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ABSTRACT: Bone is continuously renewed through a dynamic balance between bone resorption and formation. This process is the fundamental basis for the maintenance of normal bone mass and architecture. Osteoclasts play a crucial role in both physiological and pathological bone resorption, and receptor activator of nuclear factor-κB ligand (RANKL) is the key cytokine that induces osteoclastogenesis. Here we summarize the recent advances in the understanding of osteoclastogenic signaling by focusing on the investigation of RANKL signaling and RANKL-expressing cells in the context of osteoimmunology. The context afforded by osteoimmunology will provide a scientific basis for future therapeutic approaches to diseases related to the skeletal and immune systems.
Trends in Endocrinology and Metabolism 06/2012; 23(11):582-90. · 8.11 Impact Factor
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ABSTRACT: The bony skeleton is maintained by local factors that regulate bone-forming osteoblasts and bone-resorbing osteoclasts, in addition to hormonal activity. Osteoprotegerin protects bone by inhibiting osteoclastic bone resorption, but no factor has yet been identified as a local determinant of bone mass that regulates both osteoclasts and osteoblasts. Here we show that semaphorin 3A (Sema3A) exerts an osteoprotective effect by both suppressing osteoclastic bone resorption and increasing osteoblastic bone formation. The binding of Sema3A to neuropilin-1 (Nrp1) inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by inhibiting the immunoreceptor tyrosine-based activation motif (ITAM) and RhoA signalling pathways. In addition, Sema3A and Nrp1 binding stimulated osteoblast and inhibited adipocyte differentiation through the canonical Wnt/β-catenin signalling pathway. The osteopenic phenotype in Sema3a−/− mice was recapitulated by mice in which the Sema3A-binding site of Nrp1 had been genetically disrupted. Intravenous Sema3A administration in mice increased bone volume and expedited bone regeneration. Thus, Sema3A is a promising new therapeutic agent in bone and joint diseases.
Nature 04/2012; 485(7396):69-74. · 36.28 Impact Factor
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ABSTRACT: Bone is continuously remodeled by osteoclastic bone resorption and osteoblastic bone formation to maintain the structural integrity and mineral homeostasis. This process is called "bone remodeling" . These bone cells are regulated by mechanical stimulation and systemic (hormonal) factors in addition to autocrine, paracrine factors and cell-cell interactions. Recently, we reported that two semaphorin molecules Sema4D and Sema3A have a crucial role in the regulation of bone remodeling. Sema4D derived from osteoclasts inhibits osteoblast differentiation not to hamper osteoclastic bone resorption. Sema3A derived from osteoblast lineage cells inhibits osteoclast differentiation and promotes osteoblast differentiation synchronously to increase bone mass. These studies provide a scientific basis for future therapeutic approaches to bone diseases.
Clinical calcium 01/2012; 22(11):1693-1699.
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ABSTRACT: Bone is constantly renewed by the balanced action of osteoblastic bone formation and osteoclastic bone resorption. This restructuring process called "bone remodeling" is important not only for maintaining bone mass and strength, but also for mineral homeostasis. Excessive osteoclast activity leads to pathological bone resorption, as seen in a variety of local or generalized osteopenic conditions such as rheumatoid arthritis, cancer bone metastasis and osteoporosis. The immune and skeletal systems share various molecules including cytokines, signaling molecules, transcription factors and membrane receptors. The scope of osteoimmunology has been extended to encompass a wide range of molecular and cellular interactions, the elucidation of which will provide a scientific basis for future therapeutic approaches to diseases related to the immune and skeletal systems.
Clinical calcium 12/2011; 21(12):93-102.
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Tomoki Nakashima, Mikihito Hayashi,
Takanobu Fukunaga,
Kosaku Kurata,
Masatsugu Oh-Hora,
Jian Q Feng,
Lynda F Bonewald,
Tatsuhiko Kodama,
Anton Wutz,
Erwin F Wagner,
Josef M Penninger,
Hiroshi Takayanagi
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ABSTRACT: Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.
Nature medicine 09/2011; 17(10):1231-4. · 27.14 Impact Factor
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ABSTRACT: Bone homeostasis is maintained by a dynamic balance between bone resorption by osteoclasts and bone formation by osteoblasts. Since excessive osteoclast activity is implicated in pathological bone resorption, understanding the mechanism underlying osteoclast differentiation, function and survival is of both scientific and clinical importance. Osteoclasts are monocyte/macrophage lineage cells with a short life span that undergo rapid apoptosis, the rate of which critically determines the level of bone resorption in vivo. However, the molecular basis of rapid osteoclast apoptosis remains obscure. Here we report the role of a BH3-only protein, Noxa (encoded by the Pmaip1 gene), in bone homeostasis using Noxa-deficient mice. Among the Bcl-2 family members, Noxa was selectively induced during osteoclastogenesis. Mice lacking Noxa exhibit a severe osteoporotic phenotype due to an increased number of osteoclasts. Noxa deficiency did not have any effect on the number of osteoclast precursor cells or the expression of osteoclast-specific genes, but led to a prolonged survival of osteoclasts. Furthermore, adenovirus-mediated Noxa overexpression remarkably reduced bone loss in a model of inflammation-induced bone destruction. This study reveals Noxa to be a crucial regulator of osteoclast apoptosis, and may provide a molecular basis for a new therapeutic approach to bone diseases.
Biochemical and Biophysical Research Communications 06/2011; 410(3):620-5. · 2.48 Impact Factor
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ABSTRACT: Some P450 enzymes are expressed not only in the liver but also in the small intestine, and these enzymes play an important role in first-pass drug metabolism in the small intestine. Cytochrome P450 (CYP)2C19 has been confirmed to exist in the small intestine of white people, but not yet in Japanese. We investigated the mRNA level, protein level, and activity of CYP2C19 in the small intestine in a Japanese population. Samples were obtained from the healthy portions of resected small intestines from 18 patients who had undergone pancreatoduodenectomy. The microsomes were extracted from the epithelium of the small intestinal tissues. CYP2C19 mRNA and protein levels were analyzed using real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. CYP2C19 activity in the microsomes was evaluated based on the 5-hydroxylation of lansoprazole using HPLC. CYP2C19 mRNA and protein levels and activities in the small intestine showed interindividual differences. CYP2C19 mRNA levels were not correlated with protein levels or its activity. On the other hand, there was significant correlation between CYP2C19 protein levels and its activity. Further, CYP2C19 protein levels and activities in the small intestine were approximately equal to those in liver. These results suggest the metabolic capacity of CYP2C19 in Japanese small intestine may play as important a role as the liver in drug metabolism. Analyses of the protein level or protein activity of CYP2C19 rather than its mRNA level should be required for predicting the individual metabolic capacity of CYP2C19 in the small intestine.
Biological & Pharmaceutical Bulletin 01/2011; 34(1):71-6. · 1.66 Impact Factor
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ABSTRACT: Regulation of irreversible cell lineage commitment depends on a delicate balance between positive and negative regulators, which comprise a sophisticated network of transcription factors. Receptor activator of NF-kappaB ligand (RANKL) stimulates the differentiation of bone-resorbing osteoclasts through the induction of nuclear factor of activated T cells c1 (NFATc1), the essential transcription factor for osteoclastogenesis. Osteoclast-specific robust induction of NFATc1 is achieved through an autoamplification mechanism, in which NFATc1 is constantly activated by calcium signaling while the negative regulators of NFATc1 are suppressed. However, it has been unclear how such negative regulators are repressed during osteoclastogenesis. Here we show that B lymphocyte-induced maturation protein-1 (Blimp1; encoded by Prdm1), which is induced by RANKL through NFATc1 during osteoclastogenesis, functions as a transcriptional repressor of anti-osteoclastogenic genes such as Irf8 and Mafb. Overexpression of Blimp1 leads to an increase in osteoclast formation, and Prdm1-deficient osteoclast precursor cells do not undergo osteoclast differentiation efficiently. The importance of Blimp1 in bone homeostasis is underscored by the observation that mice with an osteoclast-specific deficiency in the Prdm1 gene exhibit a high bone mass phenotype caused by a decreased number of osteoclasts. Thus, NFATc1 choreographs the determination of cell fate in the osteoclast lineage by inducing the repression of negative regulators as well as through its effect on positive regulators.
Proceedings of the National Academy of Sciences 02/2010; 107(7):3117-22. · 9.68 Impact Factor
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ABSTRACT: Osteoclasts, multinucleated cells that resorb bone, play a key role in bone remodeling. Although immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling is critical for osteoclast differentiation, the significance of immunoreceptor tyrosine-based inhibitory motif (ITIM) has not been well understood. Here we report the function of Ly49Q, an Ly49 family member possessing an ITIM motif, in osteoclastogenesis. Ly49Q is selectively induced by receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) stimulation in bone marrow-derived monocyte/macrophage precursor cells (BMMs) among the Ly49 family of NK receptors. The knockdown of Ly49Q resulted in a significant reduction in the RANKL-induced formation of tartrate-resistance acid phosphatase (TRAP)-positive multinucleated cells, accompanied by a decreased expression of osteoclast-specific genes such as Nfatc1, Tm7sf4, Oscar, Ctsk, and Acp5. Osteoclastogenesis was also significantly impaired in Ly49Q-deficient cells in vitro. The inhibitory effect of Ly49Q-deficiency may be explained by the finding that Ly49Q competed for the association of Src-homology domain-2 phosphatase-1 (SHP-1) with paired immunoglobulin-like receptor-B (PIR-B), an ITIM-bearing receptor which negatively regulates osteoclast differentiation. Unexpectedly, Ly49Q deficiency did not lead to impaired osteoclast formation in vivo, suggesting the existence of a compensatory mechanism. This study provides an example in which an ITIM-bearing receptor functions as a positive regulator of osteoclast differentiation.
Biochemical and Biophysical Research Communications 02/2010; 393(3):432-8. · 2.48 Impact Factor
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ABSTRACT: Cytochrome P450 (CYP) 3A enzymes are responsible for the metabolism of many drugs. It is useful to know CYP3A activity in individual patients undergoing drug therapy so as to predict the efficacies or adverse events. Lansoprazole is metabolized to Lansoprazole sulfone (LS) by CYP3A, while to 5-hydroxylansoprasole by CYP2C19. The aim of this study was to evaluate whether lansoprazole can be used to assess CYP 3A activity in human liver. Lansoprazole sulfoxidation activity in 14 human liver microsomes was determined as the ratio of lansoprazole/LS, measuring these parameters by high-performance liquid chromatography. Testosterone 6beta-hydroxylation (T6beta-OH) activity, a known marker for CYP3A activity was also measured together with lansoprazole sulfoxidation activity. Lansoprazole sulfoxidation activity was also analyzed in microsomes preincubat-ed with anti-CYP2C19 antibody. Interindividual variation was observed in lansoprazole sulfoxidation activity and T6beta-OH activities of those microsomes, respectively. Lansoprazole sulfoxidation activity was significantly correlated with T6beta-OH activity and CYP3A protein level. Lansoprazole sulfoxidation activity in microsomes with anti-CYP2C19 antibody was closely correlated with T6beta-OH activity. In contrast, lansoprazole 5-hydroxylation activity was correlated with the CYP2C19 activity. These results suggest that metabolism of lansoprazole to LS by CYP3A occurs independently of metabolism by CYP2C19. LS can be used as a new marker of CYP3A activity.
Biological & Pharmaceutical Bulletin 09/2009; 32(8):1422-6. · 1.66 Impact Factor
