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Josef M. Penninger - One of the best experts on this subject based on the ideXlab platform.
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RANKL, RANK, and OPG
2020Co-Authors: Young-yun Kong, Josef M. PenningerAbstract:Tumor necrosis factor (TNF) and TNF receptor (R) family proteins play important roles in the control of cell death, proliferation, autoimmunity, the function of immune cells, or the organogenesis of lymphoid organs. Recently, novel members of this large family have been identified that couple immunity with other organ systems such as bone morphogenesis and mammary gland formation in pregnancy. The TNF-family molecule receptor activator of nuclear factor KB ligand (RANKL) [osteoprotegerin (OPGL), TNF-related activation-induced cytokine (TRANCE) osteoclast differentiation factor (ODF)l, its receptor RANK, and the decoy receptor osteoprotegerin (OPG) are essential for the development and activation of osteoclasts and are key regulators of bone remodeling. Intriguingly, RANKL/RANK interactions also regulate T-cell/dendritic cell communications, dendritic cell survival, and lymph node formation. T-cell-derived RANKL can mediate bone loss in arthritis and periodontal disease. Moreover, RANKL and RANK are expressed in mammary gland epithelial cells, where they control the development of a lactating mammary gland during pregnancy required for the propagation of mammalian species. RANKL can also induce angiogenesis, and inflammatory cytokines can trigger the expression of RANKL, RANK, and OPG in vascular endothelial cells. Modulation of these systems provides us with a unique opportunity to design novel therapeutics to inhibit bone loss in osteoporosis, arthritis, periodontal disease, and cancer metastasis.
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coupling of bone resorption and formation by RANKL reverse signalling
Nature, 2018Co-Authors: Yuki Ikebuchi, Shigeki Aoki, Masashi Honma, Madoka Hayashi, Yasutaka Sugamori, Masud Khan, Yoshiaki Kariya, Genki Kato, Yasuhiko Tabata, Josef M. PenningerAbstract:Receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL) binds RANK on the surface of osteoclast precursors to trigger osteoclastogenesis. Recent studies have indicated that osteocytic RANKL has an important role in osteoclastogenesis during bone remodelling; however, the role of osteoblastic RANKL remains unclear. Here we show that vesicular RANK, which is secreted from the maturing osteoclasts, binds osteoblastic RANKL and promotes bone formation by triggering RANKL reverse signalling, which activates Runt-related transcription factor 2 (Runx2). The proline-rich motif in the RANKL cytoplasmic tail is required for reverse signalling, and a RANKL(Pro29Ala) point mutation reduces activation of the reverse signalling pathway. The coupling of bone resorption and formation is disrupted in RANKL(Pro29Ala) mutant mice, indicating that osteoblastic RANKL functions as a coupling signal acceptor that recognizes vesicular RANK. RANKL reverse signalling is therefore a potential pharmacological target for avoiding the reduced bone formation associated with inhibition of osteoclastogenesis. Osteoclasts secrete small extracellular vesicles that stimulate osteoblasts, promoting bone formation via receptor activator of nuclear factor-kappa B ligand (RANKL), thereby linking bone formation and resorption.
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lox fails to substitute for RANKL in osteoclastogenesis
Journal of Bone and Mineral Research, 2017Co-Authors: Masayuki Tsukasaki, Asuka Terashima, Kazuo Okamoto, Koki Hamada, Kazuki Nagashima, Noriko Komatsu, Tadashi Okamura, Takeshi Nitta, Hisataka Yasuda, Josef M. PenningerAbstract:Osteoclasts are the exclusive bone-resorbing cells that have a central role in bone homeostasis as well as bone destruction in cancer and autoimmune disease. Both mouse and human genetic studies have clearly proven that receptor activator of NF-κB ligand (RANKL; encoded by the Tnfsf11 gene) and its receptor RANK are essential for osteoclastogenesis. Although there have been several reports on RANKL-independent osteoclastogenesis, previous studies have never provided in vivo evidence showing RANKL can be substituted for by other molecules using RANKL- or RANK-deficient genetic backgrounds. Thus, to date, there is no clear evidence of RANKL-independent osteoclastogenesis and no molecule has ever been proven capable of inducing osteoclast differentiation more efficiently than RANKL. Recently lysyl oxidase (LOX), the enzyme which mediates collagen cross-linking, has been shown to induce human osteoclasts in the absence of RANKL and has a stronger osteoclastogenic activity than RANKL. Here we investigated the effect of LOX on osteoclast differentiation using RANKL- and RANK-deficient cells to strictly explore RANKL-independent osteoclastogenesis. CD14+ human peripheral blood cells as well as osteoclast precursor cells derived from wild-type, RANKL- and RANK-deficient mice were treated with RANKL and/or LOX in short-term (3 days) or long-term (3 weeks) experimental settings. LOX treatment alone did not result in the formation of tartrate-resistant acid phosphatase (TRAP)+ cells or resorption pits in either short-term or long-term culture. In combination with RANKL, long-term treatment with LOX synergistically promoted osteoclastogenesis in cells derived from wild-type mice; however, this was abrogated in RANKL-deficient cells. Long-term treatment with LOX stimulated RANKL expression in mouse bone marrow stromal cells via the production of reactive oxygen species (ROS). Furthermore, LOX injection failed to rescue the phenotype of RANKL-deficient mice. These results suggest that LOX has the ability to induce RANKL expression on stromal cells; however, fails to substitute for RANKL in osteoclastogenesis. This article is protected by copyright. All rights reserved
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The RANKL-RANK Story
Gerontology, 2015Co-Authors: Vanja Nagy, Josef M. PenningerAbstract:Receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) have originally been described for their key roles in bone metabolism and the immune system. Subsequently, it has been shown
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RANKL/RANK - from bone physiology to breast cancer.
Cytokine & Growth Factor Reviews, 2014Co-Authors: Verena Sigl, Josef M. PenningerAbstract:Abstract RANK and its ligand RANKL are key molecules in bone metabolism and are critically involved in pathologic bone disorders. Deregulation of the RANK/RANKL system is for example a main reason for the development of postmenopausal osteoporosis, which affects millions of women worldwide. Another essential function of RANK and RANKL is the development of a functional lactating mammary gland during pregnancy. Sex hormones, in particular progesterone, induce RANKL expression resulting in proliferation of mammary epithelial cells. Moreover, RANK and RANKL have been shown to regulate mammary epithelial stem cells. RANK and RANKL were also identified as critical mechanism in the development of hormone-induced breast cancer and metastatic spread to bone. In this review, we will focus on the various RANK/RANKL functions ranging from bone physiology, immune regulation, and initiation of breast cancer.
Lianping Xing - One of the best experts on this subject based on the ideXlab platform.
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functions of RANKL rank opg in bone modeling and remodeling
Archives of Biochemistry and Biophysics, 2008Co-Authors: Brendan F. Boyce, Lianping XingAbstract:The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-κB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.
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The RANKL/RANK/OPG pathway
Current Osteoporosis Reports, 2007Co-Authors: Brendan F. Boyce, Lianping XingAbstract:Understanding of osteoclast formation and activation has advanced considerably since the discovery of the RANKL/RANK/OPG system in the mid 1990s. Osteoblasts and stromal stem cells express receptor activator of NF-κB ligand (RANKL), which binds to its receptor, RANK, on the surface of osteoclasts and their precursors. This regulates the differentiation of precursors into multinucleated osteoclasts and osteoclast activation and survival both normally and in most pathologic conditions associated with increased bone resorption. Osteoprotegerin (OPG) is secreted by osteoblasts and osteogenic stromal stem cells and protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from interacting with RANK. The RANKL/OPG ratio in bone marrow is thus an important determinant of bone mass in normal and disease states. RANKL/RANK signaling also regulates lymph node formation and mammary gland lactational hyperplasia in mice, and OPG protects large arteries of mice from medial calcification. This article reviews the roles of the RANKL/RANK/OPG system in bone and other tissues.
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the RANKL rank opg pathway
Current Osteoporosis Reports, 2007Co-Authors: Brendan F. Boyce, Lianping XingAbstract:Understanding of osteoclast formation and activation has advanced considerably since the discovery of the RANKL/RANK/OPG system in the mid 1990s. Osteoblasts and stromal stem cells express receptor activator of NF-κB ligand (RANKL), which binds to its receptor, RANK, on the surface of osteoclasts and their precursors. This regulates the differentiation of precursors into multinucleated osteoclasts and osteoclast activation and survival both normally and in most pathologic conditions associated with increased bone resorption. Osteoprotegerin (OPG) is secreted by osteoblasts and osteogenic stromal stem cells and protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from interacting with RANK. The RANKL/OPG ratio in bone marrow is thus an important determinant of bone mass in normal and disease states. RANKL/RANK signaling also regulates lymph node formation and mammary gland lactational hyperplasia in mice, and OPG protects large arteries of mice from medial calcification. This article reviews the roles of the RANKL/RANK/OPG system in bone and other tissues.
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Biology of RANK, RANKL, and osteoprotegerin
Arthritis Research & Therapy, 2007Co-Authors: Brendan F. Boyce, Lianping XingAbstract:The discovery of the receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) system and its role in the regulation of bone resorption exemplifies how both serendipity and a logic-based approach can identify factors that regulate cell function. Before this discovery in the mid to late 1990s, it had long been recognized that osteoclast formation was regulated by factors expressed by osteoblast/stromal cells, but it had not been anticipated that members of the tumor necrosis factor superfamily of ligands and receptors would be involved or that the factors involved would have extensive functions beyond bone remodeling. RANKL/RANK signaling regulates the formation of multinucleated osteoclasts from their precursors as well as their activation and survival in normal bone remodeling and in a variety of pathologic conditions. OPG protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from binding to its receptor, RANK. Thus, RANKL/OPG ratio is an important determinant of bone mass and skeletal integrity. Genetic studies in mice indicate that RANKL/RANK signaling is also required for lymph node formation and mammary gland lactational hyperplasia, and that OPG also protects arteries from medial calcification. Thus, these tumor necrosis factor superfamily members have important functions outside bone. Although our understanding of the mechanisms whereby they regulate osteoclast formation has advanced rapidly during the past 10 years, many questions remain about their roles in health and disease. Here we review our current understanding of the role of the RANKL/RANK/OPG system in bone and other tissues.
Brendan F. Boyce - One of the best experts on this subject based on the ideXlab platform.
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functions of RANKL rank opg in bone modeling and remodeling
Archives of Biochemistry and Biophysics, 2008Co-Authors: Brendan F. Boyce, Lianping XingAbstract:The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-κB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.
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The RANKL/RANK/OPG pathway
Current Osteoporosis Reports, 2007Co-Authors: Brendan F. Boyce, Lianping XingAbstract:Understanding of osteoclast formation and activation has advanced considerably since the discovery of the RANKL/RANK/OPG system in the mid 1990s. Osteoblasts and stromal stem cells express receptor activator of NF-κB ligand (RANKL), which binds to its receptor, RANK, on the surface of osteoclasts and their precursors. This regulates the differentiation of precursors into multinucleated osteoclasts and osteoclast activation and survival both normally and in most pathologic conditions associated with increased bone resorption. Osteoprotegerin (OPG) is secreted by osteoblasts and osteogenic stromal stem cells and protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from interacting with RANK. The RANKL/OPG ratio in bone marrow is thus an important determinant of bone mass in normal and disease states. RANKL/RANK signaling also regulates lymph node formation and mammary gland lactational hyperplasia in mice, and OPG protects large arteries of mice from medial calcification. This article reviews the roles of the RANKL/RANK/OPG system in bone and other tissues.
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the RANKL rank opg pathway
Current Osteoporosis Reports, 2007Co-Authors: Brendan F. Boyce, Lianping XingAbstract:Understanding of osteoclast formation and activation has advanced considerably since the discovery of the RANKL/RANK/OPG system in the mid 1990s. Osteoblasts and stromal stem cells express receptor activator of NF-κB ligand (RANKL), which binds to its receptor, RANK, on the surface of osteoclasts and their precursors. This regulates the differentiation of precursors into multinucleated osteoclasts and osteoclast activation and survival both normally and in most pathologic conditions associated with increased bone resorption. Osteoprotegerin (OPG) is secreted by osteoblasts and osteogenic stromal stem cells and protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from interacting with RANK. The RANKL/OPG ratio in bone marrow is thus an important determinant of bone mass in normal and disease states. RANKL/RANK signaling also regulates lymph node formation and mammary gland lactational hyperplasia in mice, and OPG protects large arteries of mice from medial calcification. This article reviews the roles of the RANKL/RANK/OPG system in bone and other tissues.
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Biology of RANK, RANKL, and osteoprotegerin
Arthritis Research & Therapy, 2007Co-Authors: Brendan F. Boyce, Lianping XingAbstract:The discovery of the receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) system and its role in the regulation of bone resorption exemplifies how both serendipity and a logic-based approach can identify factors that regulate cell function. Before this discovery in the mid to late 1990s, it had long been recognized that osteoclast formation was regulated by factors expressed by osteoblast/stromal cells, but it had not been anticipated that members of the tumor necrosis factor superfamily of ligands and receptors would be involved or that the factors involved would have extensive functions beyond bone remodeling. RANKL/RANK signaling regulates the formation of multinucleated osteoclasts from their precursors as well as their activation and survival in normal bone remodeling and in a variety of pathologic conditions. OPG protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from binding to its receptor, RANK. Thus, RANKL/OPG ratio is an important determinant of bone mass and skeletal integrity. Genetic studies in mice indicate that RANKL/RANK signaling is also required for lymph node formation and mammary gland lactational hyperplasia, and that OPG also protects arteries from medial calcification. Thus, these tumor necrosis factor superfamily members have important functions outside bone. Although our understanding of the mechanisms whereby they regulate osteoclast formation has advanced rapidly during the past 10 years, many questions remain about their roles in health and disease. Here we review our current understanding of the role of the RANKL/RANK/OPG system in bone and other tissues.
Tomoki Nakashima - One of the best experts on this subject based on the ideXlab platform.
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RANKL biology: bone metabolism, the immune system, and beyond
Inflammation and Regeneration, 2020Co-Authors: Mikihito Hayashi, Fumiyuki Sasaki, Tomoki NakashimaAbstract:Receptor activator of NF-κB (RANK) ligand (RANKL) induces the differentiation of monocyte/macrophage–lineage cells into the bone–resorbing cells called osteoclasts. Because abnormalities in RANKL, its signaling receptor RANK, or decoy receptor osteoprotegerin (OPG) lead to bone diseases such as osteopetrosis, the RANKL/RANK/OPG system is essential for bone resorption. RANKL was first discovered as a T cell-derived activator of dendritic cells (DCs) and has many functions in the immune system, including organogenesis, cellular development. The essentiality of RANKL in the bone and the immune systems lies at the root of the field of “osteoimmunology.” Furthermore, this cytokine functions beyond the domains of bone metabolism and the immune system, e.g., mammary gland and hair follicle formation, body temperature regulation, muscle metabolism, and tumor development. In this review, we will summarize the current understanding of the functions of the RANKL/RANK/OPG system in biological processes.
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Recent advances in osteoclast biology
Histochemistry and Cell Biology, 2018Co-Authors: Tomoki NakashimaAbstract:The bone is an essential organ for locomotion and protection of the body, as well as hematopoiesis and mineral homeostasis. In order to exert these functions throughout life, bone tissue undergoes a repeating cycle of osteoclastic bone resorption and osteoblastic bone formation. The osteoclast is a large, multinucleated cell that is differentiated from monocyte/macrophage lineage cells by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). RANKL transduces its signal through the signaling receptor, RANK. RANKL/RANK signaling activates NFATc1, the master regulator of osteoclastogenesis, to induce osteoclastogenic gene expression. Many types of cells express RANKL to support osteoclastogenesis depending on the biological context and the dysregulation of RANKL signaling leads to bone diseases such as osteoporosis and osteopetrosis. This review outlines the findings on osteoclast and RANKL/RANK signaling that have accumulated to date.
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Bone metastasis and RANKL
Clinical calcium, 2014Co-Authors: Tomoki NakashimaAbstract:Abstract The mice with a disruption of Rank or RANKL exhibit normal mammary development during puberty, but their mammary epithelium fails to proliferate and form lobuloalveolar structures during pregnancy, resulting in the death of newborns. Hormone replacement therapy is associated with an increased risk of breast cancer. Importantly, specific deletion of RANK in mammary epithelium cells prevents both the onset and progression of medroxyprogesterone acetate (MPA) -driven mammary cancer and impairs self-renewal of breast cancer stem cells. Furthermore, RANK is highly expressed in several cancer cells. Functionally, it has been shown that RANKL can stimulate the directed migration of mammary epithelial cells as well as prostate cancer and melanoma cells toward a source of RANKL. In an in vivo metastasis model, OPG reduced the tumor burden in bones and ameliorated clinical paralysis, but did not affect the frequency of the spread of metastases into other tissues. These findings show that the RANK/RANKL system is crucial for mammary development, breast tumorigenesis and bone metastasis.
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The crucial role of osteocyte-derived RANKL in bone homeostasis
Arthritis Research & Therapy, 2012Co-Authors: Tomoki Nakashima, Mikihito Hayashi, Hiroshi TakayanagiAbstract:Receptor activator of NF-κB ligand (RANKL; also known as TNFSF11), a TNF family molecule, and its receptor RANK (TNFRSF11A) are key regulators of osteoclast differentiation and function. Aberrant expression of RANKL explains why autoimmune diseases, cancers, leukemia and periodontal disease result in systemic and local bone loss. In particular, RANKL is the pathogenic factor that cause bone and cartilage destruction in arthritis. Inhibition of RANKL function by the natural decoy receptor osteoprotegerin (OPG; also known as TNFRSF11B) or anti-RANKL antibody prevents bone loss in postmenopausal osteoporosis, cancer metastases and arthritis. RANKL also regulates T cell/dendritic cell communications, dendritic cell survival and lymph node organogenesis. Intriguingly, RANKL and RANK play an essential role in the maturation of mammary glands in pregnancy and lactation. Bone homeostasis depends on the coordination of osteoclastic bone resorption and osteoblastic bone formation. We reported that RANKL induces osteoclast differentiation through activating a transcriptional programme mediated by the master transcription factor nuclear factor of activated T cells (NFAT) c1. Although it is well accepted that the RANKL-NFATc1 pathway is crucially important for osteoclast differentiation, little is known about the major cellular source of RANKL in the skeletal tissue. RANKL has been postulated to be mainly expressed by osteoblasts and bone marrow stromal cells. However, here we show that osteocytes embedded within the bone matrix are the critical source of RANKL in bone remodeling. Osteocytes, the most abundant cell type in bone, are thought to orchestrate bone homeostasis by regulating both osteoclastic bone resorption and osteoblastic bone formation, but in vivo evidence and the molecular basis for the regulation has not been sufficiently demonstrated. Using a newly established method for the isolation of high-purity dentin matrix protein 1-positive osteocytes from bone, we have found that osteocytes express a much higher amount of RANKL and have a much greater capacity to support osteoclast formation than osteoblasts and bone marrow stromal cells. The crucial role of RANKL expressed by osteocytes was validated by the severe osteopetrotic phenotype observed in mice lacking RANKL specifically in osteocytes. Thus, we provide in vivo evidence for the key role of osteocyte-derived RANKL in bone homeostasis, establishing a molecular basis for osteocyte regulation of bone resorption.
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regulation of cancer cell migration and bone metastasis by RANKL
Nature, 2006Co-Authors: Holstead D Jones, Tomoki Nakashima, Otto Sanchez, I Kozieradzki, Svetlana V Komarova, Ildiko Sarosi, Sean Morony, Evelyn RubinAbstract:Cancer cells that express the receptor protein RANK migrate to bone tissue where the RANK ligand, RANKL, is found. This contributes to bone metastases and offers a potential therapeutic approach to prevent cancer metastases. Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain1,2,3. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile ‘soil’4. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs5. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour6, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-κB ligand)7,8 triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis9, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells.
Naoyuki Takahashi - One of the best experts on this subject based on the ideXlab platform.
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Control of bone resorption by RANKL-RANK system
Clinical calcium, 2011Co-Authors: Suguru Harada, Naoyuki TakahashiAbstract:Abstract Differentiation and function of osteoclasts is regulated by RANKL and OPG, both of which are produced by osteoblasts. Osteoclast precursors express RANK, the receptor of RANKL. The activation of the RANKL-RANK system stimulates osteoclast differentiation and function. OPG is a decoy receptor of RANKL, which inhibits the RANKL-RANK interaction. Several genetic disorders in RANKL, RANK and OPG genes cause osteoclast abnormalities. Therefore, the development of anti-osteoporosis drugs that suppress the RANKL-RANK system is advanced now. Recently, anti-RANKL antibody, denosumab, is developed and being used as a new treatment for osteoporosis.
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action of RANKL and opg for osteoclastogenesis
Critical Reviews in Eukaryotic Gene Expression, 2009Co-Authors: Yasuhiro Kobayashi, Nobuyuki Udagawa, Naoyuki TakahashiAbstract:: Osteoclasts develop from hematopoietic cells of the monocyte-macrophage lineage. The coculture system of osteoblasts and hematopoietic cells was devised to examine osteoclastogenesis in vitro. Experiments using the coculture system have established the concept that osteoblasts are crucially involved in osteoclastogenesis. Remarkable progress has been achieved during the last decade in our understanding the molecular mechanism of osteoclast differentiation, largely because of the discovery of receptor activator of NF-kappaB ligand (RANKL), an essential cytokine for osteoclastogenesis. Osteoblasts express RANKL in response to bone-resorbing factors. Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor for RANKL, which inhibits osteoclast differentiation and function by interrupting the interaction between RANKL and RANK, a receptor of RANKL. The identification of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) as a master transcription! factor for RANKL-induced osteoclastogenesis has provided major insight into the molecular mechanism of osteoclast differentiation. The discovery of the immunoreceptor tyrosine-based activation motif (ITAM)-mediated signals as a costimulatory signal in osteoclastogenesis has confirmed that osteoblasts play another important role in osteoclastogenesis. Mutations of RANK, OPG, and RANKL found in humans cause bone diseases associated with expected skeletal abnormalities. Thus, the RANKL/RANK/OPG axis is now recognized as the central regulator of osteoclast differentiation and function.
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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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osteoblasts stromal cells stimulate osteoclast activation through expression of osteoclast differentiation factor RANKL but not macrophage colony stimulating factor
Bone, 1999Co-Authors: Nobuyuki Udagawa, Naoyuki Takahashi, Hisataka Yasuda, Eijiro Jimi, Kenichiro Matsuzaki, Taro Tsurukai, Kanami Itoh, Nobuaki Nakagawa, Masaaki Goto, Eisuke 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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a new member of tumor necrosis factor ligand family odf opgl trance RANKL regulates osteoclast differentiation and function
Biochemical and Biophysical Research Communications, 1999Co-Authors: Naoyuki Takahashi, Nobuyuki Udagawa, Tatsuo SudaAbstract:Abstract Osteoclasts, the multinucleated giant cells that resorb bone, develop from monocyte-macrophage lineage cells. Osteoblasts or bone marrow stromal cells have been suggested to be involved in osteoclastic bone resorption. The recent discovery of new members of the tumor necrosis factor (TNF) receptor-ligand family has elucidated the precise mechanism by which osteoblasts/stromal cells regulate osteoclast differentiation and function. Osteoblasts/stromal cells express a new member of the TNF-ligand family “osteoclast differentiation factor(ODF)/osteoprotegerin ligand (OPGL)/TNF-related activation-induced cytokine (TRANCE)/receptor activator of NF-kB ligand (RANKL)” as a membrane associated factor. Osteoclast precursors which possess RANK, a TNF receptor family member, recognize ODF/OPGL/TRANCE/RANKL through cell-to-cell interaction with osteoblasts/stromal cells, and differentiate into osteoclasts in the presence of macrophage colony-stimulating factor. Mature osteoclasts also express RANK, and their bone-resorbingactivity is also induced by ODF/OPGL/TRANCE/RANKL which osteoblasts/stromal cells possess. Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF)/TNF receptor-like molecule 1 (TR1) is a soluble decoy receptor for ODF/OPGL/ TRANCE/RANKL. Activation of NF-kB and c-Jun N-terminal kinase through the RANK-mediated signaling system appears to be involved in differentiation and activation of osteoclasts.