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1.
Life Sci ; 244: 117336, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972206

RESUMO

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.


Assuntos
Reabsorção Óssea/prevenção & controle , Ácido Oleanólico/análogos & derivados , Osteogênese/efeitos dos fármacos , Ovariectomia/efeitos adversos , Substâncias Protetoras/farmacologia , Ligante RANK/metabolismo , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Feminino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ácido Oleanólico/farmacologia , Ligante RANK/genética , Transdução de Sinais
3.
Nat Commun ; 10(1): 4579, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594926

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive bone erosion. Leflunomide is originally developed to suppress inflammation via its metabolite A77 1726 to attenuate bone erosion. However, distinctive responsiveness to Leflunomide is observed among RA individuals. Here we show that Leflunomide exerts immunosuppression but limited efficacy in RA individuals distinguished by higher serum C-reactive protein (CRPHigher, CRPH), whereas the others with satisfactory responsiveness to Leflunomide show lower CRP (CRPLower, CRPL). CRP inhibition decreases bone erosion in arthritic rats. Besides the immunomodulation via A77 1726, Leflunomide itself induces AHR-ARNT interaction to inhibit hepatic CRP production and attenuate bone erosion in CRPL arthritic rats. Nevertheless, high CRP in CRPH rats upregulates HIF1α, which competes with AHR for ARNT association and interferes Leflunomide-AHR-CRP signaling. Hepatocyte-specific HIF1α deletion or a HIF1α inhibitor Acriflavine re-activates Leflunomide-AHR-CRP signaling to inhibit bone erosion. This study presents a precision medicine-based therapeutic strategy for RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Reabsorção Óssea/prevenção & controle , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Imunossupressores/farmacologia , Leflunomida/farmacologia , Acriflavina/farmacologia , Acriflavina/uso terapêutico , Adulto , Animais , Artrite Experimental/sangue , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Reabsorção Óssea/sangue , Reabsorção Óssea/imunologia , Proteína C-Reativa/análise , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , Células Cultivadas , Colágeno/imunologia , Feminino , Hepatócitos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Imunossupressores/uso terapêutico , Leflunomida/uso terapêutico , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Ratos , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Resultado do Tratamento
4.
Phytother Res ; 33(11): 2948-2959, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31478281

RESUMO

The balance between the osteoblasts and the osteoclasts is important for the maintenance of the skeleton of the human body. The osteoclasts absorb bone after differentiated into polymorphonuclear cells by the fusion of monocytes/macrophages. We have found that 6,7,4'-Trihydroxyflavone (THF), a compound from the heartwood of Dalbergia Odorifera inhibits receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation, actin ring formation, and bone resorption in RAW 264.7 cells and bone marrow macrophage. THF significantly inhibited the c-Jun-N-terminal kinase signaling pathway without affecting extracellular signal-regulated kinase, p38, and AKT signaling. Moreover, THF inhibited the expression of c-Fos, nuclear factor-activated T cells cytoplasm 1, cathepsin K, and c-src by RANKL. We used a lipopolysaccharide (LPS)-induced bone loss model in mice. Consequently, bone volume per tissue volume, trabecular number's reduction was recovered in THF-treated mice, and trabecular separation's augmentation was also attenuated by THF administration. In summary, THF inhibits RANKL-induced osteoclast differentiation by MAPK signaling pathway and inhibits bone resorption by destroying the actin ring in mature osteoclasts. THF also prevented LPS-induced bone loss in a mice model. Thus, THF may be useful in the treatment of bone diseases associated with excessive osteoclast differentiation and bone resorption.


Assuntos
Reabsorção Óssea/prevenção & controle , Diferenciação Celular/efeitos dos fármacos , Isoflavonas/farmacologia , Osteoclastos/efeitos dos fármacos , Animais , Células Cultivadas , Dalbergia/química , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
5.
Int Immunopharmacol ; 75: 105826, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31437791

RESUMO

Bone homeostasis requires a dynamic balance between osteogenesis and osteoclastogenesis, and osteolytic disorders are mainly attributed to aberrant osteoclastogenesis and bone resorption. Accumulating evidence has demonstrated that cyclin-dependent kinase 9 (CDK9) regulates some inflammatory diseases without affecting the cell cycle. Whether the specific inhibitor of CDK9, LDC000067 (abbreviated as LDC067), helps to prevent from osteolytic disorders has not been fully elucidated. Interestingly, this study demonstrated that LDC067 inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption in vitro, and suppressed the expression of osteoclast-related marker genes such as cathepsin K (CTSK), tartrate-resistant acid phosphatase (TRAP), dendrite cell-specific transmembrane protein (DC-STAMP), V-ATPase D2, calcitonin receptor (CTR) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1). The bone protective effects of LDC067 can be partly explained by its suppression of nuclear factor-kappa B (NF-κB)-mediated NFATc1 activation via AKT signalling pathway. In keeping with the results obtained in vitro, inhibition of CDK9 with LDC067 was observed to delay subchondral osteolysis and substantially ameliorate LPS-induced osteolysis in murine calvaria. Collectively, these results highlight the positive effects of LDC067 in preventing osteolytic disorders and indicate that this CDK9 inhibitor may a promising therapeutic agent.


Assuntos
Reabsorção Óssea/prevenção & controle , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Reabsorção Óssea/induzido quimicamente , Osso e Ossos/citologia , Bovinos , Células Cultivadas , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Osteoclastos/fisiologia , Ligante RANK
6.
Nutrients ; 11(9)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461862

RESUMO

We determined the effects of a low glycemic-index pulse-based diet (i.e., containing lentils, chick peas, beans, and split peas) compared to a typical hospital diet on insulin sensitivity assessed by the Matsuda index from the insulin and glucose response to a two-hour oral glucose tolerance test, insulin resistance assessed by the homeostatic model assessment of insulin resistance (HOMA-IR), bone resorption assessed by 24 h excretion of urinary n-telopeptides(Ntx) and cardiovascular risk factors (blood lipids, blood pressure, arterial stiffness and heart rate variability) during bed rest. Using a randomized, counter-balanced cross-over design with one-month washout, six healthy individuals (30 ± 12 years) consumed the diets during four days of bed rest. The Matsuda index, HOMA-IR, urinary Ntx and cardiovascular risk factors were determined at baseline and after the last day of bed rest. Compared to the typical hospital diet, the pulse-based diet improved the Matsuda index (indicating increased insulin sensitivity; baseline to post-bed rest: 6.54 ± 1.94 to 6.39 ± 2.71 hospital diet vs. 7.14 ± 2.36 to 8.75 ± 3.13 pulse-based diet; p = 0.017), decreased HOMA-IR (1.38 ± 0.54 to 1.37 ± 0.50 hospital diet vs. 1.48 ± 0.54 to 0.88 ± 0.37 pulse-based diet; p = 0.022), and attenuated the increase in Ntx (+89 ± 75% hospital diet vs. +33 ± 20% pulse-based diet; p = 0.035). No differences for changes in cardiovascular risk factors were found between the two diet conditions, with the exception of decreased diastolic blood pressure during day three of bed rest in the pulse-based versus hospital diet (61 ± 9 vs. 66 ± 7 mmHg; p = 0.03). A pulse-based diet was superior to a hospital diet for maintaining insulin sensitivity, preventing insulin resistance, attenuating bone resorption and decreasing diastolic blood pressure during four days of bed rest.


Assuntos
Repouso em Cama/efeitos adversos , Reabsorção Óssea/prevenção & controle , Doenças Cardiovasculares/prevenção & controle , Fabaceae , Índice Glicêmico , Resistência à Insulina , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Glicemia/metabolismo , Pressão Sanguínea , Reabsorção Óssea/fisiopatologia , Reabsorção Óssea/urina , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/fisiopatologia , Colágeno/urina , Estudos Cross-Over , Método Duplo-Cego , Feminino , Frequência Cardíaca , Humanos , Insulina/sangue , Lipídeos/sangue , Masculino , Fatores de Proteção , Saskatchewan , Fatores de Tempo , Rigidez Vascular , Adulto Jovem
7.
South Med J ; 112(8): 428-432, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31375839

RESUMO

OBJECTIVES: Individuals with intellectual disabilities (IDs) are at increased risk for low bone mass and fragility fractures, and those who are nonambulatory may be at even higher risk. Patients with IDs often are vitamin D deficient, but there is little information concerning how vitamin D treatment of patients with IDs affects markers of bone formation and resorption. METHODS: We performed a retrospective analysis of 23 institutionalized individuals with IDs who were the subject of a performance improvement continuing medical education project designed to reduce risk for fracture by optimizing serum vitamin D levels. Patients were divided into those with normal weight-bearing (NWB) physical activity (15 patients: 14 men, 1 woman) and those with low weight-bearing (LWB) physical activity (8 patients: 7 men, 1 woman). All of the subjects received 50,000 IU of vitamin D3 weekly for 4 to 8 weeks, followed by a maintenance dose of 50,000 IU monthly for 3 to 6 months. Bone turnover markers (type 1 cross-linked C-telopeptide [CTX], type 1 N-terminal propeptide [P1NP], and parathyroid hormone [PTH]) and 25(OH)-vitamin D levels were measured before and after vitamin D supplementation. RESULTS: At baseline, there were no significant differences in the serum levels of 25OH-D, PTH, P1NP, or CTX between the two groups (NWB and LWB). Vitamin D levels were increased to a higher value in LWB subjects than in NWB subjects (61 ± 4.1 vs 48.4 ± 2.2 ng/mL, P < 0.001). Vitamin D treatment suppressed PTH (20.5% ± 14.3% vs 31.4% ± 7.7%, P = not significant) and P1NP (33.0% ± 6.2% vs 29.4% ± 6.9%, P = not significant) similarly in both groups. Although CTX levels declined by 26.4% ± 5.3% (P = 0.0002) in NWB individuals (as anticipated), vitamin D supplementation resulted in an unexpected 25.8% ± 8% increase (P = 0.01) in CTX in LWB individuals, suggesting osteoclast activation. CONCLUSIONS: Although high-dose vitamin D appeared to suppress osteoclast activity in NWB adults with IDs, the increase in serum CTX levels in those with LWB activity implies activation of osteoclasts that could exacerbate their unique low bone mass and increase fracture risk. The results support the use of a lower-dose vitamin D regimen in this patient group with LWB.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/prevenção & controle , Exercício/fisiologia , Deficiência Intelectual/complicações , Deficiência Intelectual/tratamento farmacológico , Vitamina D/farmacologia , Suporte de Carga/fisiologia , Adulto , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vitaminas/farmacologia , Adulto Jovem
8.
Nat Commun ; 10(1): 2958, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273195

RESUMO

RNAi-based bone anabolic gene therapy has demonstrated initial success, but many practical challenges are still unmet. Here, we demonstrate that a recombinant adeno-associated virus 9 (rAAV9) is highly effective for transducing osteoblast lineage cells in the bone. The adaptor protein Schnurri-3 (SHN3) is a promising therapeutic target for osteoporosis, as deletion of shn3 prevents bone loss in osteoporotic mice and short-term inhibition of shn3 in adult mice increases bone mass. Accordingly, systemic and direct joint administration of an rAAV9 vector carrying an artificial-microRNA that targets shn3 (rAAV9-amiR-shn3) in mice markedly enhanced bone formation via augmented osteoblast activity. Additionally, systemic delivery of rAAV9-amiR-shn3 in osteoporotic mice counteracted bone loss and enhanced bone mechanical properties. Finally, we rationally designed a capsid that exhibits improved specificity to bone by grafting the bone-targeting peptide motif (AspSerSer)6 onto the AAV9-VP2 capsid protein. Collectively, our results identify a bone-targeting rAAV-mediated gene therapy for osteoporosis.


Assuntos
Reabsorção Óssea/complicações , Reabsorção Óssea/prevenção & controle , Osso e Ossos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dependovirus/metabolismo , Inativação Gênica , Osteoporose/complicações , Animais , Reabsorção Óssea/patologia , Osso e Ossos/virologia , Capsídeo/metabolismo , Cartilagem/virologia , Modelos Animais de Doenças , Deleção de Genes , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Osteoblastos/metabolismo , Sorogrupo
9.
Maturitas ; 127: 35-42, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31351518

RESUMO

Gonadal sex steroids play a pivotal role in bone health. Medical and surgical therapies for gender dysphoria in both adolescents and adults can lead to skeletal changes. This review evaluates the literature on transgender bone health, and how the data can be translated into clinical practice.


Assuntos
Densidade Óssea , Pessoas Transgênero , Acidentes por Quedas , Animais , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/prevenção & controle , Fraturas Ósseas/prevenção & controle , Hormônios Esteroides Gonadais/uso terapêutico , Humanos
10.
Osteoporos Int ; 30(8): 1581-1589, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31115592

RESUMO

INTRODUCTION: To investigate the effect of zoledronic acid on periprosthetic bone mineral density (BMD) and bone metabolism markers after primary total hip arthroplasty in females with postmenopausal osteoporosis. METHODS: From November 2015 to April 2016, 40 female patients who met the inclusion criteria were randomized into two groups: a control group (calcium + calcitriol) and a zoledronic acid group (calcium + calcitriol + zoledronic acid). At 1 week and 3, 6, and 12 months after operation, BMD was obtained through dual-energy X-ray absorptiometry (DEXA). At pre-operation and at 3, 6, and 12 months after the operation, levels of bone metabolism markers were obtained by serum examination. RESULTS: Loss of BMD was significantly more pronounced in the control group than in the ZOL group in zones 1, 4, 6, and 7 at 6 months and in zones 1, 2, 4, 6, and 7 at 12 months after the operation. The levels of bone-resorption marker (ß-CTX) were significantly lower in the ZOL group than in the control group at 3, 6, and 12 months after operation. The levels of bone-formation marker (TP1NP) performed statistically differences only at 12 months after the operation in these two groups. CONCLUSIONS: Receiving an intravenous infusion of 5 mg zoledronic acid after THA can effectively reduce periprosthetic BMD loss and improve bone remodeling in females with postmenopausal osteoporosis. Zoledronic acid significantly inhibited bone mass loss in zones 1, 2, 4, 6, and 7 after THA and inhibited bone-resorption marker (ß-CTX) to improve bone remodeling. Zoledronic acid treatment is potentially important for patients with osteoporosis after THA.


Assuntos
Artroplastia de Quadril/efeitos adversos , Conservadores da Densidade Óssea/farmacologia , Densidade Óssea/efeitos dos fármacos , Prótese de Quadril , Osteoporose Pós-Menopausa/tratamento farmacológico , Ácido Zoledrônico/farmacologia , Absorciometria de Fóton/métodos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/etiologia , Reabsorção Óssea/fisiopatologia , Reabsorção Óssea/prevenção & controle , Calcitriol/uso terapêutico , Carbonato de Cálcio/uso terapêutico , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Cuidados Pós-Operatórios/métodos , Método Simples-Cego , Ácido Zoledrônico/uso terapêutico
11.
Biomed Pharmacother ; 115: 108916, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054506

RESUMO

Lipopolysaccharide (LPS) can induce bone loss by stimulating osteoclast formation. Colony-stimulating factor 1 receptor (CSF 1R) inhibitors have great potential for the treatment of rheumatoid arthritis and tumor-related bone erosion. However, its role in LPS-induced bone loss is still not clarified. In this study, we observed the effects of CSF 1R inhibitor, PLX3397, on LPS-induced bone damage in an animal model. The models were established by LPS administration in male Sprague-Dawley rats. PLX3397 (30 mg/kg body weight) was given by oral gavage. MicroCT analysis, biomechanical properties, biomarker assay, histological examination, and mRNA expression of osteoclast differentiation-related genes (Traf6, Fra1, c-fos and NFATc1) were performed on the 8th week. LPS induced bone loss was shown as the decrease in bone volume fraction and trabecular number and increase in trabecular separation (p < 0.05). LPS exposure also markedly decreased the bone biomechanical properties. PLX3397 significantly abolished the LPS-induced bone microstructure damage (p < 0.05) and loss of biomechanical properties. PLX3397 also inhibited the increases of serum tartrate-resistant acid phosphatase 5b level enhanced by LPS (p < 0.05). PLX3397 attenuated the high expression of Traf6, Fra1, c-fos and NFATc1 stimulated by LPS. Our data demonstrated that PLX3397, a type of CSF 1R inhibitor, can suppress LPS-induced bone loss via the inhibition osteoclast formation.


Assuntos
Aminopiridinas/farmacologia , Reabsorção Óssea/prevenção & controle , Osteoclastos/efeitos dos fármacos , Osteoporose/prevenção & controle , Pirróis/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/metabolismo , Osso Esponjoso/patologia , Modelos Animais de Doenças , Lipopolissacarídeos/farmacologia , Masculino , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoporose/induzido quimicamente , Osteoporose/metabolismo , Osteoporose/patologia , Ratos Sprague-Dawley , Tíbia/efeitos dos fármacos , Tíbia/metabolismo , Tíbia/patologia
12.
Nutrients ; 11(5)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075971

RESUMO

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia that induces other pathologies including diabetic retinopathy and bone disease. Adult Danio rerio (zebrafish) represents a powerful model to study both glucose and bone metabolism. Then, the aim of this study was to evaluate the effects of liquiritigenin (LTG) on blood glucose level and diabetes complications in hyperglycemic adult zebrafish. LTG is a flavonoid extracted from Glycyrrhiza glabra roots which possess important antioxidant, anti-inflammatory, and anti-diabetic properties. During four weeks of glucose treatment, LTG significantly prevented the onset of the hyperglycemia in adult zebrafish. Moreover, hyperglycemic fish showed increased advanced glycation end-products (AGEs) and parathormone levels whereas LTG completely prevented both of these metabolic alterations. Large bone-loss areas were found in the scales of glucose-treated fish whereas only small resorption lacunae were detected after glucose/LTG treatment. Biochemical and histological tartrate resistant acid phosphatase (TRAP) assays performed on explanted scales confirmed that LTG prevented the increase of osteoclastic activity in hyperglycemic fish. The osteoblastic alkaline phosphatase (ALP) activity was clearly lost in scales of glucose-treated fish whereas the co-treatment with LTG completely prevented such alteration. Gene expression analysis showed that LTG prevents the alteration in crucial bone regulatory genes. Our study confirmed that LTG is a very promising natural therapeutic approach for blood glucose lowering and to contrast the development of bone complications correlated to chronic hyperglycemia.


Assuntos
Glicemia/metabolismo , Reabsorção Óssea/prevenção & controle , Osso e Ossos/efeitos dos fármacos , Flavanonas/uso terapêutico , Glycyrrhiza/química , Hiperglicemia/prevenção & controle , Fitoterapia , Fosfatase Alcalina/metabolismo , Animais , Reabsorção Óssea/etiologia , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus/sangue , Diabetes Mellitus/patologia , Diabetes Mellitus/prevenção & controle , Modelos Animais de Doenças , Flavanonas/farmacologia , Expressão Gênica , Produtos Finais de Glicação Avançada/sangue , Hiperglicemia/sangue , Hiperglicemia/complicações , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Hormônio Paratireóideo/sangue , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Raízes de Plantas , Fosfatase Ácida Resistente a Tartarato/metabolismo , Peixe-Zebra
13.
Eur J Orthop Surg Traumatol ; 29(6): 1235-1242, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30989339

RESUMO

PURPOSE: Stem design is usually accused for proximal femoral remodeling following total hip arthroplasty (THA). The aim of this prospective study was to compare the in vivo changes in bone mineral density (BMD) of the proximal femur after implantation of cementless THA with two length alternative stems. METHODS: Between May 2011 and March 2014, 50 patients, who met our selection criteria and received cementless THA, randomized into two groups. Group A received cementless standard femoral stems, while group B received short stems. Harris Hip Score (HHS) and visual analog scale (VAS) were used for clinical assessment. Stem and cup positions and stability were radiologically evaluated. Dual-energy X-ray absorptiometry was used to follow and compare changes in BMD in different zones of proximal femur between both groups. RESULTS: After a mean follow-up of 21.4 ± 3.53 months, there was a significant (p < 0.05) improvement in mean HHS and VAS with no significant differences (p > 0.05) between groups. There was no significant difference (p > 0.05) between groups regarding radiological results and rates of complications. The mean overall BMD was decreased by 11.26% for group A and 8.68% for group B at the final follow-up (p > 0.05). The greatest loss was found in greater trochanter region for group A and so for group B, but to a lesser extent (p < 0.05). CONCLUSIONS: Cementless short stem was not able to hold back proximal femoral bone loss, but only can modify or decrease its incidence within limits.


Assuntos
Artroplastia de Quadril , Remodelação Óssea , Reabsorção Óssea , Fêmur , Prótese de Quadril/classificação , Complicações Pós-Operatórias , Absorciometria de Fóton/métodos , Idoso , Artroplastia de Quadril/efeitos adversos , Artroplastia de Quadril/instrumentação , Artroplastia de Quadril/métodos , Densidade Óssea , Reabsorção Óssea/diagnóstico , Reabsorção Óssea/etiologia , Reabsorção Óssea/prevenção & controle , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Humanos , Masculino , Osseointegração , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Desenho de Prótese , Resultado do Tratamento
14.
J Endocrinol Invest ; 42(9): 1125-1131, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30955181

RESUMO

OBJECTIVE: This study aimed to investigate the effects of liraglutide on bone metabolism markers in rat models with glucocorticoid-induced osteoporosis (GIOP), including the effects on bone mass, bone tissue microstructure, bone biomechanics, and bone turnover markers. METHOD: Thirty male Sprague-Dawley rats aged 8 weeks were randomly divided into three groups: the control group (n = 10) was intramuscularly injected with an equal volume of 0.9% sodium chloride, the dexamethasone group (n = 10) was intramuscularly injected with dexamethasone at 1 mg/kg (twice a week) to induce GIOP, the dexamethasone plus liraglutide group (n = 10) was subcutaneously injected with liraglutide at 200 µg/kg daily, simultaneously. The bilateral femurs and the fifth lumbar vertebrae were collected after 12 weeks to perform micro-computed tomography and bone biomechanical examinations. Also, tartrate-resistant acid phosphatase (TRACP), cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I), alkaline phosphatase (ALP), and osteocalcin (OC) were tested. RESULTS: The bone mineral density (BMD), bone microstructure, and bone biomechanical markers reduced significantly in the dexamethasone group compared with the control group. The bone resorption indicators (TRACP and CTX-I) increased, while the bone formation indicators (ALP and OC) decreased. After liraglutide treatment, BMD, bone microstructure, and bone biomechanical markers improved significantly. Moreover, TRACP and CTX-I decreased significantly, while ALP and OC increased compared with the dexamethasone group. CONCLUSIONS: Liraglutide improved BMD, bone microstructure, and bone strength and reversed GIOP, primarily through the reduction of bone resorption and promotion of bone formation.


Assuntos
Reabsorção Óssea/prevenção & controle , Glucocorticoides/efeitos adversos , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Animais , Biomarcadores/análise , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/induzido quimicamente , Masculino , Osteoporose/induzido quimicamente , Ratos , Ratos Sprague-Dawley
15.
Fertil Steril ; 111(5): 1020-1029.e2, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30922647

RESUMO

OBJECTIVE: To evaluate the potentially protective effects of oral contraceptives (OC) on bone loss in a large population of young women with anorexia nervosa (AN). DESIGN: Cross-sectional study. SETTING: University hospital. PATIENT(S): Three hundred and five patients with AN (99 of them using OC) and 121 age-matched controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Areal bone mineral density (aBMD) evaluated by dual-energy X-ray absorptiometry and bone turnover markers, with leptin evaluated concomitantly. RESULT(S): Although the AN patients taking OC presented lower aBMD compared with the controls at all bone sites, the whole body excepted, their aBMD values were systematically higher than those of AN patients who were not taking OC for the whole body and the lumbar spine, femoral neck, hip, and radius. These differences persisted after multiple adjustments. Preservation of aBMD improved with longer durations of OC use and shorter delays between disease onset and the start of OC. Moreover, patients with the lowest body mass index showed the best bone tissue responses to OC. Bone formation markers were systematically lower in the two groups of patients with AN compared with the controls. The markers of bone resorption were normalized in AN patients using OC. CONCLUSION(S): Although OC use does not provide total protection of aBMD, our data suggest that OC might be prescribed for young women with AN to limit their bone loss.


Assuntos
Anorexia Nervosa/tratamento farmacológico , Anorexia Nervosa/epidemiologia , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/epidemiologia , Reabsorção Óssea/prevenção & controle , Anticoncepcionais Orais/administração & dosagem , Adolescente , Adulto , Anorexia Nervosa/diagnóstico , Densidade Óssea/fisiologia , Reabsorção Óssea/diagnóstico , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Adulto Jovem
16.
Int J Mol Med ; 43(4): 1669-1678, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816431

RESUMO

Magnolol is the active component of the traditional Chinese medicine Magnolia officinalis, and has antioxidant, anti­inflammatory and anticancer activities, as well as an effect on bone metabolism in vitro. In the present study, it is reported that magnolol suppresses osteoclastogenesis in vivo and in vitro. Magnolol prevented ovariectomy­induced bone loss and osteoclastogenesis in vivo, and decreased the serum levels of C­terminal telopeptide of type 1 collagen, interleukin­6, tumor necrosis factor (TNF)­α and tartrate­resistant acid phosphatase 5B. In vitro, magnolol inhibited the osteoclastogenesis induced by the receptor activator for nuclear factor­κB ligand, and impaired the osteoclast function in bone marrow monocytes and RAW264.7 cells in a dose­dependent manner. Furthermore, magnolol suppressed the expression levels of the osteoclastogenesis markers cathepsin K, calcitonin receptor, matrix metalloproteinase 9, TNF receptor­associated factor 6 and tartrate­resistant acid phosphatase by inhibiting the nuclear factor­κB and mitogen­activated protein kinase pathways. Therefore, magnolol is a promising agent for the treatment of osteoporosis and associated disorders.


Assuntos
Compostos de Bifenilo/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/prevenção & controle , Lignanas/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Osteogênese , Ovariectomia/efeitos adversos , Actinas/metabolismo , Animais , Biomarcadores/metabolismo , Compostos de Bifenilo/farmacologia , Reabsorção Óssea/patologia , Lignanas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Células RAW 264.7
17.
J Craniofac Surg ; 30(4): 1085-1088, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30908448

RESUMO

BACKGROUND: Dental implants and bone augmentation are well-established procedures used for oral rehabilitation. There is an increasing interest in biological mediators used topically for prevention of bone resorption maybe enhancement of osseointegration of dental implants. The purpose of the manuscript is to describe preliminarily the effect of bisphosphonates on the ossification pattern of bone grafts in a rat model. MATERIAL AND METHODS: Twenty Wistar-derived male rats were divided into 2 groups study and control. Bone substitute was added to mandibular defects and was covered by a resorbable collagen membrane. In the study group, the membrane was soaked with bisphosphonates suspension. In the control group, the membrane was soaked with saline solution. Radiographic and histomorphometric evaluation were performed. RESULTS: Radiographically, it was found that bone density was significantly higher in the study group. Histomorphometric analysis revealed a trend of higher bone volume fraction along with reduced bone substitute volume fraction in the study group, and increased number of osteoclasts and blood vessels in the control group. CONCLUSIONS: Within the limitations of our study it was found that there is a trend of increasing bone quantity and radiographic bone density by application of bisphosphonates.


Assuntos
Reabsorção Óssea/prevenção & controle , Substitutos Ósseos/farmacologia , Difosfonatos/farmacologia , Animais , Densidade Óssea/efeitos dos fármacos , Colágeno , Implantação Dentária Endo-Óssea , Masculino , Mandíbula/citologia , Mandíbula/diagnóstico por imagem , Modelos Animais , Osseointegração/efeitos dos fármacos , Ratos , Ratos Wistar
18.
Biochem Pharmacol ; 163: 279-289, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30721671

RESUMO

Osteoporosis is a chronic bone lytic disease, because of inadequate bone ossification and/or excessive bone resorption. Even though drugs are currently available for the treatment of osteoporosis, there remains an unmet need for the development of more specific novel agents with less adverse effects. Dehydrocostus lactone (DHC), a natural sesquiterpene lactone, was previously found to affect the differentiation of inflammatory cells by inhibiting NF-κB pathways, and garnered much interest for its anti-cancer properties via SOCS-mediated cell cycle arrest and apoptosis. As NF-κB pathway plays an essential role in osteoclast differentiation, we sought to discover the biological effects of DHC on osteoclast differentiation and resorptive activity, as well as the underlying mechanisms on these effects. Our research found that DHC inhibited RANKL-induced osteoclast differentiation, bone resorption and osteoclast specific genes expression via suppression of NF-κB and NFAT signaling pathways in vitro. We further demonstrated that DHC protected against ovariectomy (OVX)-induced bone loss in mice and the protective effect was mediated at least in part through the attenuation of NF-κB signaling pathway. Thus, this study provides insight that DHC might be used as a potential pharmacological treatment for osteoporosis.


Assuntos
Lactonas/farmacologia , Osteoporose/prevenção & controle , Sesquiterpenos/farmacologia , Animais , Reabsorção Óssea/prevenção & controle , Sobrevivência Celular/efeitos dos fármacos , Feminino , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia , Ligante RANK
19.
J Am Soc Nephrol ; 30(2): 355-365, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30606784

RESUMO

BACKGROUND: Bone and mineral disorders commonly affect kidney transplant (KTx) recipients and have been associated with a high risk of fracture. Bisphosphonates may prevent or treat bone loss in such patients, but there is concern that these drugs might induce adynamic bone disease (ABD). METHODS: In an open label, randomized trial to assess the safety and efficacy of zoledronate for preventing bone loss in the first year after kidney transplant, we randomized 34 patients before transplant to receive zoledronate or no treatment. We used dual-energy x-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone biopsies to evaluate changes in bone in the 32 evaluable participants between the time of KTx and 12 months post-transplant. RESULTS: Both groups of patients experienced decreased bone turnover after KTx, but zoledronate itself did not affect this outcome. Unlike previous studies, DXA showed no post-transplant bone loss in either group; we instead observed an increase of bone mineral density in both lumbar spine and total hip sites, with a significant positive effect of zoledronate. However, bone biopsies showed post-transplant impairment of trabecular connectivity (and no benefit from zoledronate); HR-pQCT detected trabecular bone loss at the peripheral skeleton, which zoledronate partially attenuated. CONCLUSIONS: Current immunosuppressive regimens do not contribute to post-transplant central skeleton trabecular bone loss, and zoledronate does not induce ABD. Because fractures in transplant recipients are most commonly peripheral fractures, clinicians should consider bisphosphonate use in patients at high fracture risk who have evidence of significantly low bone mass at these sites at the time of KTx.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/prevenção & controle , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Ácido Zoledrônico/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Estudos Prospectivos
20.
Eur J Orthod ; 41(1): 1-8, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29608684

RESUMO

Background: Because orthodontic tooth movement is dependent upon osteoclast-mediated resorption of alveolar bone adjacent to the pressure side of tooth roots, biologic mediators that regulate osteoclasts can be utilized to control tooth movement. Objectives: To develop a novel method to locally enhance orthodontic anchorage. Methods: We encapsulated osteoprotegerin (OPG) in polymer microspheres and tested the effectiveness of microsphere encapsulated versus non-encapsulated OPG for enhancing orthodontic anchorage in a rodent model of tooth movement. A single injection of 1 mg/kg non-encapsulated or microsphere encapsulated OPG was delivered into the palatal mucosa mesial to the first maxillary molar 1 day prior to tooth movement. A positive control group received injections of 5 mg/kg non-encapsulated OPG every 3 days during tooth movement. After 28 days of tooth movement, hemi-maxillae and femurs were dissected. Molar mesial and incisor distal tooth movement was measured using stone casts that were scanned and magnified. Local alveolar, distant femur bone, and tooth root volumes were analyzed by micro computed tomography. Serum OPG levels were measured by ELISA. Osteoclast numbers were quantified by histomorphometry. Results: The single injection of microsphere encapsulated OPG significantly enhanced orthodontic anchorage, while the single injection of non-encapsulated OPG did not. Injection of encapsulated OPG inhibited molar mesial movement but did not inhibit incisor tooth movement, and did not alter alveolar or femur bone volume fraction, density, or mineral content. Multiple injections of 5 mg/kg non-encapsulated OPG enhanced orthodontic anchorage, but also inhibited incisor retraction and altered alveolar and femur bone quality parameters. Increased OPG levels were found only in animals receiving multiple injections of non-encapsulated 5 mg/kg OPG. Osteoclast numbers were higher upon tooth movement in animals that did not receive OPG. Osteoclast numbers in OPG injected animals were variable within groups. Conclusions: Microsphere encapsulation of OPG allows for controlled drug release, and enhances site-specific orthodontic anchorage without systemic side effects. With additional refinements, this drug delivery system could be applicable to a broad array of potential biologic orthodontic therapeutics.


Assuntos
Reabsorção Óssea/prevenção & controle , Procedimentos de Ancoragem Ortodôntica/métodos , Osteoprotegerina/administração & dosagem , Técnicas de Movimentação Dentária/métodos , Animais , Reabsorção Óssea/diagnóstico por imagem , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Incisivo/diagnóstico por imagem , Incisivo/efeitos dos fármacos , Masculino , Microesferas , Dente Molar/diagnóstico por imagem , Dente Molar/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoprotegerina/uso terapêutico , Ratos Sprague-Dawley , Microtomografia por Raio-X
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