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1.
Front Cell Dev Biol ; 9: 648084, 2021.
Article de Anglais | MEDLINE | ID: mdl-34295889

RÉSUMÉ

Receptor activator of NF-κB ligand (RANKL)-binding peptides inhibit bone resorption and were recently shown to activate bone formation. The stimulatory mechanism underlying bone formation associated with these peptides was explained as RANKL-reverse signaling, wherein RANKL molecules on osteoblasts work as receptors to stimulate osteoblast differentiation. However, why RANKL-binding peptides stimulate osteoblast differentiation while osteoprotegerin (OPG), which is well known to bind to RANKL, cannot activate osteoblast differentiation has remained unclear. In this mini-review, we introduce three main issues: (1) The inhibitory effects of two RANKL-binding peptides (W9 and OP3-4) on bone resorption; (2) The stimulatory effects of the RANKL-binding peptides on osteoblast differentiation; and (3) The accumulation and membrane clustering of RANKL molecules at the cell surface of osteoblasts as a potential molecular switch stimulating osteoblast differentiation by RANKL-binding peptides.

2.
Bone Rep ; 13: 100713, 2020 Dec.
Article de Anglais | MEDLINE | ID: mdl-32964075

RÉSUMÉ

Considering that stress condition associated with osteoporosis, the hypothalamic-pituitary-adrenal (HPA) axis, which is essential for central stress response system, is implicated in regulating bone mass accrual. Melanocortin 2 receptor (MC2R), the receptor of adrenocorticotropic hormone is expressed in both adrenal gland cells and bone cells. To elucidate the role of HPA axis in bone metabolism, we assessed the skeletal phenotype of MC2R deficient mice (MC2R -/- mice). We first examined bone mineral density and cortical thickness of femur using dual x-ray absorptiometry and micro-computed tomography. We then conducted histomorphometric analysis to calculate the static and dynamic parameters of vertebrae in MC2R -/- mice. The levels of osteoblastic marker genes were examined by quantitative PCR in primary osteoblasts derived from MC2R -/- mice. Based on these observations, bone mineral density of femur in MC2R -/- mice was increasing relative to litter controls. Meanwhile, the thickness of cortical bone of femur in MC2R -/- mice was remarkably elevated. Moreover, serum osteocalcin level was drastically raised in MC2R -/- mice. However, bone histomorphometry revealed that static and dynamic parameters reflecting bone formation and resorption were unchanged in vertebrae of MC2R -/- mice compared to the control, indicating that MC2R function may be specific to appendicular bone than axis bone. Taken together, the HPA axis due to deletion of MC2R is involved in bone metabolism.

3.
Nature ; 561(7722): 195-200, 2018 09.
Article de Anglais | MEDLINE | ID: mdl-30185903

RÉSUMÉ

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.


Sujet(s)
Résorption osseuse/métabolisme , Ostéogenèse , Ligand de RANK/métabolisme , Transduction du signal , Substitution d'acide aminé , Animaux , Différenciation cellulaire , Sous-unité alpha 1 du facteur CBF/métabolisme , Réactifs réticulants/composition chimique , Vésicules cytoplasmiques/métabolisme , Femelle , Mâle , Souris , Souris de lignée C57BL , Ostéoblastes/cytologie , Ostéoblastes/métabolisme , Ostéoclastes/cytologie , Ostéoclastes/métabolisme , Ligand de RANK/composition chimique , Ligand de RANK/déficit , Ligand de RANK/génétique , Récepteur activateur du facteur nucléaire Kappa B/génétique , Récepteur activateur du facteur nucléaire Kappa B/métabolisme
4.
Stud Health Technol Inform ; 245: 536-538, 2017.
Article de Anglais | MEDLINE | ID: mdl-29295152

RÉSUMÉ

A New legal structure for rare disease (nambyo) has been established in Japan this year, after 42 years of measures of nambyo. We have been accumulating registry for nambyo from 2003, however, as it was based on paper registration, quality was not enough. Our new registry system will be based under ISO13606 which is a new medical international standard. Authorized doctors can put in data On Line by the new system, which has data cleaning filter for accurate data entry. Patients will be supported their medical expense by authorization by this system, so the registry will be efficient.


Sujet(s)
Maladies rares , Enregistrements , Humains , Japon
5.
Bioessays ; 38(8): 717-25, 2016 08.
Article de Anglais | MEDLINE | ID: mdl-27345003

RÉSUMÉ

Both W9 and OP3-4 were known to bind the receptor activator of NF-κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide-induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, an upstream molecule of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3-4 accelerated BMP-2-induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL-binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP-2-induced bone regeneration by the RANKL-binding peptides.


Sujet(s)
Protéine morphogénétique osseuse de type 2 , Régénération osseuse/effets des médicaments et des substances chimiques , Différenciation cellulaire , Oligopeptides/pharmacologie , Ostéoblastes/effets des médicaments et des substances chimiques , Animaux , Mâle , Complexe-1 cible mécanistique de la rapamycine , Souris , Complexes multiprotéiques , Oligopeptides/métabolisme , Ostéoblastes/métabolisme , Ostéoblastes/physiologie , Liaison aux protéines , Ligand de RANK/métabolisme , Transduction du signal , Sérine-thréonine kinases TOR
6.
Sci Rep ; 5: 14172, 2015 Sep 21.
Article de Anglais | MEDLINE | ID: mdl-26387549

RÉSUMÉ

The bone mineral density (BMD) of astronauts decreases specifically in the weight-bearing sites during spaceflight. It seems that osteoclasts would be affected by a change in gravity; however, the molecular mechanism involved remains unclear. Here, we show that the mineral density of the pharyngeal bone and teeth region of TRAP-GFP/Osterix-DsRed double transgenic medaka fish was decreased and that osteoclasts were activated when the fish were reared for 56 days at the international space station. In addition, electron microscopy observation revealed a low degree of roundness of mitochondria in osteoclasts. In the whole transcriptome analysis, fkbp5 and ddit4 genes were strongly up-regulated in the flight group. The fish were filmed for abnormal behavior; and, interestingly, the medaka tended to become motionless in the late stage of exposure. These results reveal impaired physiological function with a change in mechanical force under microgravity, which impairment was accompanied by osteoclast activation.


Sujet(s)
Densité osseuse/physiologie , Résorption osseuse/physiopathologie , Ostéoclastes/physiologie , Ostéogenèse/physiologie , Impesanteur , Animaux , Animal génétiquement modifié , Os et tissu osseux/physiologie , Environnement extraterrestre , Mitochondries/physiologie , Oryzias , Ostéoblastes/physiologie , Vol spatial , Vaisseaux spatiaux , Protéines de liaison au tacrolimus/biosynthèse , Protéines de liaison au tacrolimus/génétique , Dent/physiologie , Facteurs de transcription/biosynthèse , Facteurs de transcription/génétique , Régulation positive
7.
Arthritis Res Ther ; 17: 251, 2015 Sep 12.
Article de Anglais | MEDLINE | ID: mdl-26373710

RÉSUMÉ

INTRODUCTION: We designed OP3-4 (YCEIEFCYLIR), a cyclic peptide, to mimic the soluble osteoprotegerin (OPG), and was proven to bind to RANKL (receptor activator of NF-κB ligand), thereby inhibiting osteoclastogenesis. We recently found that another RANKL binding peptide, W9, could accelerate bone formation by affecting RANKL signaling in osteoblasts. We herein demonstrate the effects of OP3-4 on bone formation and bone loss in a murine model of rheumatoid arthritis. METHODS: Twenty-four seven-week-old male DBA/1J mice were used to generate a murine model of collagen-induced arthritis (CIA). Then, vehicle or OP3-4 (9 mg/kg/day or 18 mg/kg/day) was subcutaneously infused using infusion pumps for three weeks beginning seven days after the second immunization. The arthritis score was assessed, and the mice were sacrificed on day 49. Thereafter, radiographic, histological and biochemical analyses were performed. RESULTS: The OP3-4 treatment did not significantly inhibit the CIA-induced arthritis, but limited bone loss. Micro-CT images and quantitative measurements of the bone mineral density revealed that 18 mg/kg/day OP3-4 prevented the CIA-induced bone loss at both articular and periarticular sites of tibiae. As expected, OP3-4 significantly reduced the CIA-induced serum CTX levels, a marker of bone resorption. Interestingly, the bone histomorphometric analyses using undecalcified sections showed that OP3-4 prevented the CIA-induced reduction of bone formation-related parameters at the periarticular sites. CONCLUSION: The peptide that mimicked OPG prevented inflammatory bone loss by inhibiting bone resorption and stimulating bone formation. It could therefore be a useful template for the development of small molecule drugs for inflammatory bone loss.


Sujet(s)
Arthrite expérimentale/traitement médicamenteux , Résorption osseuse/prévention et contrôle , Cartilage articulaire/effets des médicaments et des substances chimiques , Oligopeptides/pharmacologie , Ligand de RANK/métabolisme , Séquence d'acides aminés , Animaux , Arthrite expérimentale/métabolisme , Arthrite expérimentale/anatomopathologie , Polyarthrite rhumatoïde/traitement médicamenteux , Polyarthrite rhumatoïde/métabolisme , Polyarthrite rhumatoïde/anatomopathologie , Densité osseuse/effets des médicaments et des substances chimiques , Résorption osseuse/métabolisme , Cartilage articulaire/métabolisme , Cartilage articulaire/anatomopathologie , Différenciation cellulaire/effets des médicaments et des substances chimiques , Cellules cultivées , Collagène de type I/sang , Test ELISA , Perfusions sous-cutanées , Mâle , Souris de lignée DBA , Oligopeptides/administration et posologie , Oligopeptides/métabolisme , Ostéoblastes/effets des médicaments et des substances chimiques , Ostéoblastes/métabolisme , Ostéoclastes/effets des médicaments et des substances chimiques , Ostéoclastes/métabolisme , Ostéogenèse/effets des médicaments et des substances chimiques , Ostéoprotégérine/administration et posologie , Ostéoprotégérine/métabolisme , Ostéoprotégérine/pharmacologie , Peptides/sang , Liaison aux protéines , Tibia/effets des médicaments et des substances chimiques , Tibia/métabolisme , Tibia/anatomopathologie , Microtomographie aux rayons X
8.
Oncotarget ; 5(23): 12317-30, 2014 Dec 15.
Article de Anglais | MEDLINE | ID: mdl-25373602

RÉSUMÉ

Oral squamous cell carcinoma (OSCC) cells display significantly augmented nuclear factor-κB (NF-κB) activity, and inhibiting this activity suppresses malignant tumor characteristics. Thus, we evaluated the effect of IMD-0560, a novel inhibitor of IκB kinase (IKK) ß that is under assessment in a clinical trial of rheumatoid arthritis, on bone invasion by the mouse OSCC cell line SCCVII. We examined the inhibitory effects of IMD-0560 on NF-κB activity and tumor invasion using human OSCC cell lines and SCCVII cells in vitro. Using a mouse model of jaw bone invasion by SCCVII cells, we assessed the inhibitory effect of IMD-0560 on jaw bone invasion, tumor growth, and matrix degradation in vivo. IMD-0560 suppressed the nuclear translocation of NF-κB and the degradation of IκBα in OSCC cells. IMD-0560 also inhibited invasion by suppressing matrix metalloproteinase-9 (MMP-9) production in OSCC cells. IMD-0560 protected against zygoma and mandible destruction by SCCVII cells, reduced the number of osteoclasts by inhibiting receptor activator of NF-κB ligand (RANKL) expression in osteoblastic cells and SCCVII cells, increased SCCVII cell death and suppressed cell proliferation and MMP-9 production in SCCVII cells. Based on these results, IMD-0560 may represent a new therapeutic agent for bone invasion by OSCC cells.


Sujet(s)
Benzamides/pharmacologie , Tumeurs osseuses/prévention et contrôle , Tumeurs osseuses/secondaire , Carcinome épidermoïde/secondaire , Antienzymes/pharmacologie , Tumeurs de la bouche/anatomopathologie , Métastase tumorale/prévention et contrôle , Animaux , Technique de Western , Lignée cellulaire tumorale , Modèles animaux de maladie humaine , Humains , Protéines I-kappa B/antagonistes et inhibiteurs , Mâle , Souris , Microscopie de fluorescence , Invasion tumorale/prévention et contrôle , Réaction de polymérisation en chaine en temps réel
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