow of gp130Y757F/Y757F mice was elevated, revealing that while gp130 family cytokines stimulate Osteoclastogenesis through the osteoblast lineage, gp130, via SHP2/Ras/MAPK, inhibits Osteoclastogenesis in a cell lineage–autonomous manner. Genetic ablation of IL-6 in gp130Y757F/Y757F mice exacerbated this osteopenia by reducing ObS/BS without affecting OcS/BS. Thus, while IL-6 is critical for high bone formation in gp130Y757F/Y757F mice, it is not involved in the increased Osteoclastogenesis. In conclusion, gp130 is essential for normal bone growth and trabecular bone mass, with balanced regulation depending on selective activation of STAT1/3 and SHP2/ras/MAPK, respectively. Furthermore, the latter pathway can directly inhibit Osteoclastogenesis in vivo.
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modulation of Osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families
Endocrine Reviews, 1999Co-Authors: Tatsuo Suda, Eijiro Jimi, Nobuyuki Udagawa, Naoyuki Takahashi, Matthew T Gillespie, T J MartinAbstract:I. Introduction II. Role of Osteoblasts/Stromal Cells in Osteoclast Differentiation and Function A. Origin of Osteoclasts B. Stimulation of Osteoclast differentiation by osteoblasts/stromal cells C. Stimulation of Osteoclast function by osteoblasts/stromal cells III. New Members of the Tumor Necrosis Factor (TNF) Receptor and Ligand Families A. Osteoprotegerin (OPG) B. Osteoclast differentiation factor (ODF) and stromal Osteoclast-forming activity (SOFA) IV. Regulatory Mechanism in Osteoclast Development and Function A. Regulatory mechanism of Osteoclast differentiation by RANKL B. Regulatory mechanism of RANKL action on Osteoclast function C. Signals induced by interleukin-1 (IL-1) and RANKL in Osteoclasts V. Regulation of Human Osteoclast Development VI. Summary and Conclusion
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il 17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of Osteoclastogenesis
Journal of Clinical Investigation, 1999Co-Authors: Shigeru Kotake, Kenichiro Matsuzaki, Nobuyuki Udagawa, Naoyuki Takahashi, Kanami Itoh, Shigeru Ishiyama, Seiji Saito, Kazuhiko Inoue, Naoyuki Kamatani, Matthew T GillespieAbstract:IL-17 is a newly discovered T cell–derived cytokine whose role in Osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of Osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between Osteoclast progenitors and osteoblasts was required for IL-17–induced Osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E2 (PGE2) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of Osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to Osteoclast progenitors for differentiation into Osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17–induced Osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti–IL-17 antibody significantly inhibited Osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2–dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of Osteoclast progenitors into mature Osteoclasts, and that IL-17 is a crucial cytokine for Osteoclastic bone resorption in RA patients.
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interleukins in the control of Osteoclast differentiation
Critical Reviews in Eukaryotic Gene Expression, 1998Co-Authors: T J Martin, Evange Romas, Matthew T GillespieAbstract:: To maintain homeostasis of bone, the production of osteoblasts and Osteoclasts is tightly regulated. At the local level, hormones and cytokines control formation of Osteoclasts from hemopoietic precursors by acting upon osteoblastic-stromal cells and in some cases also upon cells of the immune system. Osteoblasts regulate Osteoclast formation by providing physical support and cytokines such as M-CSF and IL-11, which promote Osteoclast differentiation. Osteoblasts are also a source of IL-18, which limits Osteoclast formation. The requirement of contact between osteoblasts and hemopoietic cells for successful Osteoclast formation led to a concept of a membrane-anchored stromal cell molecule that programs Osteoclast differentiation. This mechanism has been highlighted by the discovery of osteoprotegerin (OPG), a soluble tumor necrosis factor (TNF) family member that inhibits Osteoclast formation. The ligand for OPG is a novel transmembrane TNF receptor superfamily member, the Osteoclast differentiating factor (ODF). The recognition of the osteoprotegerin/osteoprotegerin-ligand axis will lead to new insights into the control of Osteoclast differentiation by interleukins.
Eijiro Jimi - One of the best experts on this subject based on the ideXlab platform.
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tumor necrosis factor α stimulates Osteoclast differentiation by a mechanism independent of the odf rankl rank interaction
Journal of Experimental Medicine, 2000Co-Authors: Kanichiro Kobayashi, Nobuaki Nakagawa, Eijiro Jimi, Nobuyuki Udagawa, Naoyuki Takahashi, Shigeru Kotake, Masamichi Takami, Masahiko Kinosaki, Kyoji Yamaguchi, Nobuyuki ShimaAbstract:Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of Osteoclast progenitors of the monocyte/macrophage lineage into Osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF–dependent bone marrow macrophages (M-BMMφ) appeared within 3 d. Tartrate-resistant acid phosphatase–positive Osteoclasts were also formed when M-BMMφ were further cultured for 3 d with mouse tumor necrosis factor α (TNF-α) in the presence of M-CSF. Osteoclast formation induced by TNF-α was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by Osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti–RANK (ODF/RANKL receptor) antibody. Experiments using M-BMMφ prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for Osteoclast formation induced by TNF-α. Osteoclasts induced by TNF-α formed resorption pits on dentine slices only in the presence of IL-1α. These results demonstrate that TNF-α stimulates Osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL–RANK system. TNF-α together with IL-1α may play an important role in bone resorption of inflammatory bone diseases.
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osteoblasts stromal cells stimulate Osteoclast activation through expression of Osteoclast differentiation factor rankl but not macrophage colony stimulating factor
Bone, 1999Co-Authors: Nobuyuki Udagawa, Kenichiro Matsuzaki, Taro Tsurukai, Nobuaki Nakagawa, Eijiro Jimi, Naoyuki Takahashi, Hisataka Yasuda, Kanami Itoh, Masaaki Goto, E TsudaAbstract:We previously reported that osteoblasts/stromal cells are essentially involved in the activation as well as differentiation of Osteoclasts through a mechanism involving cell-to-cell contact between osteoblasts/stromal cells and Osteoclast precursors/Osteoclasts. Osteoclast differentiation factor (ODF, also called RANKL/OPGL/TRANCE) and macrophage colony-stimulating factor (M-CSF, also called CSF-1) are two essential factors produced by osteoblasts/stromal cells for Osteoclastogenesis. In other words, osteoblasts/stromal cells were not necessary to generate Osteoclasts from spleen cells in the presence of both ODF/RANKL and M-CSF. In the present study, we examined the precise roles of ODF/RANKL and M-CSF in the activation of Osteoclasts induced by calvarial osteoblasts. Osteoclasts were formed in mouse bone marrow cultures on collagen gel-coated dishes in response to a soluble form of ODF/RANKL (sODF/sRANKL) and M-CSF, and recovered by collagenase digestion. When recovered Osteoclasts were further cultured on plastic dishes, most of the Osteoclasts spontaneously died within 24 h. Osteoclasts cultured for 24 h on dentine slices could not form resorption pits. Addition of sODF/sRANKL to the recovered Osteoclasts markedly enhanced their survival and pit-forming activity. M-CSF similarly stimulated the survival of Osteoclasts, but did not induce their pit-forming activity. When primary mouse osteoblasts were added to the recovered Osteoclasts, resorption pits were formed on dentine slices. Bone-resorbing factors such as 1alpha,25-dihydroxyvitamin D3, parathyroid hormone, or prostaglandin E2 enhanced pit-forming activity of Osteoclasts only in the presence of osteoblasts. M-CSF-deficient osteoblasts prepared from op/op mice similarly enhanced pit-forming activity of Osteoclasts. The pit-forming activity of Osteoclasts induced by sODF/sRANKL or osteoblasts was completely inhibited by simultaneous addition of osteoprotegerin/Osteoclastogenesis inhibitory factor, a decoy receptor of ODF/RANKL. Primary osteoblasts constitutively expressed ODF/RANKL mRNA, and its level was upregulated by treatment with 1alpha,25-dihydroxyvitamin D3, parathyroid hormone, and prostaglandin E2. These results, obtained by using an assay system that unequivocally assesses Osteoclast activation, suggest that ODF/RANKL but not M-CSF mediates osteoblast-induced pit-forming activity of Osteoclasts, and that bone-resorbing factors stimulate Osteoclast activation through upregulation of ODF/RANKL by osteoblasts/stromal cells.
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modulation of Osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families
Endocrine Reviews, 1999Co-Authors: Tatsuo Suda, Eijiro Jimi, Nobuyuki Udagawa, Naoyuki Takahashi, Matthew T Gillespie, T J MartinAbstract:I. Introduction II. Role of Osteoblasts/Stromal Cells in Osteoclast Differentiation and Function A. Origin of Osteoclasts B. Stimulation of Osteoclast differentiation by osteoblasts/stromal cells C. Stimulation of Osteoclast function by osteoblasts/stromal cells III. New Members of the Tumor Necrosis Factor (TNF) Receptor and Ligand Families A. Osteoprotegerin (OPG) B. Osteoclast differentiation factor (ODF) and stromal Osteoclast-forming activity (SOFA) IV. Regulatory Mechanism in Osteoclast Development and Function A. Regulatory mechanism of Osteoclast differentiation by RANKL B. Regulatory mechanism of RANKL action on Osteoclast function C. Signals induced by interleukin-1 (IL-1) and RANKL in Osteoclasts V. Regulation of Human Osteoclast Development VI. Summary and Conclusion
