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1.
Br J Radiol ; 94(1117): 20200981, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33125270

RESUMEN

OBJECTIVES: To predict the progression of femoral head collapse in Association Research Circulation Osseous (ARCO) Stage 2-3A osteonecrosis based on the initial bone resorption lesion. METHODS: A retrospective analysis of the location, attenuation, and maximum area in coronal position (MAC) of the initial bone resorption lesion in ARCO Stage 2 and 3A was conducted in 85 cases of osteonecrosis of the femoral head (ONFH). The cases were divided into rapid and slow progression groups according to whether femoral head collapse at follow-up was greater than 2 mm. The characteristics of the bone resorption lesion between the two groups were compared by analysis of variance. Receiver operating characteristic curve was used to analyze the MAC, regions of A2, and C1 of bone resorption lesion in predicting collapse progression. RESULTS: The MAC of initial bone resorption lesion in rapid progression group (117.8 ± 72.1 mm2) was significantly larger than slow (53.1 ± 39.5 mm2) (p < 0.001). Regions of A2 and C1 involved were significantly higher in rapid than slow progression group. The area under the receiver operating characteristic curve of MAC, regions of A2 and C1 of bone resorption lesion to predict collapse progression were 0.81, 0.72 and 0.62 respectively. A threshold MAC of 49 mm2 had sensitivity of 86.1% and specificity of 61.9% to predict collapse progression. CONCLUSIONS: The MAC of initial bone resorption lesion in ARCO Stage 2-3A ONFH can predict the progression of femoral head collapse. If it is greater than 49 mm2 and located in regions of A2 and C1, the possibility of rapid progression is high, active monitoring and intervention should be recommended. ADVANCES IN KNOWLEDGE: This study is the first to find that the maximum area in coronal position of initial bone resorption lesion in ARCO Stage 2 or 3A can predict progression of the femoral head collapse with a threshold of 49 mm2. If the maximum area is larger than 49 mm2 and located in the anterolateral or lateral column of the femoral head, the possibility of rapid collapse progression is high, therefore, monitoring should be strengthened and active intervention should be considered.


Asunto(s)
Resorción Ósea/diagnóstico por imagen , Resorción Ósea/patología , Necrosis de la Cabeza Femoral/diagnóstico por imagen , Necrosis de la Cabeza Femoral/patología , Tomografía Computarizada por Rayos X/métodos , Adulto , Progresión de la Enfermedad , Femenino , Cabeza Femoral/diagnóstico por imagen , Cabeza Femoral/patología , Estudios de Seguimiento , Humanos , Masculino , Estudios Retrospectivos , Índice de Severidad de la Enfermedad
2.
Life Sci ; 266: 118938, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33347878

RESUMEN

Oxidative stress is a promoting factor in the pathologic process of glucocorticoid - induced osteoporosis (GIO), while the mechanism is still unclear. Thioredoxin-interacting protein (TXNIP) is a vital protein responsible for regulation of cellular reactive oxygen species (ROS) generation elicited by mitochondrial oxidative stress, and which may activate oxidative phosphorylation under the pathogenic status. In this research, the results showed that signaling pathway associated with the mitochondrial oxidative phosphorylation (MOP) down-regulated under conditions of TXNIP siRNA in MG63 cells. Furthermore, the evidence revealed that the expression level of TXNIP in serum and bone was elevated in a rat of GIO. Moreover, the differential proteins (Ndufs3, SDHD, Cyt B, COX IV, and ATP B) related to MOP pathway were identified to down-regulate in the proteomics of bone tissues by using isobaric Tags for Relative and Absolute Quantification (iTRAQ) method in TXNIP knockout mice treated with glucocorticoid, and the proteins were also verified by simple western blot. Taken together, the present findings highlights that TXNIP involves in triggering the process of bone loss via up-regulation of the MOP pathway, resulting to GIO, while TXNIP knockout can prevent the pathogenesis of GIO to some extent.


Asunto(s)
Resorción Ósea/etiología , Proteínas Portadoras/fisiología , Proteínas de Ciclo Celular/metabolismo , Glucocorticoides/toxicidad , Mitocondrias/patología , Osteoporosis/patología , Fosforilación Oxidativa , Tiorredoxinas/fisiología , Animales , Resorción Ósea/metabolismo , Resorción Ósea/patología , Proteínas de Ciclo Celular/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Osteoporosis/inducido químicamente , Osteoporosis/metabolismo , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal
3.
PLoS One ; 15(7): e0236891, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32730332

RESUMEN

Signal Transducer and Activator of Transcription 3 (STAT3) has recently been shown to be involved in bone development and has been implicated in bone diseases, such as Job's Syndrome. Bone growth and changes have been known for many years to differ between sexes with male bones tending to have higher bone mass than female bones and older females tending to lose bone mass at faster rates than older males. Previous studies using conditional knock mice with Stat3 specifically deleted from the osteoblasts showed both sexes exhibited decreased bone mineral density (BMD) and strength. Using the Cre-Lox system with Cathepsin K promotor driving Cre to target the deletion of the Stat3 gene in mature osteoclasts (STAT3-cKO mice), we observed that 8-week old STAT3-cKO female femurs exhibited significantly lower BMD and bone mineral content (BMC) compared to littermate control (CN) females. There were no differences in BMD and BMC observed between male knock-out and male CN femurs. However, micro-computed tomography (µCT) analysis showed that both male and female STAT3-cKO mice had significant decreases in bone volume/tissue volume (BV/TV). Bone histomorphometry analysis of the distal femur, further revealed a decrease in bone formation rate and mineralizing surface/bone surface (MS/BS) with a significant decrease in osteoclast surface in female, but not male, STAT3-cKO mice. Profiling gene expression in an osteoclastic cell line with a knockdown of STAT3 showed an upregulation of a number of genes that are directly regulated by estrogen receptors. These data collectively suggest that regulation of STAT3 differs in male and female osteoclasts and that inactivation of STAT3 in osteoclasts affects bone turnover more in females than males, demonstrating the complicated nature of STAT3 signaling pathways in osteoclastogenesis. Drugs targeting the STAT3 pathway may be used for treatment of diseases such as Job's Syndrome and osteoporosis.


Asunto(s)
Resorción Ósea/patología , Huesos/patología , Osteoclastos/patología , Osteogénesis , Osteoporosis/patología , Factor de Transcripción STAT3/fisiología , Animales , Densidad Ósea , Remodelación Ósea , Resorción Ósea/etiología , Huesos/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoclastos/metabolismo , Osteoporosis/etiología
4.
Proc Natl Acad Sci U S A ; 117(29): 17187-17194, 2020 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-32636266

RESUMEN

Osteoprotegerin (OPG), a secreted decoy receptor for receptor activator of nuclear factor B ligand (RANKL), plays an essential role in regulating bone resorption. While much is known about the function of the N-terminal domains of OPG, which is responsible for binding to RANKL, the exact biological functions of the three C-terminal domains of OPG remain uncertain. We have previously shown that one likely function of the C-terminal domains of OPG is to bind cell surface heparan sulfate (HS), but the in vivo evidence was lacking. To investigate the biological significance of OPG-HS interaction in bone remodeling, we created OPG knock-in mice (opg AAA ). The mutated OPG is incapable of binding to HS but binds RANKL normally. Surprisingly, opg AAA/AAA mice displayed a severe osteoporotic phenotype that is very similar to opg-null mice, suggesting that the antiresorption activity of OPG requires HS. Mechanistically, we propose that the HS immobilizes secreted OPG at the surface of osteoblasts lineage cells, which facilitates binding of OPG to membrane-anchored RANKL. To further support this model, we altered the structure of osteoblast HS genetically to make it incapable of binding to OPG. Interestingly, osteocalcin-Cre;Hs2st f/f mice also displayed osteoporotic phenotype with similar severity to opg AAA/AAA mice. Combined, our data provide strong genetic evidence that OPG-HS interaction is indispensable for normal bone homeostasis.


Asunto(s)
Conservadores de la Densidad Ósea/metabolismo , Conservadores de la Densidad Ósea/farmacología , Heparitina Sulfato/metabolismo , Osteoprotegerina/metabolismo , Osteoprotegerina/farmacología , Animales , Sitios de Unión , Resorción Ósea/metabolismo , Resorción Ósea/patología , Huesos/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogénesis/genética , Osteogénesis/fisiología , Osteoporosis/genética , Osteoporosis/metabolismo , Osteoporosis/patología , Osteoprotegerina/genética , Ligando RANK/metabolismo , Transcriptoma
5.
Comput Methods Biomech Biomed Engin ; 23(13): 1005-1013, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32597215

RESUMEN

Implant body and threads direct the functional loads from implant to bones. Appropriate design of implant helps implant stability. Therefore, implant length, diameter, and thread depth, width, pitch, and inner angle are assessed to recognize their effects on von-Mises stress and micromotion of implant and bones. The FE model of mandible with a threaded dental implant is modeled then the central composite design is used to assess the effects of parameters. The optimization is conducted to find the optimum design; however, it reduced the Max von-Mises stress in implant-abutment, cancellous, and cortical bones by 10%, 35%, and 27%, respectively.


Asunto(s)
Resorción Ósea/patología , Implantes Dentales , Diseño de Prótesis Dental , Fenómenos Biomecánicos , Simulación por Computador , Análisis del Estrés Dental , Elasticidad , Análisis de Elementos Finitos , Humanos , Modelos Teóricos , Reproducibilidad de los Resultados , Programas Informáticos , Estrés Mecánico
6.
PLoS Biol ; 18(6): e3000731, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32479501

RESUMEN

The nuclear lamina protein lamin A/C is a key component of the nuclear envelope. Mutations in the lamin A/C gene (LMNA) are identified in patients with various types of laminopathy-containing diseases, which have features of accelerated aging and osteoporosis. However, the underlying mechanisms for laminopathy-associated osteoporosis remain largely unclear. Here, we provide evidence that loss of lamin A/C in skeletal muscles, but not osteoblast (OB)-lineage cells, results in not only muscle aging-like deficit but also trabecular bone loss, a feature of osteoporosis. The latter is due in large part to elevated bone resorption. Further cellular studies show an increase of osteoclast (OC) differentiation in cocultures of bone marrow macrophages/monocytes (BMMs) and OBs after treatment with the conditioned medium (CM) from lamin A/C-deficient muscle cells. Antibody array screening analysis of the CM proteins identifies interleukin (IL)-6, whose expression is markedly increased in lamin A/C-deficient muscles. Inhibition of IL-6 by its blocking antibody in BMM-OB cocultures diminishes the increase of osteoclastogenesis. Knockout (KO) of IL-6 in muscle lamin A/C-KO mice diminishes the deficits in trabecular bone mass but not muscle. Further mechanistic studies reveal an elevation of cellular senescence marked by senescence-associated beta-galactosidase (SA-ß-gal), p16Ink4a, and p53 in lamin A/C-deficient muscles and C2C12 muscle cells, and the p16Ink4a may induce senescence-associated secretory phenotype (SASP) and IL-6 expression. Taken together, these results suggest a critical role for skeletal muscle lamin A/C to prevent cellular senescence, IL-6 expression, hyperosteoclastogenesis, and trabecular bone loss, uncovering a pathological mechanism underlying the link between muscle aging/senescence and osteoporosis.


Asunto(s)
Envejecimiento/patología , Lamina Tipo A/deficiencia , Músculo Esquelético/patología , Osteoporosis/patología , Animales , Anticuerpos Bloqueadores/farmacología , Fenómenos Biomecánicos , Resorción Ósea/complicaciones , Resorción Ósea/patología , Hueso Esponjoso/efectos de los fármacos , Hueso Esponjoso/patología , Diferenciación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Interleucina-6/metabolismo , Ratones Noqueados , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Osteoclastos/patología , Osteogénesis/efectos de los fármacos , Osteoporosis/sangre , Fenotipo
7.
Biochem Biophys Res Commun ; 526(4): 1028-1035, 2020 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-32321638

RESUMEN

Osteoblast-induced bone formation and osteoclast-regulated bone resorption are the essential events contributing to bone homeostasis. It is critical to investigate the underlying molecular mechanisms. In this study, we explored the effects of receptor-interacting serine-threonine kinases (RIPKs) on osteoclastogenesis and bone loss in vitro and in vivo. We found that both RIPK1 and RIPK3 expression levels were highly up-regulated during osteoclastogenesis. Inhibiting RIPK1 and RIPK3 by their inhibitors Necrostatin-1 (Nec-1) and GSK-872, respectively, showed effective activities against osteoclast differentiation and bone resorption induced by receptor activator of nuclear factor-κB ligand (Rankl). Osteoclast-specific gene expression levels were also impeded by RIPK1/RIPK3 blockage in a time-dependent manner. Subsequently, we found that the pyrin domain-containing protein 3 (NLRP3) inflammasome stimulated by Rankl during osteoclastogenesis was greatly inhibited by Nec-1 and GSK-872. Additionally, reducing RIPK1/RIPK3 overtly reduced the activation of NF-κB (p65) and mitogen-activated protein kinases (MAPKs) signaling during Rankl-induced osteoclast formation. Notably, adenovirus-regulated NLRP3 over-expression significantly abrogated the inhibitory effects of Nec-1 and GSK-872 on NF-κB and MAPKs signaling pathways, as well as the osteoclastogenesis. Finally, the in vivo studies indicated that suppressing RIPK1/RIPK3 could effectively ameliorate ovariectomy (OVX)-induced bone loss in mice through repressing osteoclastogenesis, as proved by the clearly down-regulated number of osteoclasts via histological staining. In conclusion, our study elucidated that restraining RIPK1/RIPK3 could hinder osteoclastogenesis and attenuate bone loss through suppressing NLRP3-dependent NF-κB and MAPKs signaling pathways. Therefore, targeting RIPK1/RIPK3 signaling might be a potential therapeutic strategy to develop effective treatments against osteoclast-related bone lytic diseases.


Asunto(s)
Sistema de Señalización de MAP Quinasas , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Osteogénesis , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Animales , Benzotiazoles/farmacología , Resorción Ósea/metabolismo , Resorción Ósea/patología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Imidazoles/farmacología , Indoles/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Ovariectomía , Quinolinas/farmacología , Ligando RANK/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo
8.
Cient. dent. (Ed. impr.) ; 17(1): 35-40, ene.-abr. 2020. ilus
Artículo en Español | IBECS | ID: ibc-189747

RESUMEN

Los implantes dentales constituyen una alternativa predecible para la rehabilitación de los maxilares edéntulos, sin embargo, el éxito del tratamiento puede ver-se comprometido cuando existen graves atrofias maxilares. Para el tratamiento de estos casos complejos, se han desarrolla-do técnicas de regeneración ósea, entre las que destacan la regeneración ósea guiada y los injertos en bloque. Dentro de estos últimos, cabe destacar la técnica de Khoury. Se trata de un procedimiento indicado para regenerar defectos horizontales y verticales, mediante la obtención de finas láminas de hueso autógeno procedentes de la línea oblicua externa mandibular. Se presenta un caso clínico de un gran defecto mandibular reconstruido con la técnica de Khoury, secundario a un fracaso implantológico que además ocasionó patología nerviosa


Dental implants constitute a predictable alternative for the rehabilitation of edentulous jaws. However, the success of the treatment can be limited when severe atrophic alveolar ridges are present. For the treatment of these complex cases, several regeneration techniques have been developed, such as guided bone regeneration and block grafts. Within the last, it should be noted the Khoury technique. It is a procedure indicated for the regeneration of horizontal and vertical defects, through the obtention of autologous graft in form of thin plates, derived from mandibular external oblique line.A clinical case is presented, that consists in a great mandibular defect which was reconstructed by the Khoury technique. The defect was secondary to an implant failure, which was also related with nervous pathology


Asunto(s)
Humanos , Masculino , Anciano , Regeneración Ósea , Atrofia/cirugía , Hipoestesia/cirugía , Fracaso de la Restauración Dental , Maxilar/cirugía , Elevación del Piso del Seno Maxilar/métodos , Procedimientos Quirúrgicos Reconstructivos/métodos , Implantes Dentales , Resorción Ósea/patología , Boca Edéntula/cirugía
9.
Oxid Med Cell Longev ; 2020: 3721383, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32184915

RESUMEN

Intraplaque hemorrhage frequently occurs in atherosclerotic plaques resulting in cell-free hemoglobin, which is oxidized to ferryl hemoglobin (FHb) in the highly oxidative environment. Osteoclast-like cells (OLCs) derived from macrophages signify a counterbalance mechanism for calcium deposition in atherosclerosis. Our aim was to investigate whether oxidized hemoglobin alters osteoclast formation, thereby affecting calcium removal from mineralized atherosclerotic lesions. RANKL- (receptor activator of nuclear factor kappa-Β ligand-) induced osteoclastogenic differentiation and osteoclast activity of RAW264.7 cells were studied in response to oxidized hemoglobin via assessing bone resorption activity, expression of osteoclast-specific genes, and the activation of signalization pathways. OLCs in diseased human carotid arteries were assessed by immunohistochemistry. FHb, but not ferrohemoglobin, decreased bone resorption activity and inhibited osteoclast-specific gene expression (tartrate-resistant acid phosphatase, calcitonin receptor, and dendritic cell-specific transmembrane protein) induced by RANKL. In addition, FHb inhibited osteoclastogenic signaling pathways downstream of RANK (receptor activator of nuclear factor kappa-Β). It prevented the induction of TRAF6 (tumor necrosis factor (TNF) receptor-associated factor 6) and c-Fos, phosphorylation of p-38 and JNK (c-Jun N-terminal kinase), and nuclear translocation of NFκB (nuclear factor kappa-Β) and NFATc1 (nuclear factor of activated T-cells, cytoplasmic 1). These effects were independent of heme oxygenase-1 demonstrated by knocking down HO-1 gene in RAW264.7 cells and in mice. Importantly, FHb competed with RANK for RANKL binding suggesting possible mechanisms by which FHb impairs osteoclastic differentiation. In diseased human carotid arteries, OLCs were abundantly present in calcified plaques and colocalized with regions of calcium deposition, while the number of these cells were lower in hemorrhagic lesions exhibiting accumulation of FHb despite calcium deposition. We conclude that FHb inhibits RANKL-induced osteoclastic differentiation of macrophages and suggest that accumulation of FHb in a calcified area of atherosclerotic lesion with hemorrhage retards the formation of OLCs potentially impairing calcium resorption.


Asunto(s)
Diferenciación Celular , Hemoglobinas/farmacología , Hemorragia/patología , Macrófagos/patología , Osteoclastos/patología , Placa Aterosclerótica/patología , Animales , Resorción Ósea/patología , Calcinosis , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/patología , Diferenciación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Placa Aterosclerótica/genética , Unión Proteica/efectos de los fármacos , Ligando RANK/genética , Ligando RANK/metabolismo , Células RAW 264.7 , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Transducción de Señal/efectos de los fármacos
10.
Phytomedicine ; 69: 153195, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32200293

RESUMEN

BACKGROUND: Areca nut has anti-inflammatory, antiparasitic, antihypertensive, and antidepressant properties. The pathological hallmarks of inflammatory joint diseases are an increased number of osteoclasts and impaired differentiation of osteoblasts, which may disrupt the bone remodeling balance and eventually lead to bone loss. PURPOSE: The present study assessed the effects of arecoline, the main alkaloid found in areca nut, on osteoclast and osteoblast differentiation and function. METHOD: M-CSF/RANKL-stimulated murine bone marrow-derived macrophages (BMMs) were incubated with several concentrations of arecoline, and TRAP staining and pit formation were assessed to monitor osteoclast formation. Quantitative real-time RT-PCR and western blot analyses were used to analyze the expression of osteoclast-associated genes and signaling pathways. The effects of arecoline on bone were investigated in an in vivo mouse model of lipopolysaccharide (LPS)-induced trabecular bone loss after oral administration of arecoline. Alizarin red S staining and assays to measure ALP activity and the transcription level of osteoblast-related genes were used to evaluate the effects of arecoline on osteoblast differentiation and bone mineralization. RESULTS: In a dose-dependent manner, arecoline at concentrations of 50-100 µM reduced both the development of TRAP-positive multinucleated osteoclasts and the formation of resorption pits in M-CSF/RANKL-stimulated BMMs. In M-CSF/RANKL-stimulated BMMs, arecoline also suppressed the expression and translocation of c-Fos and NFATcl, and osteoclast differentiated-related genes via interference with the AKT, MAPK, and NF-kB activation pathways. Femur bone loss and microcomputed tomography parameters were recovered by oral administration of arecoline in the mouse LPS-induced bone loss model. Lastly, arecoline increased ALP activity, bone mineralization, and the expression of osteoblast differentiation-related genes, such as ALP and Runx2, in MC3T3-E1 cells. CONCLUSION: Our data suggest that arecoline may attenuate or prevent bone loss by suppressing osteoclastogenesis and promoting osteoblastogenesis. These findings provide evidence supporting arecoline's use as a potential therapeutic agent in bone-loss disorders and diseases.


Asunto(s)
Arecolina/farmacología , Resorción Ósea/tratamiento farmacológico , Osteoclastos/efectos de los fármacos , Animales , Resorción Ósea/metabolismo , Resorción Ósea/patología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Genes fos , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , Masculino , Ratones Endogámicos DBA , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Osteoblastos/efectos de los fármacos , Osteoblastos/fisiología , Osteoclastos/citología , Osteoclastos/fisiología , Osteogénesis/efectos de los fármacos , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Ligando RANK/metabolismo , Ligando RANK/farmacología , Microtomografía por Rayos X
11.
Int J Mol Sci ; 21(5)2020 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-32121289

RESUMEN

Osteoclast differentiation and function are crucial for maintaining bone homeostasis and preserving skeletal integrity. N6-methyladenosine (m6A) is an abundant mRNA modification that has recently been shown to be important in regulating cell lineage differentiation. Nevertheless, the effect of m6A on osteoclast differentiation remains unknown. In the present study, we observed that the m6A level and methyltransferase METTL3 expression increased during osteoclast differentiation. Mettl3 knockdown resulted in an increased size but a decreased bone-resorbing ability of osteoclasts. The expression of osteoclast-specific genes (Nfatc1, c-Fos, Ctsk, Acp5 and Dcstamp) was inhibited by Mettl3 depletion, while the expression of the cellular fusion-specific gene Atp6v0d2 was upregulated. Mechanistically, Mettl3 knockdown elevated the mRNA stability of Atp6v0d2 and the same result was obtained when the m6A-binding protein YTHDF2 was silenced. Moreover, the phosphorylation levels of key molecules in the MAPK, NF-κB and PI3K-AKT signaling pathways were reduced upon Mettl3 deficiency. Depletion of Mettl3 maintained the retention of Traf6 mRNA in the nucleus and reduced the protein levels of TRAF6. Taken together, our data suggest that METTL3 regulates osteoclast differentiation and function through different mechanisms involving Atp6v0d2 mRNA degradation mediated by YTHDF2 and Traf6 mRNA nuclear export. These findings elucidate the molecular basis of RNA epigenetic regulation in osteoclast development.


Asunto(s)
Adenosina/análogos & derivados , Diferenciación Celular , Núcleo Celular/metabolismo , Metiltransferasas/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Estabilidad del ARN/genética , Transporte Activo de Núcleo Celular , Adenosina/metabolismo , Animales , Resorción Ósea/patología , Proliferación Celular , Técnicas de Silenciamiento del Gen , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , FN-kappa B/metabolismo , Osteogénesis , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ligando RANK/metabolismo , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Transducción de Señal , Factor 6 Asociado a Receptor de TNF/metabolismo , ATPasas de Translocación de Protón Vacuolares/metabolismo
12.
Nat Commun ; 11(1): 1578, 2020 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-32221289

RESUMEN

PARP1 and PARP2 dual inhibitors, such as olaparib, have been recently FDA approved for the treatment of advanced breast and ovarian cancers. However, their effects on bone mass and bone metastasis are unknown. Here we show that olaparib increases breast cancer bone metastasis through PARP2, but not PARP1, specifically in the myeloid lineage, but not in the cancer cells. Olaparib treatment or PARP1/2 deletion promotes osteoclast differentiation and bone loss. Intriguingly, myeloid deletion of PARP2, but not PARP1, increases the population of immature myeloid cells in bone marrow, and impairs the expression of chemokines such as CCL3 through enhancing the transcriptional repression by ß-catenin. Compromised CCL3 production in turn creates an immune-suppressive milieu by altering T cell subpopulations. Our findings warrant careful examination of current PARP inhibitors on bone metastasis and bone loss, and suggest cotreatment with CCL3, ß-catenin inhibitors, anti-RANKL or bisphosphonates as potential combination therapy for PARP inhibitors.


Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Animales , Resorción Ósea/patología , Neoplasias de la Mama/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Quimiocina CCL3/deficiencia , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Femenino , Eliminación de Gen , Humanos , Ratones Noqueados , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteoclastos/patología , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/deficiencia , Regiones Promotoras Genéticas/genética , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Tibia/diagnóstico por imagen , Tibia/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , beta Catenina/metabolismo
13.
Arthroscopy ; 36(6): 1517-1522, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32057985

RESUMEN

PURPOSE: The purpose of this study was to determine if there are significant side-to-side anthropometric differences between paired glenoids. METHODS: Forty-six matched-pair cadaver glenoids were harvested, and their glenoid heights (GHs) and glenoid widths (GWs) were measured with digital calipers. The glenoid surface area was calculated using the standard assumption that the inferior two-thirds of the glenoid is a perfect circle. RESULTS: There was a statistically significant difference between matched-pair GHs of 0.96 ± 3.07 mm (P = .020) and GWs of 0.46 ± 1.64 mm (P = .033). There was a significant difference of glenoid cavity area of 20.30 ± 81.53 mm2 (P = .044), or a difference of ∼3%. A total of 4 of 46 pairs of glenoids (8.6%) showed a difference in width >3 mm. CONCLUSIONS: This study demonstrates the fallacy of use of the contralateral glenoid in measuring glenoid bone loss. Although many paired samples exhibited similar side-to-side glenoid measurements, the number of cadaveric pairs that showed differences of >3 mm was substantial. Caution should be taken when using calculation methods that include this assumption for surgical decision making, as surface area, GW, and GH were all shown to have statistically significant side-to-side differences in their measurements. CLINICAL RELEVANCE: Many methods exist for measuring glenoid bone loss after anterior shoulder dislocation, but some of the current methods may be inaccurate and lead to unreliable estimations.


Asunto(s)
Cavidad Glenoidea/patología , Inestabilidad de la Articulación/cirugía , Articulación del Hombro/cirugía , Resorción Ósea/patología , Cadáver , Femenino , Humanos , Masculino , Persona de Mediana Edad
14.
Int Immunopharmacol ; 80: 106202, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32004923

RESUMEN

Type 2 diabetes mellitus is often companied with osteoporosis, a process which involves osteoclast activation. In this study, we found tubeimoside I, a natural compound isolated from the Chinese medicinal herb Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), significantly ameliorated the decrease of bone mass in type 2 diabetes-induced osteoporosis in rats. It appears that tubeimoside I exerts this protecting effect through inhibiting osteoclast formation and function. Futhermore, our study showed that tubeimoside I inhibits NF-κB transcriptional activation and degradation of IκBα. Collectively, our results reveal that tubeimoside I attenuates osteoclastogenesis through down-regulating NF-κB signaling pathway, and is a potential candidate for the treatment of bone-destructive diseases like type 2 diabetic osteoporosis.


Asunto(s)
Resorción Ósea/prevención & control , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Osteoporosis/prevención & control , Saponinas/farmacología , Triterpenos/farmacología , Animales , Resorción Ósea/etiología , Resorción Ósea/patología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/complicaciones , Regulación hacia Abajo/efectos de los fármacos , Humanos , Masculino , Ratones , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/metabolismo , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Osteoporosis/etiología , Osteoporosis/patología , Cultivo Primario de Células , Proteolisis/efectos de los fármacos , Ligando RANK/metabolismo , Células RAW 264.7 , Ratas , Saponinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Organismos Libres de Patógenos Específicos , Estreptozocina/toxicidad , Triterpenos/uso terapéutico
15.
Biochem Biophys Res Commun ; 525(2): 433-439, 2020 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-32102755

RESUMEN

Bone marrow adipose tissue (BMAT) has recently been found to induce osteoclastogenesis by secreting RANKL. Although Type 1 diabetes mellitus (T1DM) has been reported to be associated with increased BMAT and bone loss, little is known about the relationship between BMAT and osteoclasts in T1DM. We studied the role of BMAT in the alterations of osteoclast activities in early-stage T1DM, by using a streptozotocin-induced T1DM mouse model. Our results showed that osteoclast activity was enhanced in the long bones of T1DM mice, accompanied by increased protein expression of RANKL. However, RANKL mRNA levels in bone tissues of T1DM mice remained unchanged. Meanwhile, we found that BMAT was significantly increased in the long bones of T1DM mice, and both mRNA and protein levels of RANKL were elevated in the diabetic BMAT. More importantly, RANKL protein was mainly expressed on the cell membranes of the increased adipocytes, most of which were located next to the metaphyseal region. These results suggest that the enhanced bone resorption in early-stage diabetic mice is induced by RANKL derived from BMAT rather than the bone tissue itself.


Asunto(s)
Adipocitos/patología , Resorción Ósea/patología , Diabetes Mellitus Tipo 1/patología , Ligando RANK/metabolismo , Adipocitos/metabolismo , Animales , Médula Ósea/metabolismo , Médula Ósea/patología , Resorción Ósea/etiología , Resorción Ósea/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ligando RANK/análisis
16.
Int. j. morphol ; 38(1): 129-134, Feb. 2020. tab, graf
Artículo en Inglés | LILACS | ID: biblio-1056410

RESUMEN

Menopause complications such as cardiovascular and bone diseases represent a major public health concern. We sought to determine whether a high-fat diet (HFD) can augment ovariectomy-induced bone resorption in a rat model of menopause possibly via the upregulation of the inflammatory biomarkers and dyslipidemia. Rats were either ovariectomized and fed a standard laboratory chow (model group) or were ovariectomized and fed with a HFD for 15 weeks before being sacrificed. Ovariectomy significantly (p<0.05) increased body weight, dyslipidemia, insulin resistance, pro-inflammatory cytokines tumor necrosis factor-a (TNF-α) and interleukin-6 (IL-6), and biomarker of bone resorption, nuclear factor-kB (NF-kB), which were augmented by feeding animals with a HFD. This was confirmed through immunohistochemical study, where ovariectomy induced expression of p65/NF-kB protein in tibia bone sections of the model group, which were augmented by HFD. HFD augments ovariectomy-induced bone resorption through increased inflammatory biomarkers and NF-kB in rats.


Las complicaciones de la menopausia, como las enfermedades cardiovasculares y óseas, representan un importante problema de salud pública. Intentamos determinar si una dieta alta en grasas (HFD) puede aumentar la resorción ósea inducida por ovariectomía en un modelo de menopausia en ratas, a través de la regulación positiva de los biomarcadores inflamatorios y la dislipidemia. Las ratas fueron ovariectomizadas y alimentadas con una comida estándar de laboratorio (grupo modelo) o fueron ovariectomizadas y alimentadas con un HFD durante 15 semanas antes de ser sacrificadas. La ovariectomía aumentó significativamente (p <0,05) el peso corporal, dislipidemia, resistencia a la insulina, citocinas proinflamatorias, factor de necrosis tumoral a (TNF-α) e interleucina-6 (IL-6), y el biomarcador de resorción ósea, factor nuclear-kB (NF-kB), que se aumentaron alimentando animales con un HFD. Esto se confirmó a través del estudio inmunohistoquímico, donde la ovariectomía indujo la expresión de la proteína p65 / NF-kB en secciones de hueso de tibia del grupo modelo, que fueron aumentadas por HFD. HFD aumenta la resorción ósea inducida por ovariectomía a través del aumento de biomarcadores inflamatorios y NF-kB en ratas.


Asunto(s)
Animales , Femenino , Ratas , Resorción Ósea/patología , Dieta Alta en Grasa/efectos adversos , Triglicéridos/análisis , Resorción Ósea/etiología , Resistencia a la Insulina , Menopausia , Ovariectomía/efectos adversos , Ratas Wistar , Modelos Animales de Enfermedad , Dislipidemias/complicaciones
17.
Life Sci ; 244: 117336, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31972206

RESUMEN

AIMS: Postmenopausal osteoporosis and other osteolytic bone diseases are often caused by the elevation in osteoclastogenesis and/or increased osteoclastic bone resorption, leading to excessive bone loss. Hederagenin (Hed) is a pentacyclic triterpenoid saponin extracted from various natural medicinal plants and exhibits numerous biological activities and may offer benefits against bone-related conditions. We evaluated the effects of Hed on osteoclast formation and bone resorption in vitro and the in vivo therapeutic benefits in the mouse model of ovariectomy (OVX)-induced bone loss. MAIN METHODS: In vitro, osteoclast formation were determined by TRAcp staining; bone resorption were examined using Hydroxyapatite resorption assay and Podosomal actin belt formation assay; Related molecular mechanisms were determined by western blot assay. Construction of OVX mice by bilateral oophorectomy to simulate bone loss in vivo. KEY FINDINGS: In vitro cellular assays showed that Hed inhibited RANKL-induced osteoclast formation and osteoclast bone (hydroxyapatite) resorption as well as marker gene expression from BMM culture. Mechanistically, Hed attenuated RANKL-induced intracellular reactive oxygen species (ROS) production, and MAPK signaling pathway (ERK and p38) activation which curbed the downstream induction of c-Fos and NFATc1. Consistent with the in vitro findings, Hed administration effectively protected OVX mice from bone loss by reducing osteoclast number and activity on bone surface. SIGNIFICANCE: Our data provided promising evidence for the potential use of Hederagenin in the treatment of osteoclast-mediated osteolytic bone diseases such as postmenopausal osteoporosis.


Asunto(s)
Resorción Ósea/prevención & control , Ácido Oleanólico/análogos & derivados , Osteogénesis/efectos de los fármacos , Ovariectomía/efectos adversos , Sustancias Protectoras/farmacología , Ligando RANK/metabolismo , Animales , Resorción Ósea/etiología , Resorción Ósea/metabolismo , Resorción Ósea/patología , Femenino , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ácido Oleanólico/farmacología , Ligando RANK/genética , Transducción de Señal
18.
Exp Cell Res ; 388(2): 111857, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31972221

RESUMEN

Bone resorption, caused by osteoclasts (OCs), is important to bone homeostasis. The abnormalities of bone resorption may induce a series of diseases, including osteoarthritis, osteoporosis and aseptic peri-implant loosening. The latest research developed,a novel tyrosine and phosphoinositide kinase dual inhibitor, named PP121, inhibited Src in anaplastic thyroid carcinoma cell. However, the therapeutic function of PP121 on abnormal bone resorption is still uncertain. In the present study, we showed that PP121 could potently suppress osteoclast differentiation, osteoclast-specific gene expression and bone resorption via suppressing Src/MAPK (ERK and p38)/Akt-mediated NFATc1 induction in vitro. \It was found that PP121 could suppress the formation of osteoclasts from bone marrow macrophages (BMMs) without causing cytotoxicity, inhibit bone resorption and downregulate the mRNA level of osteoclast-specific markers, including calcitonin receptor (CTR), tartrate resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase 3 (MMP3), Cellular oncogene fos (C-Fos) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Consistent with in vitro observation, we found that PP121 greatly ameliorated LPS-induced bone resorption. Our results provide promising evidence of the therapeutic potential of PP121 for osteolytic diseases related to excessive osteoclast-mediated bone resorption.


Asunto(s)
Resorción Ósea/tratamiento farmacológico , Diferenciación Celular , Lipopolisacáridos/toxicidad , Osteoclastos/efectos de los fármacos , Osteogénesis , Pirazoles/farmacología , Pirimidinas/farmacología , Ligando RANK/metabolismo , Animales , Resorción Ósea/inducido químicamente , Resorción Ósea/metabolismo , Resorción Ósea/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Osteoclastos/metabolismo , Ligando RANK/genética
19.
Nat Commun ; 11(1): 282, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31941964

RESUMEN

Wolff's law and the Utah Paradigm of skeletal physiology state that bone architecture adapts to mechanical loads. These models predict the existence of a mechanostat that links strain induced by mechanical forces to skeletal remodeling. However, how the mechanostat influences bone remodeling remains elusive. Here, we find that Piezo1 deficiency in osteoblastic cells leads to loss of bone mass and spontaneous fractures with increased bone resorption. Furthermore, Piezo1-deficient mice are resistant to further bone loss and bone resorption induced by hind limb unloading, demonstrating that PIEZO1 can affect osteoblast-osteoclast crosstalk in response to mechanical forces. At the mechanistic level, in response to mechanical loads, PIEZO1 in osteoblastic cells controls the YAP-dependent expression of type II and IX collagens. In turn, these collagen isoforms regulate osteoclast differentiation. Taken together, our data identify PIEZO1 as the major skeletal mechanosensor that tunes bone homeostasis.


Asunto(s)
Resorción Ósea/patología , Canales Iónicos/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Animales , Resorción Ósea/genética , Diferenciación Celular , Colágeno Tipo II/metabolismo , Colágeno Tipo IX/metabolismo , Femenino , Fracturas Óseas/genética , Fracturas Óseas/patología , Suspensión Trasera , Homeostasis , Canales Iónicos/genética , Masculino , Ratones Noqueados , Osteoclastos/citología , Osteoporosis/genética , Estrés Mecánico
20.
Environ Toxicol ; 35(4): 487-494, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31793751

RESUMEN

Cadmium (Cd) is a toxic heavy metal that represents an occupational hazard and environmental pollutant toxic heavy metal, which can cause osteoporosis following accumulation in the body. The purpose of this study was to investigate the effect of Cd on bone tissue osteoclast differentiation in vivo. Female BALB/c mice were randomly divided into three groups and given drinking water with various concentrations of Cd (0, 5, and 25 mg/L) for 16 weeks, after which the mice were sacrificed after collecting urine and blood. The level of Cd, calcium (Ca), phosphorus (P), trace elements, and some biochemical indicators were measured, and the bone was fixed in a 4% formaldehyde solution for histological observation. Bone marrow cells were isolated to determine the expression of osteoclast-associated mRNA and proteins. Cd was increased in the blood, urine, and bone in response to Cd in drinking water in a dose-dependent manner. The content of iron (Fe), manganese (Mn), and zinc (Zn) was significantly increased, whereas Ca and P were decreased in bone compared to the control group. Cd affected the histological structure of the bone, and induced the upregulation and downregulation of tartrate-resistant acid phosphatase 5b (TRACP-5b) and estradiol in the serum, respectively. Cd had no significant effect on the alkaline phosphatase activity in the serum. The expression of osteoclast marker proteins, including TRACP, cathepsin K, matrix metalloprotein 9, and carbonic anhydrases were all increased in the Cd-treated bone marrow cells. Cd significantly increased the expression of receptor activator of nuclear factor kappa B ligand (RANKL), but had lower effect on the expression of osteoprotegerin (OPG) in both bone marrow cells and bone tissue. Thus, Cd exposure destroyed the bone microstructure, promoted the formation of osteoclasts in the bone tissue, and accelerated bone resorption, in which the OPG/RANKL pathway may play an important role.


Asunto(s)
Resorción Ósea/inducido químicamente , Huesos/efectos de los fármacos , Cadmio/toxicidad , Diferenciación Celular/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Osteoclastos/efectos de los fármacos , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Resorción Ósea/metabolismo , Resorción Ósea/patología , Huesos/metabolismo , Huesos/patología , Catepsina K/metabolismo , Femenino , Ratones , Ratones Endogámicos BALB C , Osteoclastos/metabolismo , Osteoclastos/patología , Osteoporosis/metabolismo , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Fosfatasa Ácida Tartratorresistente/metabolismo
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