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2.
J Cell Physiol ; 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31975377

RESUMO

Deletion of TGFß inducible early gene-1 (TIEG) in mice results in an osteopenic phenotype that exists only in female animals. Molecular analyses on female TIEG knockout (KO) mouse bones identified increased expression of sclerostin, an effect that was confirmed at the protein level in serum. Sclerostin antibody (Scl-Ab) therapy has been shown to elicit bone beneficial effects in multiple animal model systems and human clinical trials. For these reasons, we hypothesized that Scl-Ab therapy would reverse the low bone mass phenotype of female TIEG KO mice. In this study, wildtype (WT) and TIEG KO female mice were randomized to either vehicle control (Veh, n = 12/group) or Scl-Ab therapy (10 mg/kg, 1×/wk, s.c.; n = 12/group) and treated for 6 weeks. Following treatment, bone imaging analyses revealed that Scl-Ab therapy significantly increased cancellous and cortical bone in the femur of both WT and TIEG KO mice. Similar effects also occurred in the vertebra of both WT and TIEG KO animals. Additionally, histomorphometric analyses revealed that Scl-Ab therapy resulted in increased osteoblast perimeter/bone perimeter in both WT and TIEG KO animals, with a concomitant increase in P1NP, a serum marker of bone formation. In contrast, osteoclast perimeter/bone perimeter and CTX-1 serum levels were unaffected by Scl-Ab therapy, irrespective of mouse genotype. Overall, our findings demonstrate that Scl-Ab therapy elicits potent bone-forming effects in both WT and TIEG KO mice and effectively increases bone mass in female TIEG KO mice.

3.
Genome ; 63(3): 133-143, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31794256

RESUMO

Bone size is an important trait for chickens because of its association with osteoporosis in layers and meat production in broilers. Here, we employed high density genotyping platforms to detect candidate genes for bone traits. Estimates of the narrow heritabilities ranged from 0.37 ± 0.04 for shank length to 0.59 ± 0.04 for tibia length. The dominance heritability was 0.12 ± 0.04 for shank length. Using a linear mixed model approach, we identified a promising locus within NCAPG on chromosome 4, which was associated with tibia length and mass, femur length and area, and shank length. In addition, three other loci were associated with bone size or mass at a Bonferroni-corrected genome-wide significance threshold of 1%. One region on chicken chromosome 1 between 168.38 and 171.82 Mb harbored HTR2A, LPAR6, CAB39L, and TRPC4. A second region that accounted for 2.2% of the phenotypic variance was located around WNT9A on chromosome 2, where allele substitution was predicted to be associated with tibia length. Four candidate genes identified on chromosome 27 comprising SPOP, NGFR, GIP, and HOXB3 were associated with tibia length and mass, femur length and area, and shank length. Genome partitioning analysis indicated that the variance explained by each chromosome was proportional to its length.

4.
Acta Crystallogr C Struct Chem ; 75(Pt 8): 1128-1133, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31380795

RESUMO

Noncovalent interactions, such as π-π stacking interactions, C-H...π interactions and hydrogen bonding, are important driving forces for self-assembly in the construction of functional supermolecules and materials, especially in multicomponent supramolecular systems. Herein, a novel compound based on a π-acidic naphthalene diimide derivative and a double hydroxide-bridged dinuclear Al3+ aqua ion cluster, namely bis[N,N'-bis(2-sulfonatoethyl)-1,4,5,8-naphthalene diimide] di-µ-hydroxido-bis[tetraaquaaluminium(III)] tetrahydrate, (C18H12N2O10S2)2[Al2(OH)2(H2O)8]·4H2O, was obtained using the above-mentioned common noncovalent interactions, as well as uncommon lone-pair-π interactions. Functional molecular modules were connected by these noncovalent interactions to generate obvious photochromic properties. The compound was prepared by the self-assembly of N,N'-bis(2-sulfoethyl)-1,4,5,8-naphthalene diimide and Al(NO3)3·9H2O under mixed solvothermal conditions, and was characterized in detail by single-crystal X-ray diffraction, powder X-ray diffraction and FT-IR spectroscopy. The thermal stability and photochromic properties were also investigated; furthermore, in-situ solid-state UV-Vis absorption spectroscopy and electron spin resonance (ESR) were used to clarify the photochromic mechanism.

5.
Cancer Res ; 79(17): 4339-4347, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31300474

RESUMO

Lung carcinoids (LC) are rare and slow growing primary lung neuroendocrine tumors. We performed targeted exome sequencing, mRNA sequencing, and DNA methylation array analysis on macro-dissected LCs. Recurrent mutations were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%; MEN1, ARID1A, KMT2C, and KMT2A) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed three robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be exclusively enriched in the LC2 subtype. LC1 and LC3 subtypes were predominately found at peripheral and endobronchial lung, respectively. The LC3 subtype was diagnosed at a younger age than LC1 and LC2 subtypes. IHC staining of two biomarkers, ASCL1 and S100, sufficiently stratified the three subtypes. This molecular classification of LCs into three subtypes may facilitate understanding of their molecular mechanisms and improve diagnosis and clinical management. SIGNIFICANCE: Integrative genomic analysis of lung carcinoids identifies three novel molecular subtypes with distinct clinical features and provides insight into their distinctive molecular signatures of tumorigenesis, diagnosis, and prognosis.

6.
Nat Chem ; 11(5): 470-477, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936522

RESUMO

Dissipative self-assembly is common in biological systems, where it serves to maintain a far-from-equilibrium functional state through fuel consumption. Synthetic dissipative systems have been prepared that can mimic some of the properties of biological systems, but they often show poor mechanical performance. Here, we report a shear-induced transient hydrogel that is highly stretchable. The system is constructed by adding Cu(II) into the aqueous solution of a pseudopolyrotaxane, which is itself formed by threading molecular tubes on polyethylene glycol chains. Vigorous shaking transforms the solution into a gel, which gradually relaxes back to the sol state over time. This cycle can be repeated at least five times. A mechanism is proposed that relies on a shear-induced transition from intrachain to interchain coordination and subsequent thermal relaxation. The far-from-equilibrium hydrogel is highly stretchable, which is probably due to 'frictional' sliding of the molecular tubes on the polyethylene glycol chains. On shaking, the hydrogel undergoes fast self-healing.

7.
World J Clin Cases ; 7(1): 79-88, 2019 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-30637256

RESUMO

BACKGROUND: The complex anatomy of the maxillary first molars has always been a major challenge for complete root canal treatment in endodontic therapy. Here, we present two cases of maxillary first molars, each with only two root canals, which have been rarely reported. We also perform a literature review of maxillary first molar anatomy. CASE SUMMARY: The two patients were referred to the hospital after 1) finding a cavity in their tooth with a color change and, 2) a toothache during mastication, respectively. Both of these cases were diagnosed as apical periodontitis by X-ray imaging and cone beam computed tomography (CBCT). Non-surgical endodontic therapy was performed with the assistance of a dental operating microscope (DOM). CBCT showed rare but accurate images of both patients, each with two root canals and two roots in their maxillary first molars. Both roots were located in the buccal in the palatal direction, and each root had only one clear root canal. In addition, each maxillary first molar in both patients was symmetrical to that on the opposing side with only two separate root canals. Non-surgical endodontic therapy was performed with the assistance of a DOM. Finally, the teeth were restored using composite resin and the patients were satisfied with the results. CONCLUSION: Making full use of CBCT and DOM would contribute to helping dentists make correct diagnoses and successfully treat teeth with rare root canal morphologies.

8.
Ann N Y Acad Sci ; 1442(1): 91-103, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30644553

RESUMO

Prolonged mechanical unloading in bedridden patients and concurrent hormonal dysregulation represents the cause of one of the severest forms of osteoporosis, a condition for which there are very few efficacious interventions available to date. Sclerostin, a Wnt antagonist, acts as a negative regulator of bone formation. Sclerostin antibody (Scl-Ab)-mediated blockade of sclerostin can dramatically enhance bone formation and reduce bone resorption. This study was designed to investigate the therapeutic effect of the Scl-Ab on severe bone loss induced by concurrent mechanical unloading and estrogen deficiency in a hindlimb-suspended and ovariectomized rat model, and to study the cellular mechanisms underlying severe osteoporosis and Scl-Ab action. Unloading and ovariectomy resulted in severe loss of trabecular and cortical bone mass and strength; Scl-Ab can significantly counteract the deterioration of bone in unloaded and/or ovariectomized rats, with noticeably increased cortical bone formation. Scanning electron microscopy analysis revealed that unloading and ovariectomy lead to multiple morphological and structural abnormalities of osteocytes in cortical bone and the abnormalities were abolished by Scl-Ab administration. This study extends our previous conclusion that Scl-Ab represents a promising therapeutic approach for severe bone loss that occurs after being exposed to estrogen deficiency and prolonged mechanical unloading.


Assuntos
Anticorpos/uso terapêutico , Proteínas Morfogenéticas Ósseas/imunologia , Marcadores Genéticos/imunologia , Osteócitos/citologia , Ovariectomia , Animais , Anticorpos/imunologia , Feminino , Camundongos , Tamanho do Órgão , Osteoporose/prevenção & controle , Ratos , Ratos Sprague-Dawley
9.
J Mol Endocrinol ; 62(2): R167-R185, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30532996

RESUMO

The discovery that two rare autosomal recessive high bone mass conditions were caused by the loss of sclerostin expression prompted studies into its role in bone homeostasis. In this article, we aim to bring together the wealth of information relating to sclerostin in bone though discussion of rare human disorders in which sclerostin is reduced or absent, sclerostin manipulation via genetic approaches and treatment with antibodies that neutralise sclerostin in animal models and in human. Together, these findings demonstrate the importance of sclerostin as a regulator of bone homeostasis and provide valuable insights into its biological mechanism of action. We summarise the current state of knowledge in the field, including the current understanding of the direct effects of sclerostin on the canonical WNT signalling pathway and the actions of sclerostin as an inhibitor of bone formation. We review the effects of sclerostin, and its inhibition, on bone at the cellular and tissue level and discuss new findings that suggest that sclerostin may also regulate adipose tissue. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of sclerostin.

10.
J Am Chem Soc ; 140(41): 13466-13477, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-30244569

RESUMO

During the last half a century, great achievements have been made in molecular recognition in parallel with the invention of numerous synthetic receptors. However, the selective recognition of hydrophilic molecules in water remains a generally accepted challenge in supramolecular chemistry but is commonplace in nature. In an earlier Communication [ Huang et al. J. Am. Chem. Soc. 2016 , 138 , 14550 ], we reported a pair of endo-functionalized molecular tubes that surprisingly prefer highly hydrophilic molecules over hydrophobic molecules of a similar size and shape. The hydrophobic effect and hydrogen bonding were proposed to be responsible, but their exact roles were not fully elucidated. In this Article, we present a thorough study on the binding behavior of these molecular tubes toward 44 hydrophilic molecules in water. Principal component analysis reveals that the binding strength is weakly correlated to the hydrophobicity, volume, surface area, and dipole moment of guests. Furthermore, molecular dynamics simulations show the hydrophobic effect through releasing the poorly hydrogen-bonded cavity water contributes to the binding of all the hydrophilic molecules, while hydrogen bonding differentiates these molecules and is thus the key to achieve a high selectivity toward certain hydrophilic molecules over other molecules with a similar size and shape. Therefore, a good guest for these molecular tubes should meet the following criteria: the hydrogen-bonding sites should be complementary, and the molecular volume should be large enough to expel all the cavity water but not too large to cause steric hindrance. This rule of thumb may also be used to design a selective receptor for certain hydrophilic molecules. Following these guidelines, a "best-fit" guest was found for the syn-configured molecular tube with a binding constant as high as 106 M-1.

11.
Chemistry ; 24(63): 16757-16761, 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30203870

RESUMO

A rigid molecular cleft shows unique aggregation-induced emission (AIE) by restricting the motion of aldehyde through intermolecular lone pair⋅⋅⋅π interactions, which are tuned by side chains. This AIE luminogen was demonstrated to work as a fluorescent sensor for aniline and an optical chirality sensor for chiral amine.

12.
Environ Sci Pollut Res Int ; 25(26): 25933-25941, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29961905

RESUMO

The purpose of this study was to investigate the phytoremediation potential of two hyperaccumulator plants, Phytolacca americana L. and Polygonum hydropiper L., on manganese-contaminated paddy soils. The biomass growth, Mn concentrations in plant tissues, and potential Mn removal efficiency from soils of these two plants were studied with citric acid, and the mechanisms of citric acid on these two plants were analyzed by examining the root activity, the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) in leaves, as well as the concentrations of O2·- and H2O2 in leaves. The results showed that the biomass of these two plants were both promoted under low level of citric acid (3 mmol kg-1). The concentration of Mn in the plants and the amount of Mn removed from the soil by the plants through harvesting were enhanced at low and intermediate (10 mmol kg-1) citric acid application levels. The results also showed that root activity was enhanced at the low citric acid level and significantly inhibited under the intermediate and high levels (15 mmol kg-1), which indicates the facilitative function of the low level of citric acid and the inhibitive function of the high level of citric acid application on plant biomass growth. Under the low and intermediate levels of citric acid application, O2·- in the plant leaves increased sharply, and the SOD, POD, and CAT activities also increased sharply, which made the level of H2O2 very similar to that of the control, ensuring the health of the plants. At the high level of citric acid application, however, the O2·- continued to rise sharply, while the activity of the three antioxidant enzymes declined sharply, causing the concentration of hydrogen peroxide to be much higher than that in the control, thus endangering the plants. The present study shows the potential of P. hydropiper for use in the phytoremediation of soil contaminated with a relatively low level of manganese.


Assuntos
Manganês/metabolismo , Phytolacca americana/metabolismo , Polygonum/metabolismo , Poluentes do Solo/metabolismo , Antioxidantes/metabolismo , Biodegradação Ambiental , Catalase/metabolismo , Ácido Cítrico/farmacologia , Peróxido de Hidrogênio , Manganês/química , Peroxidase/metabolismo , Phytolacca americana/efeitos dos fármacos , Desenvolvimento Vegetal/efeitos dos fármacos , Folhas de Planta/química , Raízes de Plantas/efeitos dos fármacos , Plantas/efeitos dos fármacos , Polygonum/efeitos dos fármacos , Poluentes do Solo/química , Superóxido Dismutase/metabolismo
13.
Huan Jing Ke Xue ; 39(8): 3557-3562, 2018 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-29998661

RESUMO

To study the emission characteristics of volatile organic malodorous compounds and identify the characteristic substances of associated industries, the components of VOCs of typical industries were detected and analyzed in an industrial area of south China. The results showed that there are certain differences in the material composition among different companies, and there are also certain differences in the composition of different processes in the same company. For the automobile manufacturing industry, alcohols and esters were the main substances in the spraying workshop, accounting for 21.87% and 21.62%, respectively, and aromatic hydrocarbons were the typical substances in the drying workshop, accounting for 41.14%. Concerning the electronic components industry, esters were the main substances, accounting for 67.99% in the spraying and coating workshop. Regarding the coating production industry, esters were the main substances in the two paint companies, but the emission ratio of aromatic hydrocarbons was the second highest in one company and the emission ratio of ketone was the second highest in the other company. For the printing industry, alcohols were the characteristic substances, accounting for 99.32%. Concerning the refrigeration industry, alkanes were the most abundant compounds, accounting for 83.01%. Esters (ethyl acetate, butyl acetate, and isobutyl acetate), aromatic hydrocarbons (toluene, ethylbenzene, and styrene), and alcohol ketones (ethanol, methyl isobutyone, and 2-butanone) were preliminarily identified as characteristic malodorous compounds of the industries using organic solvents.

14.
Chem Commun (Camb) ; 54(55): 7677-7680, 2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-29938266

RESUMO

Two new naphthotubes with ester linkers were synthesized and characterized. With the syn isomers of an ester naphthotube and an ether naphthotube, strong positive allosteric cooperativity in a ternary complex with two different hosts on one guest was achieved. This paves the way to construct robust supramolecular architectures with high complexity and diversity.

15.
Calcif Tissue Int ; 103(4): 443-454, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29931461

RESUMO

To date, no efficacious therapy exists that will prevent or treat the severe osteoporosis in individuals with neurologically motor-complete spinal cord injury (SCI). Recent preclinical studies have demonstrated that sclerostin antibody (Scl-Ab) can prevent sublesional bone loss after acute SCI in rats. However, it remains unknown whether sclerostin inhibition reverses substantial bone loss in the vast majority of the SCI population who have been injured for several years. This preclinical study tested the efficacy of Scl-Ab to reverse the bone loss that has occurred in a rodent model after chronic motor-complete SCI. Male Wistar rats underwent either complete spinal cord transection or only laminectomy. Twelve weeks after SCI, the rats were treated with Scl-Ab at 25 mg/kg/week or vehicle for 8 weeks. In the SCI group that did not receive Scl-Ab, 20 weeks of SCI resulted in a significant reduction of bone mineral density (BMD) and estimated bone strength, and deterioration of bone structure at the distal femoral metaphysis. Treatment with Scl-Ab largely restored BMD, bone structure, and bone mechanical strength. Histomorphometric analysis showed that Scl-Ab increased bone formation in animals with chronic SCI. In ex vivo cultures of bone marrow cells, Scl-Ab inhibited osteoclastogenesis, and promoted osteoblastogenesis accompanied by increased Tcf7, ENC1, and the OPG/RANKL ratio expression, and decreased SOST expression. Our findings demonstrate for the first time that Scl-Ab reverses the sublesional bone loss when therapy is begun after relatively prolonged spinal cord transection. The study suggests that, in addition to being a treatment option to prevent bone loss after acute SCI, sclerostin antagonism may be a valid clinical approach to reverse the severe bone loss that invariably occurs in patients with chronic SCI.


Assuntos
Densidade Óssea/efeitos dos fármacos , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Reabsorção Óssea/etiologia , Traumatismos da Medula Espinal/complicações , Animais , Anticorpos/farmacologia , Doença Crônica , Marcadores Genéticos , Masculino , Osteogênese/efeitos dos fármacos , Ratos , Ratos Wistar
16.
Curr Osteoporos Rep ; 16(3): 289-298, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29725836

RESUMO

PURPOSE OF REVIEW: The development of therapeutics that target anabolic pathways involved in skeletogenesis is of great importance with regard to disease resulting in bone loss, or in cases of impaired bone repair. This review aims to summarize recent developments in this area. RECENT FINDINGS: A greater understanding of how drugs that modulate signaling pathways involved in skeletogenesis exert their efficacy, and the molecular mechanisms resulting in bone formation has led to novel pharmacological bone repair strategies. Furthermore, crosstalk between pathways and molecules has suggested signaling synergies that may be exploited for enhanced tissue formation. The sequential pharmacological stimulation of the molecular cascades resulting in tissue repair is a promising strategy for the treatment of bone fractures. It is proposed that a therapeutic strategy which mimics the natural cascade of events observed during fracture repair may be achieved through temporal targeting of tissue repair pathways.


Assuntos
Remodelação Óssea , Consolidação da Fratura , Fraturas Ósseas/terapia , Osteogênese , Anabolizantes , Anticorpos Neutralizantes/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/imunologia , Proteínas Morfogenéticas Ósseas/uso terapêutico , Calo Ósseo , Fator 2 de Crescimento de Fibroblastos/uso terapêutico , Fraturas não Consolidadas/terapia , Marcadores Genéticos/imunologia , Humanos , Fator de Crescimento Derivado de Plaquetas/uso terapêutico , Transdução de Sinais , Teriparatida/uso terapêutico , Fator de Crescimento Transformador beta , Via de Sinalização Wnt
17.
Angew Chem Int Ed Engl ; 57(26): 7809-7814, 2018 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-29696797

RESUMO

Rotaxane-based molecular shuttles are often operated using low-symmetry axles and changing the states of the binding stations. A molecular shuttle capable of directional shuttling of an acid-responsive cone-like macrocycle on a single-state symmetric dumbbell axle is now presented. The axle contains three binding stations: one symmetric di(quaternary ammonium) station and two nonsymmetric phenyl triazole stations arranged in opposite orientations. Upon addition of an acid, the protonated macrocycle shuttles from the di(quaternary ammonium) station to the phenyl triazole binding station closer to its butyl groups. This directional shuttling presumably originates from charge repulsion and an orientational binding preference between the cone-like cavity and the nonsymmetric phenyl triazole station. This mechanism for achieving directional shuttling by manipulating only the wheels instead of the tracks is new for artificial molecular machines.

18.
Angew Chem Int Ed Engl ; 57(3): 709-713, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29139184

RESUMO

Positive cooperativity achieved through activating weak non-covalent interactions is common in biological assemblies but is rarely observed in synthetic complexes. Two new molecular tubes have been synthesized and the syn isomer binds DABCO-based organic cations with high orientational selectivity. Surprisingly, the ternary complex with two hosts and one guest shows a high cooperativity factor (α=580), which is the highest reported for synthetic systems without involving ion-pairing interactions. The X-ray single-crystal structure revealed that the strong positive cooperativity likely originates from eight C-H⋅⋅⋅O hydrogen bonds between the two head-to-head-arranged syn tube molecules. These relatively weak hydrogen bonds were not observed in the free hosts and only emerged in the complex. Furthermore, this complex was used as a basic motif to construct a robust [2+2] cyclic assembly, thus demonstrating its potential in molecular self-assembly.

19.
J Orthop Res ; 36(4): 1106-1113, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28884841

RESUMO

Neutralizing monoclonal sclerostin antibodies are effective in promoting bone formation at a systemic level and in orthopedic scenarios including closed fracture repair. In this study we examined the effects of sclerostin antibody (Scl-Ab) treatment on regenerate volume, density, and strength in a rat model of distraction osteogenesis. Surgical osteotomy was performed on 179 Sprague Dawley rats. After 1 week, rats underwent distraction for 2 weeks, followed by 6 weeks for consolidation. Two treatment groups received biweekly subcutaneous Scl-AbIII (a rodent form of Scl-Ab; 25 mg/kg), either from the start of distraction onward or restricted to the consolidation phase. These groups were compared to controls receiving saline. Measurement modalities included longitudinal DXA, ex vivo QCT, and microCT, tissue histology, and biomechanical four-point bending tests. Bone volume was increased in both Scl-Ab treatments regimens by the end of consolidation (+26-38%, p < 0.05), as assessed by microCT. This was associated with increased mineral apposition. Importantly, Scl-Ab led to increased strength in united bones, and this reached statistical significance in animals receiving Scl-Ab during consolidation only (+177%, p < 0.01, maximum load to failure). These data demonstrate that Scl-Ab treatment increases bone formation, leading to regenerates with higher bone volume and improved strength. Our data also suggest that the optimal effects of Scl-Ab treatment are achieved in the latter stages of distraction osteogenesis. These findings support further investigation into the potential clinical application of sclerostin antibody to augment bone distraction, such as limb lengthening, particularly in the prevention of refracture. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1106-1113, 2018.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Proteínas Morfogenéticas Ósseas/imunologia , Regeneração Óssea/efeitos dos fármacos , Marcadores Genéticos/imunologia , Osteogênese por Distração , Osteogênese/efeitos dos fármacos , Animais , Anticorpos Neutralizantes/farmacologia , Calcificação Fisiológica/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Fêmur/cirurgia , Masculino , Osteotomia , Ratos Sprague-Dawley , Suporte de Carga
20.
Endocrinology ; 159(1): 260-271, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29069393

RESUMO

Sclerostin antibody (Scl-Ab) restored bone mass and strength in the ovariectomized rat model of postmenopausal osteoporosis. Increased bone mineral density (BMD) and decreased skeletal fragility fracture risk have been reported in postmenopausal osteoporotic women receiving Scl-Ab. In males, loss of androgen leads to rapid decreases in BMD and an increased risk of fragility fractures. We hypothesized that Scl-Ab could reverse the loss of bone mass and strength caused by androgen ablation in the orchiectomized (ORX) rat model of male osteoporosis. We treated 9-month-old ORX Sprague Dawley rats (3 months after ORX) subcutaneously twice weekly with vehicle or Scl-Ab (5 or 25 mg/kg) for 6 weeks (n = 10 per group). Both doses of Scl-Ab fully reversed the BMD deficit in the lumbar spine and femur and tibia in ORX rats. Microcomputed tomography showed that the bone mass in the fifth lumbar vertebral body, femur diaphysis, and femoral neck were dose-dependently restored by Scl-Ab. The bone strength at these sites increased significantly with Scl-Ab to levels matching those of sham-operated controls and correlated positively with improvements in bone mineral content, demonstrating bone quality maintenance. Dynamic histomorphometry of the tibial diaphysis and second lumbar vertebral body demonstrated that Scl-Ab significantly increased bone formation on periosteal, endocortical, and trabecular surfaces and significantly decreased bone resorption on endocortical and trabecular surfaces. The effects of Scl-Ab on increasing bone formation and decreasing bone resorption led to restoration of bone mass and strength in androgen-deficient rats. These findings support the ongoing evaluation of Scl-Ab as a potential therapeutic agent for osteoporosis in men.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Proteínas Morfogenéticas Ósseas/imunologia , Osso e Ossos/efeitos dos fármacos , Modelos Animais de Doenças , Marcadores Genéticos/imunologia , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Absorciometria de Fóton , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Proteínas Morfogenéticas Ósseas/metabolismo , Reabsorção Óssea/prevenção & controle , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Masculino , Terapia de Alvo Molecular , Orquiectomia , Tamanho do Órgão/efeitos dos fármacos , Osteoporose/diagnóstico por imagem , Osteoporose/patologia , Próstata/efeitos dos fármacos , Próstata/patologia , Ratos Sprague-Dawley , Glândulas Seminais/efeitos dos fármacos , Glândulas Seminais/patologia , Resistência ao Cisalhamento/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos , Microtomografia por Raio-X
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