Nobuyuki Udagawa

Matsumoto Dental University, Sioziri, Nagano, Japan

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Publications (197)842.43 Total impact

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    ABSTRACT: The canonical Wnt/β-catenin signaling pathway in osteoblast-lineage cells inhibits osteoclastogenesis through the expression of osteoprotegerin (Opg), a decoy receptor of receptor activator of Nf-κb (Rank) ligands. Wnt5a, a typical non-canonical Wnt ligand, enhances the expression of Rank in osteoclast precursors, which, in turn, promotes the Rank ligand (Rankl)-induced formation of osteoclasts. In contrast, Wnt16 and Wnt4 have been shown to inhibit the Rankl-induced formation of osteoclasts through non-canonical Wnt signals. However, the relationships among these Wnt ligands in osteoclastogenesis remained to be elucidated. We herein showed that Wnt16, but not Wnt4, inhibited the Rankl-induced osteoclastogenesis in bone marrow-derived macrophage (BMM) cultures. Wnt3a and Wnt4 inhibited the 1α,25-dihydroxy vitamin D3 (1,25D3)-induced osteoclastogenesis in co-cultures prepared from wild-type mice, but not in those from Opg(-/-) nice. Wnt16 inhibited the 1,25D3-induced formation of osteoclasts in both wild-type and Opg(-/-) co-cultures. Wnt16, Wnt4, and Wnt3a failed to inhibit the pit-forming activity of osteoclasts. Wnt16 failed to inhibit the Wnt5a-induced expression of Rank in osteoclast precursors. In contrast, Wnt5a abrogated the inhibitory effects of Wnt16 on Rankl-induced osteoclastogenesis. These results suggested that Wnt16 inhibited osteoclastogenesis, but not the function of osteoclasts and that Wnt16, an inhibitory Wnt ligand for osteoclastogenesis, regulates bone resorption in conjunction with Wnt5a. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 06/2015; DOI:10.1016/j.bbrc.2015.06.102 · 2.28 Impact Factor
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    ABSTRACT: The cytoskeletal organization of osteoclasts is required for bone resorption. Binding of dynamin with guanosine triphosphate (GTP) was previously suggested to be required for the organization of the actin cytoskeleton. However, the role of the GTPase activity of dynamin in the organization of the actin cytoskeleton as well as in the bone-resorbing activity of osteoclasts remains unclear. This study investigated the effects of dynasore, an inhibitor of the GTPase activity of dynamin, on the bone-resorbing activity of and actin ring formation in mouse osteoclasts in vitro and in vivo. Dynasore inhibited the formation of resorption pits in osteoclast cultures by suppressing actin ring formation and rapidly disrupting actin rings in osteoclasts. A time-lapse image analysis showed that dynasore shrank actin rings in osteoclasts within 30 min. The intraperitoneal administration of dynasore inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced trabecular bone loss in mouse femurs. These in vitro and in vivo results suggest that the GTPase activity of dynamin is critical for the bone-resorbing activity of osteoclasts and that dynasore is a seed for the development of novel anti-resorbing agents.
    Journal of Bone and Mineral Metabolism 06/2015; DOI:10.1007/s00774-015-0683-1 · 2.11 Impact Factor
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    ABSTRACT: Objectives To understand the differences and similarities between immunocompetent and immunodeficient mice as ectopic transplantation animal models for bone tissue engineering.Materials and Methods Osteogenic cells from mouse leg bones were cultured, seeded on ß-TCP granules and transplanted onto the backs of either immunocompetent or immunodeficient nude mice. At 1, 2, 4 and 8 weeks postoperatively, samples were harvested and evaluated by Hematoxylin-Eosin staining, tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemical staining and quantitative PCR.ResultsIn immunocompetent mice, inflammatory cell infiltration was evident at 1 week post-operatively and relatively higher expression of TNF-α and IL-4 was observed. In immunodeficient mice, new bone area and the number of TRAP-positive cells was larger at 4 weeks than in immunocompetent mice. The volume of new bone area in immunodeficient mice was reduced by 8 weeks.Conclusions Bone regeneration was feasible in immunocompetent mice. However, some differences were observed between immunocompetent and immunodeficient mice in the bone regeneration process possibly due to different cytokine expression, which should be considered when utilizing in vivo animal models.This article is protected by copyright. All rights reserved.
    Oral Diseases 02/2015; 21(5). DOI:10.1111/odi.12319 · 2.40 Impact Factor
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    ABSTRACT: Titanium has been widely used as a dental implant material. However, it takes several months for the implant body to bind with the jawbone. To develop new bioactive modification on titanium surfaces to achieve full osseointegration expeditiously, we used fibrinogen and fibronectin as bioactive scaffolds on the titanium plate, which are common extracellular matrix (ECM) proteins. We analyzed the features of the surface of ECM-modified titanium plates by atomic force microscopy and Fourier transform infrared spectrophotometry. We also evaluated the effect of ECM modification on promoting the differentiation and mineralization of osteoblasts on these surfaces. Fibrinogen had excellent adsorption on titanium surfaces even at low concentrations, due to the binding ability of fibrinogen via its RGD motif. The surface was composed of a fibrinogen monolayer, in which the ratio of β-sheets was decreased. Osteoblast proliferation on ECM-modified titanium surface was significantly promoted compared with titanium alone. Calcification on the modified surface was also accelerated. These ECM-promoting effects correlated with increased expression of bone morphogenetic proteins (BMPs) by the osteoblasts themselves and were inhibited by Noggin, a BMP inhibitor. These results suggest that the fibrinogen monolayer-modified titanium surface is recognized as bioactive scaffolds and promotes bone formation, resulting in the acceleration of osseointegration.
    Materials Science and Engineering C 01/2015; 46:86–96. DOI:10.1016/j.msec.2014.10.025 · 2.74 Impact Factor
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    ABSTRACT: Objective Polarized osteoclasts form sealing zones, (also called clear zones) detectable as actin rings, and ruffled borders to resorb bone. They secrete protons and catabolic enzymes, including tartrate-resistant acid phosphatase (TRAP), through the ruffled borders. We previously reported that polarized osteoclasts develop areas of TRAP activity (TRAP-marks) when cultured on dentin slices [11]. In this study, we examined how osteoclasts recognize dental implant materials. Methods Osteoclasts obtained from murine co-cultures were cultured on implant materials such as titanium (Ti), alumina, zirconia, and sintered hydroxyapatite (sHA), in addition to dentin. Osteoclasts were also treated with reveromycin A (RM-A), which specifically acts on polarized osteoclasts and induces apoptosis. Polarization of osteoclasts cultured on implant materials was evaluated by measuring actin rings, TRAP-marks, and reveromycin A-induced apoptosis. Results Osteoclasts formed actin rings on all substrates examined. The formation of actin rings on Ti by osteoclasts was inhibited by the GRGDS peptide, but not by the GRGES peptide, suggesting an integrin-mediated polarization of osteoclasts on Ti. Calcitonin, an inhibitory hormone of osteoclast function, disrupted the actin rings that were preformed on Ti and sHA. Osteoclasts put TRAP-marks on sHA and dentin and formed resorption pits on dentin, but failed to form resorption pits on sHA. RM-A induced apoptosis in osteoclasts cultured on Ti and sHA; this was suppressed by calcitonin. Conclusions These results demonstrate that osteoclasts are able to polarize on dental implant materials similar to the polarization observed on bone.
    Journal of Oral Biosciences 08/2014; DOI:10.1016/j.job.2014.06.005
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    ABSTRACT: Body surface tissues, such as the oral cavity, contact directly with the external environment and are continuously exposed to microbial insults. Cathelicidins are a family of antimicrobial peptides that are found in mammalian species. Humans and mice have only one cathelicidin. Cathelicidins are expressed in a variety of surface tissues. In addition, they are abundantly expressed in bone and bone marrow. Infectious stimuli upregulate the expression of cathelicidins, which play sentinel roles in allowing the tissues to fight against microbial challenges. Cathelicidins disrupt membranes of microorganisms and kill them. They also neutralize microbe-derived pathogens, such as lipopolysaccharide (LPS) and flagellin. Besides their antimicrobial functions, cathelicidins can also control actions of host cells, such as chemotaxis, proliferation, and cytokine production, through binding to the receptors expressed on them. LPS and flagellin induce osteoclastogenesis and the production of cathelicidins, which can in turn inhibit osteoclastogenesis. Thus, cathelicidins contribute to maintaining microbiota-host homeostasis and promoting repair responses to inflammatory insults. In this review, we describe recent findings on the multiple roles of cathelicidins in host defense. We also discuss the significance of the human cathelicidin, LL-37, as a pharmaceutical target for the treatment of inflammation and bone loss in infectious diseases, such as periodontitis.
    Odontology 07/2014; 102(2). DOI:10.1007/s10266-014-0167-0 · 1.35 Impact Factor
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    ABSTRACT: Osteoclasts, the multinucleated cells that resorb bone, originate from monocyte-macrophage lineage cells. Various hormones, cytokines and growth factors are involved in osteoclastogenesis, via interaction with osteoblasts. In this review, we summarize the regulatory mechanism of bone resorption by various cytokines derived from osteoblasts and hematopoietic inflammatory cells.
    Clinical calcium 06/2014; 24(6):837-44.
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    ABSTRACT: Wnt regulates bone formation through β-catenin-dependent canonical and -independent noncanonical signaling pathways. However, the cooperation that exists between the two signaling pathways during osteoblastogenesis remains to be elucidated. Here, we showed that the lack of Wnt5a in osteoblast-lineage cells impaired Wnt/β-catenin signaling due to the reduced expression of Lrp5 and Lrp6. Pretreatment of ST2 cells, a stromal cell line, with Wnt5a enhanced canonical Wnt ligand-induced Tcf/Lef transcription activity. Short hairpin RNA-mediated knockdown of Wnt5a, but not treatment with Dkk1, an antagonist of Wnt/β-catenin signaling, reduced the expression of Lrp5 and Lrp6 in osteoblast-lineage cells under osteogenic culture conditions. Osteoblast-lineage cells from Wnt5a-deficient mice exhibited reduced Wnt/β-catenin signaling, which impaired osteoblast differentiation and enhanced adipocyte differentiation. Adenovirus-mediated gene transfer of Lrp5 into Wnt5a-deficient osteoblast-lineage cells rescued their phenotypic features. Therefore, Wnt5a-induced noncanonical signaling cooperates with Wnt/β-catenin signaling to achieve proper bone formation.
    Scientific Reports 03/2014; 4:4493. DOI:10.1038/srep04493 · 5.58 Impact Factor
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    Naoyuki Takahashi, Nobuyuki Udagawa, Tatsuo Suda
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    ABSTRACT: Vitamin D was discovered as an anti-rachitic agent preventing a failure in bone mineralization, but it is now established that the active form of vitamin D3 (1α,25(OH)2D3) induces bone resorption. Discovery of the receptor activator of nuclear factor -κB ligand (RANKL) uncovered the molecular mechanism by which 1α,25(OH)2D3 stimulates bone resorption. Treating osteoblastic cells with 1α,25(OH)2D3 stimulates RANKL expression, which in turn induces osteoclastogenesis. Nevertheless, active vitamin D compounds such as calcitriol (1α,25(OH)2D3), alfacalcidol (1α(OH)D3) and eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropoxy) vitamin D3) have been used as therapeutic drugs for osteoporosis, as they increase bone mineral density (BMD) in osteoporotic patients. Paradoxically, the increase in BMD is caused by the suppression of bone resorption. Several studies have been performed to elucidate the mechanism by which active vitamin D compounds suppress bone resorption in vivo. Our study showed that daily administration of eldecalcitol to mice suppressed neither the number of osteoclast precursors in the bone marrow nor the number of osteoclasts formed in ex vivo cultures. Eldecalcitol administration suppressed RANKL expression in osteoblasts. This review discusses how the difference between in vitro and in vivo effects of active vitamin D compounds on bone resorption is induced.
    02/2014; 3:522. DOI:10.1038/bonekey.2014.17
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    ABSTRACT: Arctigenin, a lignan-derived compound, is a constituent of the seeds of Arctium lappa. Arctigenin was previously shown to inhibit osteoclastogenesis; however, this inhibitory mechanism has yet to be elucidated. Here, we showed that arctigenin inhibited the action of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key transcription factor for osteoclastogenesis. NFATc1 in osteoclast precursors was activated through two distinct pathways: the calcineurin-dependent and osteoblastic cell-dependent pathways. Among the several lignan-derived compounds examined, arctigenin most strongly inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast-like cell formation in mouse bone marrow macrophage (BMM) cultures, in which the calcineurin-dependent NFATc1 pathway was activated. Arctigenin suppressed neither the activation of nuclear factor κB and mitogen-activated protein kinases nor the up-regulation of c-Fos expression in BMMs treated with RANKL. However, arctigenin suppressed RANKL-induced NFATc1 expression. Interestingly, the treatment of osteoclast-like cells with arctigenin converted NFATc1 into a lower molecular weight species, which was translocated into the nucleus even in the absence of RANKL. Nevertheless, arctigenin as well as cyclosporin A (CsA), a calcineurin inhibitor, suppressed the NFAT-luciferase reporter activity induced by ionomycin and phorbol 12-myristate 13-acetate in BMMs. Chromatin immunoprecipitation analysis confirmed that arctigenin inhibited the recruitment of NFATc1 to the promoter region of the NFATc1 target gene. Arctigenin, but not CsA suppressed osteoclast-like cell formation in co-cultures of osteoblastic cells and bone marrow cells, in which the osteoblastic cell-dependent NFATc1 pathway was activated. The forced expression of constitutively active NFATc1 rescued osteoclastogenesis in BMM cultures treated with CsA, but not that treated with arctigenin. Arctigenin also suppressed the pit-forming activity of osteoclast-like cells cultured on dentin slices. These results suggest that arctigenin induces a dominant negative species of NFATc1, which inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways.
    PLoS ONE 01/2014; 9(1):e85878. DOI:10.1371/journal.pone.0085878 · 3.53 Impact Factor
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    ABSTRACT: Calcification (biomineralization) is essential for maintenance of a life. The elucidation of "Osteoclast-mediated demineralization of biomineral" directly links elucidation for bone mineral balance (coupling of bone tissue) . Bone is continuously destroyed and reformed in vertebrates to maintain bone volume and calcium homeostasis. In this review, we summarize the regulatory mechanism of osteoclast-mediated demineralization of biomineral by osteoblast-derived osteoclast differentiation factor (RANKL).
    Clinical calcium 01/2014; 24(2):215-23.
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    ABSTRACT: Cathelicidin-related antimicrobial peptide (CRAMP) not only kills bacteria but also binds to lipopolysaccharide (LPS) to neutralize its activity. CRAMP is highly expressed in bone marrow. The expression of CRAMP is reported to be upregulated by inflammatory and infectious stimuli. Here, we examined the role of CRAMP in murine osteoclastogenesis. Osteoclasts were formed in cocultures of osteoblasts and bone marrow cells in response to 1α,25-dihydroxyvitamin D3 [1α,25(OH)2 D3 ], prostaglandin E2 (PGE2 ), and Toll-like receptor (TLR) ligands such as LPS and flagellin through the induction of receptor activator of nuclear factor-κB ligand (RANKL) expression in osteoblasts. CRAMP inhibited the osteoclastogenesis in cocultures treated with LPS and flagellin, but not with 1α,25(OH)2 D3 or PGE2 . Although bone marrow macrophages (BMMs) highly expressed formyl peptide receptor 2 (a receptor of CRAMP), CRAMP showed no inhibitory effect on osteoclastogenesis in BMM cultures treated with RANKL. CRAMP suppressed both LPS- and flagellin-induced RANKL expression in osteoblasts and tumor necrosis factor-α (TNFα) expression in BMMs, suggesting that CRAMP neutralizes the actions of LPS and flagellin. LPS and flagellin enhanced the expression of CRAMP mRNA in osteoblasts. Extracellularly added CRAMP suppressed LPS- and flagellin-induced CRAMP expression. These results suggest that the production of CRAMP promoted by LPS and flagellin is inhibited by CRAMP released by osteoblasts through a feedback regulation. Even though CRAMP itself has no effect on osteoclastogenesis in mice, we propose that CRAMP is an osteoblast-derived protector in bacterial infection-induced osteoclastic bone resorption. This article is protected by copyright. All rights reserved.
    Immunology 07/2013; DOI:10.1111/imm.12146 · 3.74 Impact Factor
  • Yuko Nakamichi, Nobuyuki Udagawa, Naoyuki Takahashi
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    ABSTRACT: Colony-stimulating factor-1 (CSF-1) is widely expressed and considered to regulate the development, maintenance, and function of mononuclear phagocyte lineage cells such as monocytes, macrophages, dendritic cells (DCs), Langerhans cells (LCs), microglia, and osteoclasts. Interleukin-34 (IL-34) was recently identified as an alternative ligand for the CSF-1 receptor (CSF-1R) through functional proteomics experiments. It is well established that the phenotype of CSF-1R-deficient (CSF-1R(-/-)) mice is more severe than that of mice bearing a spontaneous null mutation in CSF-1 (CSF-1(op/op)). CSF-1R(-/-) mice are severely depleted of macrophages and completely lack LCs, microglia, and osteoclasts during their lifetime. In contrast, CSF-1(op/op) mice exhibit late-onset macrophage development and osteoclastogenesis, whereas they show modestly reduced numbers of microglia and a relatively normal LC development. In contrast, IL-34-deficient (IL-34(-/-)) mice show a marked reduction of LCs and a decrease in microglia. IL-34 and CSF-1 display different spatiotemporal expression patterns and have distinct biological functions. In this review, we focus on the functional similarities and differences between IL-34 and CSF-1 in vivo.
    Journal of Bone and Mineral Metabolism 06/2013; DOI:10.1007/s00774-013-0476-3 · 2.11 Impact Factor
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    ABSTRACT: Objectives The purpose of this study was to assess the association between the cortical shape of the mandible, as detected on panoramic radiographs, and trabecular bone structure, as assessed by cone-beam computed tomography (CBCT), in Japanese adults. Methods Panoramic radiographs and CBCT images of the mandibles of 50 subjects (18 men, 32 women), aged 45–86 years, were evaluated. An experienced oral and maxillofacial radiologist categorized the cortical shape of the mandible as detected on panoramic radiographs as normal, mildly to moderately eroded, and severely eroded cortices, respectively. All mandibles were scanned using CBCT. Four bone structure parameters of the basal portion of the mandible were calculated in three dimensions using an image-analysis system: total bone volume (mm3); cortical bone volume fraction (%); trabecular bone volume fraction (%); fractal dimension. One-way analysis of covariance with Bonferroni correction was employed to evaluate differences in the four bone parameters among the three cortical shape groups. Pearson’s correlation coefficient was calculated to examine correlations between age and cortical and trabecular bone volume fractions. Results Progression of cortical bone erosion was significantly associated with increased trabecular bone volume fraction (P < 0.001) and increased fractal dimension (P = 0.01). Cortical bone volume fraction decreased significantly with age (P = 0.04). However, trabecular bone volume fraction tended to increase with age (P = 0.06). Conclusions The change in the trabecular bone structure of the mandible may differ from that of the general skeleton in Japanese adults.
    Oral Radiology 05/2013; 30(2). DOI:10.1007/s11282-013-0155-z · 0.15 Impact Factor
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    ABSTRACT: Objectives: Eroded inferior cortex of the mandible detected on panoramic radiographs is useful for identifying individuals with an increased risk of osteoporosis. However, there is no previous study about the association between this cortical porosity and trabecular structures of the mandible. We assessed this association in Japanese men and women by using cone beam CT (CBCT). Methods: Of CBCT images that were taken for the diagnosis of oral and maxillofacial diseases in Matsumoto Dental University Hospital, those of 16 men and 31 women aged 45 years and older who had also panoramic radiographs were used in this study. Matsumoto Dental University human subject committee reviewed and approved the study protocol. Cortical shape of the mandible was classified into 3 groups (normal, moderately eroded, and severely eroded) according to the previous study. Trabecular structures of the basal portion of the mandible between mental foramen and second molar were analyzed using TRI/3D-BON system (Ratoc System Engineering Co., Tokyo) on CBCT images. One way-ANOVA was used to evaluate the association between 3 cortical shapes and several parameters of trabecular bone of the mandible. Results: There was no significant differences in the whole bone volume among 3 cortical shapes (P=0.79). Subjects with severely eroded cortex had significantly larger trabecular bone volume (P=0.002), trabecular bone density (P=0.047) and fractal dimension (P=0.01) than those with normal and moderately eroded cortices. The rate of cortical bone volume significantly decreased with age (P=0.03). However, trabecular bone density significantly increased with age (P=0.04). Conclusions: Our results suggested that trabecular bone density and complexity of the mandible may increase with the progression of cortical bone porosity in the elderly.
    IADR/AADR/CADR General Session and Exhibition 2013; 03/2013
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    ABSTRACT: Tetracyclines such as doxycycline and minocycline are used to suppress bacterial growth in patients with inflammatory diseases. Tetracyclines have been shown to prevent bone loss, but the underlying mechanisms are unknown. Osteoclasts and dendritic cells (DCs) are derived from common progenitors such as bone marrow-derived macrophages (BMMs). Here, we showed that minocycline converts the differentiation pathway, which results in DC-like cells and not osteoclasts. Minocycline inhibited the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis of BMMs but had no effects on cell growth and phagocytic activity. It influenced neither the proliferation nor differentiation of bone-forming osteoblasts. Surprisingly, minocycline induced the expression of DC markers, CD11c and CD86, in BMMs in the presence of RANKL. STAT5 is involved in DC differentiation that is induced by granulocyte–macrophage colony-stimulating factor (GM-CSF). Midostaurin, which is a STAT5 signaling inhibitor and an anti-GM-CSF neutralizing antibody, suppressed the differentiation that was induced by GM-CSF but not by tetracyclines. In vivo, the injection of minocycline into RANKL-injected mice and RANKL-transgenic mice suppressed RANKL-induced osteoclastogenesis and promoted the concomitant appearance of CD11c-positive cells. These results suggest that minocycline prevents bone loss that is induced by local inflammation, including rheumatoid arthritis and periodontitis, through osteoclast-DC-like cell conversion.
    Journal of Oral Biosciences 02/2013; 55(1):16–22. DOI:10.1016/j.job.2013.01.001
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    ABSTRACT: To date, parathyroid hormone is the only clinically available bone anabolic drug. The major difficulty in the development of such drugs is the lack of clarification of the mechanisms regulating osteoblast differentiation and bone formation. Here, we report a peptide (W9) known to abrogate osteoclast differentiation in vivo via blocking receptor activator of nuclear factor-κB ligand (RANKL)-RANK signaling that we surprisingly found exhibits a bone anabolic effect in vivo. Subcutaneous administration of W9 3 times per day for 5 days significantly augmented bone mineral density in mouse cortical bone. Histomorphometrical analysis showed a decrease in osteoclastogenesis in the distal femoral metaphysis and a significant increase in bone formation in the femoral diaphysis. Our findings suggest that W9 exerts bone anabolic activity. To clarify the mechanisms involved in this activity, we investigated the effects of W9 on osteoblast differentiation/mineralization in MC3T3-E1 (E1) cells. W9 markedly increased alkaline phosphatase (ALP, a marker enzyme of osteoblasts) activity and mineralization as shown by alizarin red staining. Gene expression of several osteogenesis-related factors was increased in W9-treated E1 cells. Addition of W9 activated p38 MAP kinase and Smad1/5/8 in E1 cells, and W9 showed osteogenesis stimulatory activity synergistically with BMP-2 in vitro and ectopic bone formation. Knockdown of RANKL expression in E1 cells reduced the effect of W9. Furthermore, W9 showed weak effect on RANKL-deficient osteoblasts in ALP assay. Taken together, our findings suggest that this peptide may be useful for the treatment of bone diseases and W9 achieves its bone anabolic activity through RANKL on osteoblasts accompanied by production of several autocrine factors.
    Journal of Biological Chemistry 01/2013; 288(8). DOI:10.1074/jbc.M112.426080 · 4.60 Impact Factor
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  • 01/2013; 4(2):1-7. DOI:10.1902/cap.2013.120055

Publication Stats

17k Citations
842.43 Total Impact Points

Institutions

  • 2002–2015
    • Matsumoto Dental University
      • Institute for Oral Science
      Sioziri, Nagano, Japan
  • 1988–2009
    • Showa University
      • • Department of Biochemistry
      • • School of Dentistry
      Shinagawa, Tōkyō, Japan
  • 2006
    • Shinshu University
      • Department of Orthopaedic Surgery
      Shonai, Nagano, Japan
  • 2002–2006
    • Aichi Gakuin University
      • Department of Periodontology
      Nagoya-shi, Aichi-ken, Japan
  • 1999
    • Tokyo Women's Medical University
      Edo, Tōkyō, Japan
    • Keio University
      • Department of Orthopedic Surgery
      Edo, Tōkyō, Japan
  • 1996–1999
    • Saint Vincent's Institute
      Fitzroy, Victoria, Australia
    • Victoria University Melbourne
      Melbourne, Victoria, Australia
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
    • St. Vincent's Hospital Melbourne
      Melbourne, Victoria, Australia
  • 1998
    • St. Vincent Hospital
      Green Bay, Wisconsin, United States