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On March 16, 2020, the Director-General of the World Health Organization said: "We have a simple message to all countries-test, test, test." This seems like sound advice, but what if limiting the number of tests has a positive effect on infection control? Although this may rarely be the case, the possibility raises an important ethical question that is closely related to a central tension between deontological and consequentialist approaches to ethics. In this paper, we first argue that early during the COVID-19 pandemic, Japan offers an interesting case because it experienced few deaths due to COVID while the number of tests was limited, suggesting that there may be cases in which low testing contributes to infection control indeed. After that, we examine deontological constraints on such a "low-testing" policy, focusing on issues related to a supposed "right to know," which is a central issue in medical ethics in general.
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COVID-19 , Humanos , COVID-19/epidemiología , Pandemias , Teoría Ética , Ética Médica , JapónRESUMEN
This study is a pilot literature review that compares the interest of neuroethicists and neuroscientists. It aims to determine whether there is a significant gap between the neuroethical issues addressed in philosophical neuroethics journals and neuroscience journals. We retrieved 614 articles from two specialist neuroethics journals (Neuroethics and AJOB Neuroscience) and 82 neuroethics-focused articles from three specialist neuroscience journals (Neuron, Nature Neuroscience, and Nature Reviews Neuroscience). We classified these articles in light of the neuroethical issue in question before we compared the neuroethical issues addressed in philosophical neuroethics with those addressed by neuroscientists. A notable result is a parallelism between them as a general tendency. Neuroscientific articles cover most neuroethical issues discussed by philosophical ethicists and vice versa. Subsequently, there are notable discrepancies between the two bodies of neuroethics literature. For instance, theoretical questions, such as the ethics of moral enhancement and the philosophical implications of neuroscientific findings on our conception of personhood, are more intensely discussed in philosophical-neuroethical articles. Conversely, neuroscientific articles tend to emphasize practical questions, such as how to successfully integrate ethical perspectives into scientific research projects and justifiable practices of animal-involving neuroscientific research. These observations will help us settle the common starting point of the attempt at "ethics integration" in emerging neuroscience, contributing to better governance design and neuroethical practice.
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OBJECTIVE: This study aimed to determine the regulatory mechanism of bone marrow-derived mesenchymal stem cell (BM-MSC) differentiation mediated by humoral factors derived from human periodontal ligament (HPL) cells and human gingival fibroblasts (HGFs). We analyzed histone deacetylase (HDAC) expression and activity involved in BM-MSC differentiation and determined their regulatory effects in co-cultures of BM-MSCs with HPL cells or HGFs. BACKGROUND: BM-MSCs can differentiate into various cell types and can, thus, be used in periodontal regenerative therapy. However, the mechanism underlying their differentiation remains unclear. Transplanted BM-MSCs are affected by periodontal cells via direct contact or secretion of humoral factors. Therefore, their activity is regulated by humoral factors derived from HPL cells or HGFs. METHODS: BM-MSCs were indirectly co-cultured with HPL cells or HGFs under osteogenic or growth conditions and then analyzed for osteogenesis, HDAC1 and HDAC2 expression and activity, and histone H3 acetylation. BM-MSCs were treated with trichostatin A, or their HDAC1 or HDAC2 expression was silenced or overexpressed during osteogenesis. Subsequently, they were evaluated for osteogenesis or the effects of HDAC activity. RESULTS: BM-MSCs co-cultured with HPL cells or HGFs showed suppressed osteogenesis, HDAC1 and HDAC2 expression, and HDAC phosphorylation; however, histone H3 acetylation was enhanced. Trichostatin A treatment remarkably suppressed osteogenesis, decreasing HDAC expression and enhancing histone H3 acetylation. HDAC1 and HDAC2 silencing negatively regulated osteogenesis in BM-MSCs to the same extent as that achieved by indirect co-culture with HPL cells or HGFs. Conversely, their overexpression positively regulated osteogenesis in BM-MSCs. CONCLUSION: The suppressive effects of HPL cells and HGFs on BM-MSC osteogenesis were regulated by HDAC expression and histone H3 acetylation to a greater extent than that mediated by HDAC activity. Therefore, regulation of HDAC expression has prospects in clinical applications for effective periodontal regeneration, mainly, bone regeneration.
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Células Madre Mesenquimatosas , Osteogénesis , Humanos , Médula Ósea/metabolismo , Diferenciación Celular , Células Cultivadas , Técnicas de Cocultivo , Fibroblastos/metabolismo , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/farmacología , Histonas/metabolismo , Ligamento PeriodontalRESUMEN
BACKGROUND: The periodontal ligament contains periodontal ligament cells, which is a heterogeneous cell population, and includes progenitor cells that can differentiate into osteoblasts/cementoblasts. Mesenchymal stem cells (MSCs) can differentiate into various cells and can be used for periodontal regenerative therapy. Therefore, transplanted MSCs can be affected by humoral factors from periodontal ligament cells via the transcription factors or microRNAs (miRNAs) of MSCs. In addition, periostin (POSTN) is secreted from HPL cells and can regulate periodontal regeneration and homeostasis. To clarify the regulatory mechanism of humoral factors from periodontal ligament cells, we attempted to identify key genes, specifically microRNAs, involved in this process. METHODS: Human MSCs (hMSCs) were indirectly co-cultured with human periodontal ligament cells (HPL cells) and then evaluated for osteogenesis, undifferentiated MSCs markers, and miRNA profiles. Furthermore, hMSCs were indirectly co-cultured with HPL cells in the presence of anti-POSTN monoclonal antibody (anti-POSTN Ab) to block the effect of POSTN from HPL cells, and then evaluated for osteogenesis or undifferentiated MSC markers. Moreover, hMSCs showed alterations in miRNA expression or cultured with HPL were challenged with POSTN during osteogenesis, and cells were evaluated for osteogenesis or undifferentiated MSC markers. RESULTS: hMSCs co-cultured with HPL cells showed suppressed osteogenesis and characteristic expression of SOX11, an undifferentiated MSC marker, as well as miR-299-5p. Overexpression of miR-299-5p regulated osteogenesis and SOX11 expression as observed with indirect co-culture with HPL cells. Furthermore, MSCs co-cultured with HPL cells were recovered from the suppression of osteogenesis and SOX11 mRNA expression by anti-POSTN Ab. However, POSTN induced miR-299-5p and SOX11 expression, and enhanced osteogenesis. CONCLUSION: Humoral factors from HPL cells suppressed osteogenesis in hMSCs. The suppressive effect was mediated by miR-299-5p and SOX11 in hMSCs.
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Moléculas de Adhesión Celular/genética , Diferenciación Celular/genética , MicroARNs/genética , Ligamento Periodontal/crecimiento & desarrollo , Factores de Transcripción SOXC/genética , Linaje de la Célula/genética , Técnicas de Cocultivo , Cemento Dental/citología , Cemento Dental/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Osteoblastos/citología , Osteoblastos/metabolismo , Osteogénesis/genética , Ligamento Periodontal/citología , Ligamento Periodontal/metabolismo , Endodoncia Regenerativa/tendenciasRESUMEN
INTRODUCTION: Mesenchymal stem cells (MSCs) can differentiate into various types of cells and can thus be used for periodontal regenerative therapy. However, the mechanism of differentiation is still unclear. Transplanted MSCs are, via their transcription factors or microRNAs (miRNAs), affected by periodontal cells with direct contact or secretion of humoral factors. Therefore, transplanted MSCs are regulated by humoral factors from human gingival fibroblasts (HGF). Moreover, insulin-like growth factor (IGF)-1 is secreted from HGF and regulates periodontal regeneration. To clarify the regulatory mechanism for MSC differentiation by humoral factors from HGF, we identified key genes, specifically miRNAs, involved in this process, and determined their function in MSC differentiation. MATERIALS AND METHODS: Mesenchymal stem cells were indirectly co-cultured with HGF in osteogenic or growth conditions and then evaluated for osteogenesis, undifferentiated MSC markers, and characteristic miRNAs. MSCs had their miRNA expression levels adjusted or were challenged with IGF-1 during osteogenesis, or both of which were performed, and then, MSCs were evaluated for osteogenesis or undifferentiated MSC markers. RESULTS: Mesenchymal stem cells co-cultured with HGF showed suppression of osteogenesis and characteristic expression of ETV1, an undifferentiated MSC marker, as well as miR-101-3p. Over-expression of miR-101-3p regulated osteogenesis and ETV1 expression as well as indirect co-culture with HGF. IGF-1 induced miR-101-3p and ETV1 expression. However, IGF-1 did not suppress osteogenesis. CONCLUSIONS: Humoral factors from HGF suppressed osteogenesis in MSCs. The effect was regulated by miRNAs and undifferentiated MSC markers. miR-101-3p and ETV1 were the key factors and were regulated by IGF-1.
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Fibroblastos/metabolismo , Encía/citología , Células Madre Mesenquimatosas/metabolismo , MicroARNs/metabolismo , Osteogénesis/genética , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Células Cultivadas , Fibroblastos/efectos de los fármacos , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , MicroARNs/genética , Osteogénesis/efectos de los fármacos , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVE: SH3 domain-binding protein 2 (SH3BP2) is a signaling adapter protein that regulates the immune and skeletal systems. The present study was undertaken to investigate the role of SH3BP2 in arthritis using 2 experimental mouse models, i.e., human tumor necrosis factor α-transgenic (hTNF-Tg) mice and mice with collagen-induced arthritis (CIA). METHODS: First, Sh3bp2(-/-) and wild-type (Sh3bp2(+/+) ) mice were crossed with hTNF-Tg mice. Inflammation and bone loss were examined by clinical inspection and histologic and micro-computed tomography analysis, and osteoclastogenesis was evaluated using primary bone marrow-derived macrophage colony-stimulating factor-dependent macrophages (BMMs). Second, CIA was induced in Sh3bp2(-/-) and Sh3bp2(+/+) mice, and the incidence and severity of arthritis were evaluated. Anti-mouse type II collagen (CII) antibody levels were measured by enzyme-linked immunosorbent assay, and lymph node cell responses to CII were determined. RESULTS: SH3BP2 deficiency did not alter the severity of joint swelling but did suppress bone erosion in the hTNF-Tg mouse model. Bone loss at the talus and tibia was prevented in Sh3bp2(-/-) /hTNF-Tg mice compared to Sh3bp2(+/+) /hTNF-Tg mice. RANKL- and TNFα-induced osteoclastogenesis was suppressed in Sh3bp2(-/-) mouse BMM cultures. NF-ATc1 nuclear localization in response to TNFα was decreased in Sh3bp2(-/-) mouse BMMs compared to Sh3bp2(+/+) mouse BMMs. In the CIA model, SH3BP2 deficiency suppressed the incidence of arthritis and this was associated with decreased anti-CII antibody production, while antigen-specific T cell responses in lymph nodes were not significantly different between Sh3bp2(+/+) and Sh3bp2(-/-) mice. CONCLUSION: SH3BP2 deficiency prevents loss of bone via impaired osteoclastogenesis in the hTNF-Tg mouse model and suppresses the induction of arthritis via decreased autoantibody production in the CIA model. Therefore, SH3BP2 could potentially be a therapeutic target in rheumatoid arthritis.
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Proteínas Adaptadoras Transductoras de Señales/fisiología , Artritis Experimental/prevención & control , Resorción Ósea/prevención & control , Factor de Necrosis Tumoral alfa/genética , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Autoanticuerpos/sangre , Western Blotting , Resorción Ósea/metabolismo , Resorción Ósea/patología , Colágeno Tipo II/inmunología , Ensayo de Inmunoadsorción Enzimática , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factores de Transcripción NFATC/metabolismo , Osteoclastos/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Microtomografía por Rayos XRESUMEN
Cherubism (OMIM#118400) is a genetic disorder in children characterized by excessive jawbone destruction with proliferation of fibro-osseous lesions containing a large number of osteoclasts. Mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for cherubism. Analysis of the knock-in (KI) mouse model of cherubism showed that homozygous cherubism mice (Sh3bp2(KI/KI)) spontaneously develop systemic autoinflammation and inflammatory bone loss and that cherubism is a TNF-α-dependent hematopoietic disorder. In this study, we investigated whether bone marrow transplantation (BMT) is effective for the treatment of inflammation and bone loss in Sh3bp2(KI/KI) mice. Bone marrow (BM) cells from wild-type (Sh3bp2(+/+)) mice were transplanted to 6-week-old Sh3bp2(KI/KI) mice with developing inflammation and to 10-week-old Sh3bp2(KI/KI) mice with established inflammation. Six-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells exhibited improved body weight loss, facial swelling, and survival rate. Inflammatory lesions in the liver and lung as well as bone loss in calvaria and mandibula were ameliorated at 10weeks after BMT compared to Sh3bp2(KI/KI) mice transplanted with Sh3bp2(KI/KI) BM cells. Elevation of serum TNF-α levels was not detected after BMT. BMT was effective for up to 20weeks in 6-week-old Sh3bp2(KI/KI) mice transplanted with Sh3bp2(+/+) BM cells. BMT also ameliorated the inflammation and bone loss in 10-week-old Sh3bp2(KI/KI) mice. Thus our study demonstrates that BMT improves the inflammation and bone loss in cherubism mice. BMT may be effective for the treatment of cherubism patients.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Trasplante de Médula Ósea , Resorción Ósea/patología , Querubismo/patología , Técnicas de Sustitución del Gen , Inflamación/patología , Inflamación/terapia , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Animales , Peso Corporal , Células de la Médula Ósea/metabolismo , Femenino , Inflamación/sangre , Hígado/patología , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Cherubism is caused by mutations in SH3BP2. Studies of cherubism mice showed that tumor necrosis factor α (TNF-α)-dependent autoinflammation is a major cause of the disorder but failed to explain why human cherubism lesions are restricted to jaws and regress after puberty. We demonstrate that the inflammation in cherubism mice is MYD88 dependent and is rescued in the absence of TLR2 and TLR4. However, germ-free cherubism mice also develop inflammation. Mutant macrophages are hyperresponsive to PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) that activate Toll-like receptors (TLRs), resulting in TNF-α overproduction. Phosphorylation of SH3BP2 at Y183 is critical for the TNF-α production. Finally, SYK depletion in macrophages prevents the inflammation. These data suggest that the presence of a large amount of TLR ligands, presumably oral bacteria and DAMPs during jawbone remodeling, may cause the jaw-specific development of human cherubism lesions. Reduced levels of DAMPs after stabilization of jaw remodeling may contribute to the age-dependent regression.
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Proteínas Adaptadoras Transductoras de Señales/genética , Querubismo/etiología , Inflamación , Factor 88 de Diferenciación Mieloide/metabolismo , Transducción de Señal , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Maxilares/diagnóstico por imagen , Hígado/patología , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/deficiencia , Factor 88 de Diferenciación Mieloide/genética , FN-kappa B/metabolismo , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , ARN Mensajero/metabolismo , Radiografía , Quinasa Syk , Receptor Toll-Like 2/química , Receptor Toll-Like 4/química , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: SH3BP2 is a signaling adapter protein which regulates immune and skeletal systems. Gain-of-function mutations in SH3BP2 cause cherubism, characterized by jawbone destruction. This study was aimed to examine the role of SH3BP2 in inflammatory bone loss using a collagen-induced arthritis (CIA) model. METHODS: CIA was induced in wild-type (Sh3bp2(+/+)) and heterozygous P416R SH3BP2 cherubism mutant knock-in (Sh3bp2(KI/+)) mice, an SH3BP2 gain-of-function model. Severity of the arthritis was determined by assessing the paw swelling and histological analyses of the joints. Micro-CT analysis was used to determine the levels of bone loss. Inflammation and osteoclastogenesis in the joints were evaluated by quantitating the gene expression of inflammatory cytokines and osteoclast markers. Furthermore, involvement of the T- and B-cell responses was determined by draining lymph node cell culture and measurement of the serum anti-mouse type II collagen antibody levels, respectively. Finally, roles of the SH3BP2 mutation in macrophage activation and osteoclastogenesis were determined by evaluating the TNF-α production levels and osteoclast formation in bone marrow-derived M-CSF-dependent macrophage (BMM) cultures. RESULTS: Sh3bp2(KI/+) mice exhibited more severe inflammation and bone loss, accompanying an increased number of osteoclasts. The mRNA levels for TNF-α and osteoclast marker genes were higher in the joints of Sh3bp2(KI/+) mice. Lymph node cell culture showed that lymphocyte proliferation and IFN-γ and IL-17 production were comparable between Sh3bp2(+/+) and Sh3bp2(KI/+) cells. Serum anti-type II collagen antibody levels were comparable between Sh3bp2(+/+) and Sh3bp2(KI/+) mice. In vitro experiments showed that TNF-α production in Sh3bp2(KI/+) BMMs is elevated compared with Sh3bp2(+/+) BMMs and that RANKL-induced osteoclastogenesis is enhanced in Sh3bp2(KI/+) BMMs associated with increased NFATc1 nuclear localization. CONCLUSION: Gain-of-function of SH3BP2 augments inflammation and bone loss in the CIA model through increased macrophage activation and osteoclast formation. Therefore, modulation of the SH3BP2 expression may have therapeutic potential for the treatment of rheumatoid arthritis.
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Proteínas Adaptadoras Transductoras de Señales/genética , Artritis Experimental/genética , Artritis Experimental/patología , Resorción Ósea/genética , Mutación , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Sustitución de Aminoácidos , Animales , Artritis Experimental/diagnóstico , Artritis Experimental/inmunología , Cartílago/patología , Proliferación Celular , Citocinas/metabolismo , Expresión Génica , Tejido Linfoide/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Transgénicos , Factores de Transcripción NFATC/metabolismo , Osteoclastos/metabolismo , Ligando RANK/metabolismo , Ligando RANK/farmacología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Microtomografía por Rayos XRESUMEN
Cherubism is a genetic disorder of the craniofacial skeleton caused by gain-of-function mutations in the signaling adaptor protein, SH3-domain binding protein 2 (SH3BP2). In a knock-in mouse model for cherubism, we previously demonstrated that homozygous mutant mice develop T/B cell-independent systemic macrophage inflammation leading to bone erosion and joint destruction. Homozygous mice develop multiostotic bone lesions whereas cherubism lesions in humans are limited to jawbones. We identified a critical role of tumor necrosis factor α (TNF-α) in the development of autoinflammation by creating homozygous TNF-α-deficient cherubism mutants, in which systemic inflammation and bone destruction were rescued. In this study, we examined whether postnatal administration of an anti-TNF-α antagonist can prevent or ameliorate the disease progression in cherubism mice. Neonatal homozygous mutants, in which active inflammation has not yet developed, were treated with a high dose of etanercept (25 mg/kg, twice/week) for 7 weeks. Etanercept-treated neonatal mice showed strong rescue of facial swelling and bone loss in jaws and calvariae. Destruction of joints was fully rescued in the high-dose group. Moreover, the high-dose treatment group showed a significant decrease in lung and liver inflammatory lesions. However, inflammation and bone loss, which were successfully treated by etanercept administration, recurred after etanercept discontinuation. No significant effect was observed in low-dose-treated (0.5 mg/kg, twice/week) and vehicle-treated groups. In contrast, when 10-week-old cherubism mice with fully active inflammation were treated with etanercept for 7 weeks, even the high-dose administration did not decrease bone loss or lung or liver inflammation. Taken together, the results suggest that anti-TNF-α therapy may be effective in young cherubism patients, if treated before the inflammatory phase or bone resorption occurs. Therefore, early genetic diagnosis and early treatment with anti-TNF-α antagonists may be able to prevent or ameliorate cherubism, especially in patients with a mutation in SH3BP2.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Enfermedades Óseas Metabólicas/metabolismo , Querubismo/tratamiento farmacológico , Querubismo/metabolismo , Inmunoglobulina G/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Enfermedades Óseas Metabólicas/genética , Enfermedades Óseas Metabólicas/patología , Querubismo/genética , Querubismo/patología , Etanercept , Técnicas de Sustitución del Gen , Humanos , Inflamación , Ratones , Ratones Mutantes , Receptores del Factor de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Cherubism (OMIM# 118400) is a genetic disorder with excessive jawbone resorption caused by mutations in SH3 domain binding protein 2 (SH3BP2), a signaling adaptor protein. Studies on the mouse model for cherubism carrying a P416R knock-in (KI) mutation have revealed that mutant SH3BP2 enhances tumor necrosis factor (TNF)-α production and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation in myeloid cells. TNF-α is expressed in human cherubism lesions, which contain a large number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, and TNF-α plays a critical role in inflammatory bone destruction in homozygous cherubism mice (Sh3bp2(KI/KI) ). The data suggest a pathophysiological relationship between mutant SH3BP2 and TNF-α-mediated bone loss by osteoclasts. Therefore, we investigated whether P416R mutant SH3BP2 is involved in TNF-α-mediated osteoclast formation and bone loss. Here, we show that bone marrow-derived M-CSF-dependent macrophages (BMMs) from the heterozygous cherubism mutant (Sh3bp2(KI/+) ) mice are highly responsive to TNF-α and can differentiate into osteoclasts independently of RANKL in vitro by a mechanism that involves spleen tyrosine kinase (SYK) and phospholipase Cγ2 (PLCγ2) phosphorylation, leading to increased nuclear translocation of NFATc1. The heterozygous cherubism mutation exacerbates bone loss with increased osteoclast formation in a mouse calvarial TNF-α injection model as well as in a human TNF-α transgenic mouse model (hTNFtg). SH3BP2 knockdown in RAW264.7 cells results in decreased TRAP-positive multinucleated cell formation. These findings suggest that the SH3BP2 cherubism mutation can cause jawbone destruction by promoting osteoclast formation in response to TNF-α expressed in cherubism lesions and that SH3BP2 is a key regulator for TNF-α-induced osteoclastogenesis. Inhibition of SH3BP2 expression in osteoclast progenitors could be a potential strategy for the treatment of bone loss in cherubism as well as in other inflammatory bone disorders.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Resorción Ósea/metabolismo , Querubismo/metabolismo , Mutación , Factores de Transcripción NFATC/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Resorción Ósea/genética , Resorción Ósea/patología , Querubismo/genética , Querubismo/patología , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Transgénicos , Factores de Transcripción NFATC/genética , Osteoclastos/metabolismo , Osteoclastos/patología , Fosfolipasa C gamma/genética , Fosfolipasa C gamma/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Ligando RANK/genética , Ligando RANK/metabolismo , Quinasa Syk , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
BACKGROUND: Beneficial effects of hyperbaric oxygen on ischemic vascular diseases have been noted. Acceleration of wound healing with basic fibroblast growth factor has also been reported. The authors employed combination therapy of hyperbaric oxygen and basic fibroblast growth factor in patients with skin ulcer in legs refractory to conventional therapy. METHODS: Three men and four women were simultaneously treated with hyperbaric oxygen at 2 absolute atmospheric pressures for 90 minutes daily and spray treatment of basic fibroblast growth factor to the ulcer bed daily for an average of 2.6 months. Biopsy specimens obtained from ulcer tissues were divided into two pieces, one for histologic examination and the other for measuring fibrous protein. RESULTS: Ulcers were completely cured in five of seven patients. Two patients showed shrinkage of ulcer size. This combined therapy induced proliferation of connective tissue of the ulcer tissues, especially collagen and noncollagenous protein. CONCLUSIONS: Combined treatment with hyperbaric oxygen and basic fibroblast growth factor may be useful in patients with intractable skin ulcers in legs, and the shrinkage effect of this therapy is probably related to the proliferation of granulation tissues of the ulcer lesion.