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1.
Z Gerontol Geriatr ; 53(2): 163-170, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31950363

RESUMO

Osteoporotic bones heal more slowly and ineffectively than normal bones. A combination of antibodies against sclerosing protein (Scl-Ab), and parathyroid hormone 1-34 (PTH 1-34) may improve healing. A standard osteoporotic rat model was established 12 weeks after bilateral ovarian resection (OVX). Bone defects were created in the right femora of 80 rats, which were randomly divided into 4 groups: control, Scl-Ab (25 mg/kg twice weekly), PTH (60 µg/kg of PTH 1-34 three times a week) and PTH plus Scl-Ab. After 12 weeks of treatment the rats were sacrificed and blood and the distal femora were harvested for biochemical evaluation, histology, microcomputed tomography and biomechanical testing. Compared to the control group, monotherapy and combination therapy with PTH and/or Scl-Ab promoted the formation of new bone, enhanced maximum femoral loading and increased the levels of procollagen type I N­terminal propeptide (PINP) and osteocalcin. The administration of PTH + Scl-Ab maximally enhanced bone defect healing. Combination treatment was better than either treatment alone, indicating a synergistic effect.


Assuntos
Anticorpos/administração & dosagem , Proteínas Morfogenéticas Ósseas/imunologia , Remodelação Óssea/fisiologia , Consolidação da Fratura/efeitos dos fármacos , Hormônio Paratireóideo/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Calo Ósseo/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Humanos , Ovariectomia , Hormônio Paratireóideo/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Microtomografia por Raio-X/métodos
2.
Biomed Res Int ; 2019: 6920281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360722

RESUMO

Ankylosing spondylitis (AS) is a form of arthritis that can lead to fusion of vertebrae and sacroiliac joints following syndesmophyte formation. The etiology of this painful disease remains poorly defined due to its complex genetic background. There are no commonly accepted methods for early diagnosis of AS, nor are there any effective or efficient clinical treatments. Several noncoding RNAs (ncRNAs) have been linked to AS pathogenesis and inflammation via selective binding of their downstream targets. However, major gaps in knowledge remain to be filled before such findings can be translated into clinical treatments for AS. In this review, we outline recent findings that demonstrate essential roles of ncRNAs in AS mediated via multiple signaling pathways such as the Wnt, transforming growth factor-ß/bone morphogenetic protein, inflammatory, T-cell prosurvival, and nuclear factor-κB pathways. The summary of these findings provides insight into the molecular mechanisms by which ncRNAs can be targeted for AS diagnosis and the development of therapeutic drugs against a variety of autoimmune diseases.


Assuntos
Doenças Autoimunes , RNA não Traduzido , Espondilite Anquilosante , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Proteínas Morfogenéticas Ósseas/imunologia , Proteínas Morfogenéticas Ósseas/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , RNA não Traduzido/imunologia , RNA não Traduzido/metabolismo , Articulação Sacroilíaca/imunologia , Articulação Sacroilíaca/metabolismo , Articulação Sacroilíaca/patologia , Coluna Vertebral/imunologia , Coluna Vertebral/metabolismo , Coluna Vertebral/patologia , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/metabolismo , Espondilite Anquilosante/patologia
3.
Mol Med Rep ; 20(2): 985-994, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173222

RESUMO

As a common degenerative disease, osteoporosis (OS) is characterized by reduced bone mass and microarchitectural deterioration of bone tissue. Both genetic and environmental factors are involved in OS development. To date, ~300 genes have been confirmed to be involved in the pathogenesis of OS, a large majority of which have been independently investigated. As OS is a polygenetic disease, a comprehensive analysis focusing on the biological functions and interactions of OS­related genes would provide valuable information. In this study, OS related research deposited in PubMed was retrieved and genes related to OS were catalogued. Pathways with an enriched biological function for these genes were extracted, and the crosstalk between the enriched pathways was analyzed. A comprehensive network was constructed, and a minimal network was extracted using the Steiner minimal network algorithm. In this study, a total of 294 genes in were retrieved from PubMed. Biological processes found to be enriched included those related to bone metabolism and the immune system. In total, 58 pathways were enriched. Furthermore, the comprehensive network consisting of 3,943 nodes and 7,976 edges was constructed, among which 631 nodes and 2,581 edges contributed to the OS­specific molecular network. In this network, in excess of 300 potential genes associated with OS and two modules were identified. Thus, this study provides a mechanistic insight into OS and suggests more than 300 potential OS­related genes for future research.


Assuntos
Algoritmos , Proteínas Morfogenéticas Ósseas/genética , Osso e Ossos/metabolismo , Proteínas da Matriz Extracelular/genética , Redes Reguladoras de Genes , Osteoporose/genética , Densidade Óssea , Proteínas Morfogenéticas Ósseas/classificação , Proteínas Morfogenéticas Ósseas/imunologia , Osso e Ossos/patologia , Biologia Computacional/métodos , Proteínas da Matriz Extracelular/classificação , Proteínas da Matriz Extracelular/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Imunidade Inata , Anotação de Sequência Molecular , Osteoporose/metabolismo , Osteoporose/patologia , Receptores Acoplados a Proteínas-G/classificação , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/imunologia , Transdução de Sinais
4.
J Immunol ; 202(8): 2296-2306, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30814306

RESUMO

NK cells are innate-like lymphocytes that eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified roles for sclerostin domain-containing-1 (Sostdc1) in NK cell development and function. Sostdc1-knockout (Sostdc1 -/-) mice display a progressive accumulation of transitional NK cells (tNKs) (CD27+CD11b+) with age, indicating a partial developmental block. The NK cell Ly49 repertoire in Sostdc1 -/- mice is also changed. Lower frequencies of Sostdc1 -/- splenic tNKs express inhibitory Ly49G2 receptors, but higher frequencies express activating Ly49H and Ly49D receptors. However, the frequencies of Ly49I+, G2+, H+, and D+ populations were universally decreased at the most mature (CD27-CD11b+) stage. We hypothesized that the Ly49 repertoire in Sostdc1 -/- mice would correlate with NK killing ability and observed that Sostdc1-/- NK cells are hyporesponsive against MHC class I-deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN-γ expression to controls. Consistent with Sostdc1's known role in Wnt signaling regulation, Tcf7 and Lef1 levels were higher in Sostdc1 -/- NK cells. Expression of the NK development gene Id2 was decreased in Sostdc1-/- immature NK and tNK cells, but Eomes and Tbx21 expression was unaffected. Reciprocal bone marrow transplant experiments showed that Sostdc1 regulates NK cell maturation and expression of Ly49 receptors in a cell-extrinsic fashion from both nonhematopoietic and hematopoietic sources. Taken together, these data support a role for Sostdc1 in the regulation of NK cell maturation and cytotoxicity, and identify potential NK cell niches.


Assuntos
Proteínas Morfogenéticas Ósseas/imunologia , Imunidade Celular , Células Matadoras Naturais/imunologia , Via de Sinalização Wnt/imunologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/imunologia , Proteína 2 Inibidora de Diferenciação/genética , Proteína 2 Inibidora de Diferenciação/imunologia , Células Matadoras Naturais/citologia , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/imunologia , Camundongos , Camundongos Knockout , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Via de Sinalização Wnt/genética
5.
Nat Commun ; 10(1): 604, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30723205

RESUMO

The gut microbiota contributes to host health and fitness, and imbalances in its composition are associated with pathology. However, what shapes microbiota composition is not clear, in particular the role of genetic factors. Previous work in Caenorhabditis elegans defined a characteristic worm gut microbiota significantly influenced by host genetics. The current work explores the role of central regulators of host immunity and stress resistance, employing qPCR and CFU counts to measure abundance of core microbiota taxa in mutants raised on synthetic communities of previously-isolated worm gut commensals. This revealed a bloom, specifically of Enterobacter species, in immune-compromised TGFß/BMP mutants. Imaging of fluorescently labeled Enterobacter showed that TGFß/BMP-exerted control operated primarily in the anterior gut and depended on multi-tissue contributions. Enterobacter commensals are common in the worm gut, contributing to infection resistance. However, disruption of TGFß/BMP signaling turned a normally beneficial Enterobacter commensal to pathogenic. These results demonstrate specificity in gene-microbe interactions underlying gut microbial homeostasis and highlight the pathogenic potential of their disruption.


Assuntos
Proteínas Morfogenéticas Ósseas/imunologia , Proteínas de Caenorhabditis elegans/imunologia , Caenorhabditis elegans/imunologia , Microbioma Gastrointestinal/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Animais Geneticamente Modificados , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/microbiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Enterobacter/genética , Enterobacter/imunologia , Enterobacter/fisiologia , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Homeostase/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Mutação/imunologia , Dinâmica Populacional , RNA Ribossômico 16S/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
6.
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
7.
Int J Mol Sci ; 20(1)2018 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-30587780

RESUMO

Osteoporosis represents the most common bone disease worldwide and results in a significantly increased fracture risk. Extrinsic and intrinsic factors implicated in the development of osteoporosis are also associated with delayed fracture healing and impaired bone regeneration. Based on a steadily increasing life expectancy in modern societies, the global implications of osteoporosis and impaired bone healing are substantial. Research in the last decades has revealed several molecular pathways that stimulate bone formation and could be targeted to treat both osteoporosis and impaired fracture healing. The identification and development of therapeutic approaches modulating bone formation, rather than bone resorption, fulfils an essential clinical need, as treatment options for reversing bone loss and promoting bone regeneration are limited. This review focuses on currently available and future approaches that may have the potential to achieve these aims.


Assuntos
Anabolizantes/uso terapêutico , Regeneração Óssea/fisiologia , Osteoporose/tratamento farmacológico , Anticorpos Neutralizantes/uso terapêutico , Proteínas Morfogenéticas Ósseas/imunologia , Proteínas Morfogenéticas Ósseas/metabolismo , Fraturas Ósseas/tratamento farmacológico , Humanos , Osteoporose/metabolismo , Osteoporose/patologia , Hormônio Paratireóideo/uso terapêutico , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Via de Sinalização Wnt
8.
Front Immunol ; 9: 2467, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30410490

RESUMO

Osteocytes are terminally differentiated cells of the osteoblast lineage. They are involved in the regulation of bone remodeling by increasing osteoclast formation or decreasing bone formation by the secretion of the osteoblast inhibitor sclerostin. Monoclonal antibody anti-sclerostin, Romosozumab, has been developed and tested in clinical trials in patients with osteoporosis. In the last years, the role of osteocytes in the development of osteolytic bone lesions that occurs in multiple myeloma, have been underlined. Myeloma cells increase osteocyte death through the up-regulation of both apoptosis and autophagy that, in turn, triggers osteoclast formation, and activity. When compared to healthy controls, myeloma patients with bone disease have higher osteocyte cell death, but the treatment with proteasome inhibitor bortezomib has been shown to maintain osteocyte viability. In preclinical mouse models of multiple myeloma, treatment with blocking anti-sclerostin antibody increased osteoblast numbers and bone formation rate reducing osteolytic bone lesions. Moreover, the combination of anti-sclerostin antibody and the osteoclast inhibitor zoledronic acid increased bone mass and fracture resistance synergistically. However, anti-sclerostin antibody did not affect tumor burden in vivo or the efficacy of anti-myeloma drugs in vitro. Nevertheless, the combination therapy of anti-sclerostin antibody and the proteasome inhibitor carfilzomib, displayed potent anti-myeloma activity as well as positive effects on bone disease in vivo. In conclusion, all these data suggest that osteocytes are involved in myeloma bone disease and may be considered a novel target for the use of antibody-mediated anti-sclerostin therapy also in multiple myeloma patients.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Doenças Ósseas/patologia , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/imunologia , Marcadores Genéticos/imunologia , Mieloma Múltiplo/patologia , Osteócitos/patologia , Animais , Apoptose/imunologia , Bortezomib/farmacologia , Humanos , Camundongos , Osteogênese/fisiologia , Osteólise/patologia , Osteólise/prevenção & controle , Ácido Zoledrônico/farmacologia
9.
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
10.
Curr Osteoporos Rep ; 16(3): 269-276, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29589203

RESUMO

PURPOSE OF REVIEW: Numerous forms of osteoporosis in childhood are characterized by low bone turnover (for example, osteoporosis due to neuromuscular disorders and glucocorticoid exposure). Anti-resorptive therapy, traditionally used to treat osteoporosis in the young, is associated with further reductions in bone turnover, raising concerns about the long-term safety and efficacy of such therapy. These observations have led to increasing interest in the role of anabolic therapy to treat pediatric osteoporosis. RECENT FINDINGS: While growth hormone and androgens appears to be relatively weak anabolic modulators of bone mass, emerging therapies targeting bone formation pathways (anti-transforming growth factor beta antibody and anti-sclerostin antibody) hold considerable promise. Teriparatide remains an attractive option that merits formal study for patients post-epiphyseal fusion, although it must be considered that adult studies have shown its effect is blunted when administered following bisphosphonate therapy. Mechanical stimulation of bone through whole body vibration therapy appears to be much less effective than bisphosphonate therapy for treating osteoporosis in children. New anabolic therapies which target important pathways in skeletal metabolism merit further study in children, including their effects on fracture risk reduction and after treatment discontinuation.


Assuntos
Anabolizantes/uso terapêutico , Androgênios/uso terapêutico , Anticorpos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Osteoporose/tratamento farmacológico , Vibração/uso terapêutico , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/imunologia , Criança , Marcadores Genéticos/imunologia , Humanos , Teriparatida/uso terapêutico , Testosterona/uso terapêutico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/imunologia
11.
Head Neck ; 40(7): 1453-1460, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29522281

RESUMO

BACKGROUND: Anti-Sclerostin antibody (Scl-Ab) is a promising new bone anabolic therapy. Although anti-Scl-Ab stimulates bone formation and repair in the appendicular and axial skeleton, its efficacy in the craniofacial skeleton is still poorly understood. METHODS: Using an established model of Down syndrome-dependent bone deficiency, 10 Ts65Dn mice and 10 wild-type mice were treated weekly via i.v. tail vein injection with vehicle or anti-Sclerostin for 3 weeks and euthanized 1 week after. RESULTS: Wild-type mice treated with the anti-Scl-Ab had increased mandibular bone, trabecular thickness, and alveolar height compared with controls. Anti-Scl-Ab increased Ts65Dn mandibular bone parameters such that they were statistically indistinguishable from those in vehicle-treated wild-type mandibles. CONCLUSION: Treatment with anti-Scl-Ab significantly increased mandibular bone mass and alveolar height in wild type mice and normalized mandibular bone mass and alveolar height in Ts65Dn mice. The anti-Scl-Ab therapy represents a novel method for increasing mandibular bone formation.


Assuntos
Anticorpos/farmacologia , Proteínas Morfogenéticas Ósseas/imunologia , Glicoproteínas/imunologia , Mandíbula/fisiologia , Osteogênese/efeitos dos fármacos , Processo Alveolar/efeitos dos fármacos , Processo Alveolar/fisiologia , Animais , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular , Mandíbula/efeitos dos fármacos , Camundongos Mutantes , Osteogênese/fisiologia
12.
J Rheumatol ; 45(5): 630-637, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29419466

RESUMO

OBJECTIVE: The early diagnosis of inflammatory bowel disease (IBD)-associated spondyloarthritis (SpA/IBD) in patients affected by IBD represents a major topic in clinical practice; in particular, to date there are no available serum biomarkers revealing the presence of joint inflammation in these patients. Sclerostin (SOST), an antagonist of the Wnt/ß-catenin pathway, and antisclerostin-immunoglobulin G (anti-SOST-IgG) have been recently studied in patients with ankylosing spondylitis (AS) as a putative marker of disease activity. METHODS: SOST and anti-SOST-IgG serum levels were assayed in 125 patients with IBD, 85 with axial or peripheral SpA, and in control groups (patients with AS and rheumatoid arthritis, and healthy individuals). The diagnostic performance in discriminating the presence of SpA/IBD was assessed for both candidate biomarkers. RESULTS: Patients affected by SpA/IBD with axial involvement displayed significantly lower levels of SOST and higher levels of anti-SOST-IgG compared to patients with only peripheral arthritis, IBD, and controls. Moreover, SOST and anti-SOST-IgG serum levels were inversely correlated and were associated with the duration of articular symptoms. Both biomarkers showed good accuracy in predicting the presence of axial SpA in patients with IBD. CONCLUSION: We demonstrated that in patients with IBD, SOST and anti-SOST-IgG might represent novel biomarkers to assess the presence of axial joint involvement. Moreover, the development of anti-SOST-IgG and the subsequent decrease of SOST serum levels could play a role in the pathogenesis of SpA/IBD.


Assuntos
Anticorpos/sangue , Proteínas Morfogenéticas Ósseas/sangue , Proteínas Morfogenéticas Ósseas/imunologia , Marcadores Genéticos/imunologia , Imunoglobulina G/sangue , Doenças Inflamatórias Intestinais/sangue , Espondilite Anquilosante/sangue , Espondilite Anquilosante/diagnóstico , Adulto , Complexo Antígeno-Anticorpo/sangue , Biomarcadores/sangue , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Curva ROC , Análise de Regressão , Espondilite Anquilosante/complicações , Estatísticas não Paramétricas
13.
Z Gerontol Geriatr ; 51(5): 550-556, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28364259

RESUMO

Previous studies have demonstrated the effects of sclerostin antibody (Scl-Ab) and parathyroid hormone (1-34, PTH) on healing in osteoporosis; however, reports about the combined effects of Scl-Ab plus PTH on osteoporosis are limited. This study was designed to investigate the impact of combined treatment with Scl-Ab and PTH on osteoporosis healing in ovariectomized (OVX) rats. After bilateral ovariectomy, 12 weeks were allowed to pass for the establishment of standard conditions for osteoporosis in animal models. The rats then randomly received a vehicle (control), Scl-Ab (25 mg/kg body weight, twice weekly), PTH (60 µg/kg, three times per week) or PTH plus Scl-Ab until death at 12 weeks. The blood and distal femurs of the rats were harvested for evaluation. The results of treatment for osteoporosis were evaluated by serum analysis, histology, microcomputed tomography (micro-CT) and biomechanical tests. Results from this study indicated that PTH + Scl-Ab had stronger effects on the prevention and treatment of osteoporosis than either of the monotherapies in OVX rats. The PTH + Scl-Ab produced the strongest effects on bone volume fraction (BV/TV), bone trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular spacing (Tb.Sp), bone mineral density (BMD) and strength of distal femurs and increased the levels of procollagen type I N­terminal propeptide (PINP) and osteocalcin. In contrast, monotherapy with PTH or Scl-Ab showed no differences between treated groups in the assessment of the metaphysis of contralateral femurs by histology, serum, biomechanical tests and micro-CT. These results seem to indicate that Scl-Ab plus PTH has an additive effect on osteoporosis in OVX rats.


Assuntos
Anticorpos/farmacologia , Proteínas Morfogenéticas Ósseas/imunologia , Marcadores Genéticos/imunologia , Osteogênese/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Animais , Anticorpos/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Feminino , Humanos , Ovariectomia , Hormônio Paratireóideo/administração & dosagem , Ratos , Ratos Sprague-Dawley , Microtomografia por Raio-X
14.
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
15.
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
16.
Expert Opin Biol Ther ; 18(2): 149-157, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29113523

RESUMO

INTRODUCTION: Osteoporosis is the most widespread skeletal disease requiring innovative therapeutic strategies for its management. The understanding of receptor activator of nuclear factor kappa-B ligand (RANKL) and sclerostin's role in bone cell biology is completely changing the therapeutic landscape. RANKL supports osteoclast formation and activity and is mainly produced by cells of osteoblastic lineage. Sclerostin, an antagonist of the Wnt pathway, has a key role in bone formation and is mainly secreted by osteocytes. High levels of RANKL and sclerostin have been detected in osteoporosis, leading to the production of antibodies able to neutralize their activity. AREAS COVERED: In this review, the authors give an overview and discuss the literature and data on denosumab and romosozumab to treat osteoporosis. Clinical studies indicate that long-term treatment with denosumab causes a continuous increase in bone mineral density with low incidence of adverse effects. Romosozumab treatment gives increases bone formation and improves bone mineral density (BMD) though further studies are needed to better evaluate the adverse effects. EXPERT OPINION: Denosumab and romosozumab show promise in the treatment of osteoporosis. Furthermore, their different mechanisms of action compared to existing anti-osteoporotic drugs may permit alternative strategies for osteoporosis treatment down the line


Assuntos
Anticorpos Monoclonais/uso terapêutico , Osteoporose/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Densidade Óssea/efeitos dos fármacos , Proteínas Morfogenéticas Ósseas/imunologia , Ensaios Clínicos como Assunto , Denosumab/uso terapêutico , Feminino , Marcadores Genéticos/imunologia , Humanos , Osteoporose/patologia , Ligante RANK/imunologia , Ligante RANK/metabolismo
17.
Exp Cell Res ; 361(2): 225-235, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29074370

RESUMO

Pluripotent stem cell activity is essential to maintain regeneration and homeostasis in the Drosophila midgut following environmental challenges. Although multiple pathways have been implicated in epithelial renewal, the underlying regulatory mechanisms and correlations between relevant genes and pathways remain elusive. In this study, we show that the zinc finger protein CG12744 plays an important role in the differentiation and regeneration of epithelial cells in response to oral infection with Erwinia carotovora carotovora 15. Knocking down CG12744 in enteroblasts decreased the post-infection proportion of enteroblasts and enterocytes and increased the post-infection number of enteroendocrine cells. In addition, in precursors, CG12744 affected the Osa, jun-N-terminal kinase and bone morphogenetic protein signaling pathways to control enterocyte differentiation. Finally, CG12744 maintained epithelial architecture and cell fate in enterocytes following an acute infectious challenge.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Enterócitos/metabolismo , Células Epiteliais/metabolismo , Pectobacterium carotovorum/fisiologia , Dedos de Zinco/genética , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/imunologia , Diferenciação Celular , Proteínas de Ligação a DNA/imunologia , Proteínas de Drosophila/imunologia , Drosophila melanogaster/imunologia , Drosophila melanogaster/microbiologia , Enterócitos/imunologia , Enterócitos/microbiologia , Células Enteroendócrinas/imunologia , Células Enteroendócrinas/metabolismo , Células Enteroendócrinas/microbiologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Feminino , Regulação da Expressão Gênica , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Intestinos/microbiologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Masculino , Pectobacterium carotovorum/patogenicidade , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Regeneração/genética , Regeneração/imunologia , Transdução de Sinais , Dedos de Zinco/imunologia
18.
Blood ; 129(26): 3452-3464, 2017 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-28515094

RESUMO

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM.


Assuntos
Densidade Óssea/efeitos dos fármacos , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Fraturas Ósseas/prevenção & controle , Osteócitos/química , Osteogênese/efeitos dos fármacos , Animais , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Proteínas Morfogenéticas Ósseas/imunologia , Linhagem Celular Tumoral , Difosfonatos/uso terapêutico , Marcadores Genéticos/imunologia , Humanos , Imidazóis/uso terapêutico , Camundongos , Mieloma Múltiplo/complicações , Células Tumorais Cultivadas , Ácido Zoledrônico
19.
Calcif Tissue Int ; 101(2): 217-228, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28391431

RESUMO

Open fractures remain a challenge in orthopedics. Current strategies to intervene are often inadequate, particularly in severe fractures or when treatment is delayed. Sclerostin is a negative regulator of bone growth and sclerostin-neutralizing antibodies (Scl-Ab) can increase bone mass and strength. The application of these antibodies to improve orthopedic repair has shown varied results, and may be dependent on the location and severity of the bony injury. We examined Scl-Ab treatment within an established rat osteotomy model with periosteal stripping analogous to open fracture repair. In one study, Scl-Ab was given 25 mg/kg bi-weekly, either from the time of fracture or from 3 weeks post-fracture up to an end-point of 12 weeks. A second study treated only delayed union open fractures that did not show radiographic union by week 6 post-fracture. Outcome measures included radiographic union, microCT analysis of bone volume and architecture, and histology. In the first study, Scl-Ab given from either 0 or 3 weeks significantly improved callus bone volume (+52%, p < 0.05 and +58%, p < 0.01) at 12 weeks, as well as strength (+48%, p < 0.05 and +70%, p < 0.05). Despite these improvements, union rate was not changed. In the second study treating only established delayed fractures, bony callus volume was similarly increased by Scl-Ab treatment; however, this did not translate to increased biomechanical strength or union improvement. Sclerostin antibody treatment has limited effects on the healing of challenging open fractures with periosteal stripping, but shows the greatest benefits on callus size and strength with earlier intervention.


Assuntos
Anticorpos/farmacologia , Densidade Óssea/efeitos dos fármacos , Proteínas Morfogenéticas Ósseas/imunologia , Calo Ósseo/patologia , Marcadores Genéticos/imunologia , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Modelos Animais de Doenças , Fraturas do Fêmur/tratamento farmacológico , Fraturas do Fêmur/patologia , Fêmur/efeitos dos fármacos , Fêmur/patologia , Consolidação da Fratura/efeitos dos fármacos , Masculino , Osteogênese/efeitos dos fármacos , Osteotomia/métodos , Ratos
20.
Bone ; 96: 3-7, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28115281

RESUMO

Based on a platform of strong preclinical data, several studies in humans have demonstrated that inhibiting sclerostin with specific antibodies results in a brisk albeit transient anabolic response in the skeleton without an accompanying increase in bone resorption. Impressive increases in bone mineral density and bone strength have been demonstrated. Other than mild injection site reactions, therapy for up to 2years has been well tolerated. The restriction of sclerostin expression almost exclusively to skeletal tissues, coupled with the absence of recognized medical problems in patients with heterozygous sclerostin deficiency, provides promise that the drug can be used safely. Recent results from a Phase 3 fracture trial suggest that anti-sclerostin therapy will be a useful and welcomed new treatment for patients with severe osteoporosis in need of skeletal reconstruction.


Assuntos
Anticorpos/uso terapêutico , Proteínas Morfogenéticas Ósseas/imunologia , Ensaios Clínicos como Assunto , Humanos , Osteoporose/tratamento farmacológico
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