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1.
J Bone Miner Metab ; 38(6): 806-818, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32656644

RESUMO

INTRODUCTION: Our previous studies demonstrated that a high bone turnover state under osteoporotic changes decreased the threshold of skeletal pain. Recent studies reported that the incidence of joint pain due to osteoarthritis (OA) in postmenopausal women was higher than that in males even with the same radiographic OA grade. The aim of this study was to evaluate whether a high bone turnover state affects the induction of pain-like behaviors in mild OA model mice. MATERIALS AND METHODS: We established mild OA model mice with accompanying osteoporotic changes by monosodium iodoacetate injection after ovariectomy. We assessed pain-like behaviors by von Frey test and paw-flick test; histological changes in OA joints; the expression of Runx2, Osterix, Osteocalcin, and Rankl; bone micro-architecture by µCT and measured serum tartrate-resistant acid-phosphatase 5b levels in the model mice. RESULTS: Pain-like behaviors in mice with OA and osteoporotic changes were significantly increased in comparison with those in OA mice without osteoporotic changes. The severity of histological OA changes did not differ significantly between the OA mice with and without osteoporotic changes. Bisphosphonate significantly improved pain-like behaviors accompanied with improvement in the high bone turnover state in the OA mice with osteoporosis, while it had no significant effect on pain-like behaviors in the OA mice without osteoporosis. In addition, the improvement was maintained for more than 4 weeks even after the discontinuation of bisphosphonate treatment. CONCLUSION: These results indicated that a high bone turnover state under osteoporotic changes could affect the induction of pain-like behaviors in mild OA model mice.


Assuntos
Comportamento Animal , Remodelação Óssea , Osteoartrite/complicações , Osteoporose/complicações , Osteoporose/fisiopatologia , Dor/etiologia , Animais , Remodelação Óssea/efeitos dos fármacos , Cartilagem/patologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Inibidores de Ciclo-Oxigenase/farmacologia , Difosfonatos/farmacologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Iodoacetatos , Masculino , Camundongos Endogâmicos C57BL , Osteoartrite/sangue , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteocalcina/genética , Osteocalcina/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoporose/sangue , Ovariectomia , Dor/sangue , Fosfatase Ácida Resistente a Tartarato/sangue , Microtomografia por Raio-X
2.
J Bone Miner Metab ; 38(6): 894-902, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32656645

RESUMO

INTRODUCTION: Rapid descent in bone mineral density (BMD) and ascent in bone turnover marker (BTM) occur within the short period following denosumab (Dmab) discontinuation. In addition, the incidence of vertebral fracture also rises within the short period. The purpose of this study is to investigate the effects of sequential therapy using zoledronic acid (ZOL) on any adverse events after Dmab discontinuation. MATERIALS AND METHODS: This study was a multicenter retrospective observational study, and the subjects were osteoporosis patients who visited our institutions between 2013 and 2018. We performed sequential therapy using ZOL for 30 patients who had difficulty continuing Dmab, due to physical or social reasons, and investigated the fracture incidence and BMD/BTM changes at 4 time points (at the start of Dmab, the start of ZOL, 6 months after ZOL and 12 months after ZOL). RESULTS: No new vertebral/nonvertebral fractures were observed at each time point after switching from Dmab to ZOL in any of the 30 patients. The BMD/BTM changes were evaluated in 18 of the 30 cases, since all data of lumbar/femoral neck BMDs and TRACP-5b at 4 time points was only available in 18 cases. BMDs significantly increased at each time point compared with that at the start of Dmab. Serum TRACP-5b significantly decreased at each time point compared with that at the start of Dmab. CONCLUSION: It was suggested that sequential therapy using ZOL could suppress the decrease of BMD, and increase of BTM, if the period of Dmab administration was less than 3 years.


Assuntos
Denosumab/uso terapêutico , Suspensão de Tratamento , Ácido Zoledrônico/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Denosumab/efeitos adversos , Feminino , Fraturas Ósseas/sangue , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/sangue , Estudos Retrospectivos , Fosfatase Ácida Resistente a Tartarato/sangue , Ácido Zoledrônico/efeitos adversos
3.
J Bone Miner Metab ; 38(5): 648-657, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32350616

RESUMO

INTRODUCTION: Lactoferrin has recently been reported for its potent bone growth effects. However, the effects of lactoferrin on the healing process of fragility fracture have not yet been studied, so the purpose of this study is to investigate whether oral administration of lactoferrin can promote the fracture healing in an OVX animal model. MATERIALS AND METHODS: Three months after bilateral ovariectomy, all rats underwent unilateral tibial osteotomy and were then randomly divided into control group and bovine lactoferrin (bLF) group. At 4 and 8 weeks post-fracture, animals were sacrificed, and the fractured tibiae and serum samples were collected for evaluation. RESULTS: Our results showed that bLF treatment not only accelerated the bone growth at an early stage of OPF healing but also shortened the remolding process of OPF healing. When compared to control group, bLF treatment induced a significant rise in callus BMD (by 35.0% at 4 weeks and by 39.7% at 8 weeks; both p < 0.05) consistent with enhanced biomechanical strength of the callus, with ultimate force increased by 3.39-fold at 4 weeks (p < 0.05) and 1.95-fold at 8 weeks (p < 0.05). Besides, bLF administration resulted in a substantial increase in serum levels of BALP and a significant decrease in serum levels of TRAP 5b and TNF-α. Moreover, both the RANKL/OPG mRNA ratio and the expression of TNF-α in the callus of bLF-treated group were markedly lower than those in the control group. CONCLUSIONS: At a dose of 85mg/kg/day orally administrated bLF potently promoted the bone healing following tibial fracture in OVX rats.


Assuntos
Consolidação da Fratura/efeitos dos fármacos , Lactoferrina/administração & dosagem , Lactoferrina/farmacologia , Ovariectomia , Absorciometria de Fóton , Administração Oral , Fosfatase Alcalina/sangue , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Calo Ósseo/diagnóstico por imagem , Calo Ósseo/efeitos dos fármacos , Calo Ósseo/patologia , Feminino , Humanos , Lactoferrina/sangue , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Ratos Sprague-Dawley , Fosfatase Ácida Resistente a Tartarato/sangue , Tíbia/efeitos dos fármacos , Tíbia/patologia , Fator de Necrose Tumoral alfa/sangue , Microtomografia por Raio-X
4.
Ann Hematol ; 99(8): 1873-1882, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32451708

RESUMO

Bone turnover markers (BTMs) are useful parameters for assessing fracture risk and unlike bone mineral density (BMD), can be measured at any institution. However, BTM values have not been established in patients post-allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the practicality of BTMs in patients who underwent allo-HSCT by measuring levels of the serum bone resorption marker, tartrate-resistant acid phosphatase-5b (TRACP-5b), and the bone formation marker, bone-specific alkaline phosphatase (BAP), together with BMD, 1 month before and 6 months after allo-HSCT. Patients were classified into either the alendronate group (n = 14) if alendronate treatment (35 mg orally per week) was administered before allo-HSCT or within 1 month after allo-HSCT, or the control group (n = 16), in which patients did not receive alendronate treatment. Despite the high frequency of corticosteroids users in the alendronate group (71.4 vs. 18.9%; p < 0.01), the mean percentage changes in BMD at the lumbar spine (- 2.9 vs. - 3.1%; p = 0.44) and femoral neck (- 3.2 vs. - 4.1%; p = 1.00), TRACP-5b levels (- 4.8 vs. 9.9%; p = 0.45), and BAP levels (6.9 vs. 1.0%; p = 0.85) during 6 months did not differ significantly between the alendronate and control groups. Additionally, the percentage changes in BMD at the lumbar spine were negatively associated with the TRACP-5b levels 6 months after allo-HSCT (p = 0.03, r = 0.40). Our results indicate the possible effectiveness of alendronate treatment in allo-HSCT patients. BTM levels could be useful to monitor the BMD changes.


Assuntos
Fosfatase Alcalina/sangue , Densidade Óssea , Remodelação Óssea , Transplante de Células-Tronco Hematopoéticas , Osteoporose/sangue , Fosfatase Ácida Resistente a Tartarato/sangue , Adulto , Idoso , Alendronato/administração & dosagem , Aloenxertos , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/tratamento farmacológico , Osteoporose/etiologia
5.
Brain Dev ; 42(3): 256-263, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982226

RESUMO

OBJECTIVES: We assessed the severity and pathology of osteoporosis in children and adults with severe motor and intellectual disabilities (SMID) by evaluating bone enzymes, by which we aimed to determine adequate treatment approaches for preventing fractures. METHODS: Ninety patients (44 men, 46 women; mean age, 34.5 years) underwent bone quality assessment. Quantitative ultrasonography (QUS) was used to measure the T-score and Z-score of the calcaneus, and blood tests were used to measure bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b levels as bone formation and resorption markers, as well as calcium, phosphorous, and parathyroid hormone levels as routine examination. RESULTS: Bone formation and resorption marker levels were within normal ranges in adults, although they were high during the growth period in children and adolescents and in elderly women. Patients receiving tube feeding showed a significantly lower Z-score than those without tube feeding. Tube feeding was a significant factor for the Z-score, whereas age, vitamin supplements, and anti-epileptic drugs were not. CONCLUSIONS: The severity of osteoporosis in SMID started during the growth period and seems to be caused by a lack of an effective increase in bone mineral density. Any treatment should be started during the growth period. More study about tube feeding is needed.


Assuntos
Densidade Óssea , Nutrição Enteral , Deficiência Intelectual , Limitação da Mobilidade , Transtornos Motores , Osteoporose/diagnóstico , Fosfatase Ácida Resistente a Tartarato/sangue , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Comorbidade , Nutrição Enteral/estatística & dados numéricos , Feminino , Humanos , Deficiência Intelectual/epidemiologia , Masculino , Pessoa de Meia-Idade , Transtornos Motores/epidemiologia , Osteoporose/sangue , Osteoporose/diagnóstico por imagem , Osteoporose/epidemiologia , Tóquio/epidemiologia , Ultrassonografia , Adulto Jovem
6.
Endocr J ; 67(1): 31-35, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31527321

RESUMO

We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.


Assuntos
Inibidores da Aromatase/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/prevenção & controle , Reabsorção Óssea/sangue , Neoplasias da Mama/tratamento farmacológico , Denosumab/uso terapêutico , Desprescrições , Hipercalcemia/sangue , Tornozelo , Anorexia/etiologia , Anorexia/fisiopatologia , Antitireóideos/uso terapêutico , Artralgia/etiologia , Artralgia/fisiopatologia , Neoplasias Ósseas/secundário , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Reabsorção Óssea/fisiopatologia , Colágeno Tipo I/urina , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Doença de Graves/diagnóstico , Doença de Graves/tratamento farmacológico , Humanos , Hipercalcemia/tratamento farmacológico , Hipercalcemia/etiologia , Hipercalcemia/fisiopatologia , Metimazol/uso terapêutico , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Peptídeos/urina , Iodeto de Potássio/uso terapêutico , Cintilografia , Fosfatase Ácida Resistente a Tartarato/sangue , Sede , Ácido Zoledrônico/uso terapêutico
7.
J Bone Miner Metab ; 38(1): 14-26, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31414284

RESUMO

INTRODUCTION: Menopause can lead to osteoporosis, which is characterized by destruction of bone microstructure, poor mechanical properties, and prone to fracture. LIPUS can effectively promote bone formation and fracture healing. MSTN is a transforming growth factor-ß family member that acts as a negative regulator of skeletal muscle growth. A MSTN deficiency also has a positive effect on bone formation. However, whether LIPUS could inhibit bone loss and promote healing of bone injury of menopause through the inhibition of the MSTN signaling pathway has not been previously investigated. We herein investigated the effects of LIPUS on bone architecture, mechanical properties, the healing of bone defects, and its potential molecular mechanisms in ovariectomized rats. MATERIALS AND METHODS: The rats were randomly divided into three groups: sham ovariectomized group (Sham), ovariectomized model group (OVX), ovariectomized model with LIPUS therapy group (OVX + LIPUS). The OVX + LIPUS rats were treated with LIPUS (1.5 MHz, 30 mW/cm2) on the femur for 20 min/day that lasted for 19 days. RESULTS: LIPUS effectively improved the bone microstructure, increased mechanical properties and promoted the healing of bone defects in ovariectomized rats. Moreover, LIPUS effectively decreased the MSTN content in serum and quadriceps muscle in ovariectomized rats, and inhibited the expression of MSTN downstream signaling molecules and activated the Wnt signaling pathway in the femur. CONCLUSIONS: The present study shows that LIPUS improved osteoporosis and promoted bone defect healing in the ovariectomized rats may through the inhibition of the MSTN signal pathway.


Assuntos
Reabsorção Óssea/prevenção & controle , Miostatina/metabolismo , Ovariectomia , Transdução de Sinais , Ondas Ultrassônicas , Fosfatase Alcalina/sangue , Animais , Fenômenos Biomecânicos , Peso Corporal , Reabsorção Óssea/sangue , Feminino , Fêmur/diagnóstico por imagem , Fêmur/fisiologia , Regulação da Expressão Gênica , Fibras Musculares Esqueléticas/patologia , Músculos/patologia , Tamanho do Órgão , Ratos Sprague-Dawley , Fosfatase Ácida Resistente a Tartarato/sangue , Útero/patologia , Via de Sinalização Wnt
8.
J Bone Miner Metab ; 38(2): 240-247, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31667583

RESUMO

INTRODUCTION: In terms of the balance between benefits and risks of long-term treatment with bisphosphonate, uncertainties remain regarding the optimal treatment duration. We investigated effects of continuous long-term treatment for 10 years with bisphosphonate in postmenopausal osteoporosis patients. MATERIALS AND METHODS: Fifty five patients in the outpatient clinic of our hospital have been continuously treated with alendronate or risedronate for 10 years. All data were retrospectively collected. The age, height, weight, total muscle volume, total fat volume, and BMD at the lumbar spine, total hip and distal 1/3 radius, alkaline phosphatase (ALP), urinary type I collagen cross-linked N-telopeptide (uNTX) and tartrate-resistant acid phosphatase-5b (TRAP5b), calcium (Ca) and phosphate (P) levels were measured pre- and after the start of 10-year continuous treatment. RESULTS: BMD at the lumbar spine increased continuously over the 10-year period, while BMD at the total hip slightly but significantly decreased, and that at the 1/3 radius did not show any significant change over the 10 years. Serum Ca value was significantly decreased after the start of treatment, and became stable within the reference range from the second year. Bone resorption markers such as uNTX and TRAP5b significantly decreased from the second year after the start of treatment and no significant changes were observed thereafter. There were no serious medical adverse events including atypical femoral fractures and osteonecrosis of the jaw. CONCLUSION: We believe that the continuous use of alendronate and risedronate for 10 years could be an option for the treatment of postmenopausal osteoporosis patients.


Assuntos
Grupo com Ancestrais do Continente Asiático , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Alendronato/farmacologia , Alendronato/uso terapêutico , Fosfatase Alcalina/sangue , Densidade Óssea/efeitos dos fármacos , Cálcio/sangue , Colágeno Tipo I/sangue , Difosfonatos/farmacologia , Feminino , Humanos , Japão , Osteoporose/sangue , Osteoporose/induzido quimicamente , Osteoporose/fisiopatologia , Osteoporose Pós-Menopausa/tratamento farmacológico , Peptídeos/sangue , Fósforo/sangue , Estudos Retrospectivos , Ácido Risedrônico/uso terapêutico , Fosfatase Ácida Resistente a Tartarato/sangue , Fatores de Tempo , Resultado do Tratamento
9.
J Cell Mol Med ; 23(10): 6744-6754, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31402549

RESUMO

Here, we aim at exploring the effect of CST5 on bone resorption and activation of osteoclasts in osteoporosis (OP) rats through the NF-κB pathway. Microarray analysis was used to screen the OP-related differentially expressed genes. Osteoporosis was induced in rats by intragastric retinoic acid administration. The serum levels of tartrate-resistant acid phosphatase (TRAP), bone alkaline phosphatase (BALP) and osteocalcin (OC) and the expression of CD61 on the surface of osteoclasts were examined. The number of osteoclasts and the number and area of resorption pits were detected. Besides, the pathological changes and bone mineral density in bone tissues of rats were assessed. Also, the relationship between CST5 and the NF-κB pathway was identified through determining the expression of CST5, RANKL, RANK, OPG, p65 and IKB. Poorly expressed CST5 was indicated to affect the OP. CST5 elevation and inhibition of the NF-κB pathway decreased serum levels of TRAP, BALP and OC and expression of CD61 in vivo and in vitro. In OP rats, CST5 overexpression increased trabecular bones and bone mineral density of bone tissues, but decreased trabecular separation, fat within the bone marrow cavities and the number of osteoclasts through inhibiting the NF-κB pathway. In vivo experiments showed that CST5 elevation inhibited growth in number and area of osteoclastic resorption pits and restrained osteoclastic bone absorption by inhibiting the NF-κB pathway. In summary, overexpression of CST5 suppresses the activation and bone resorption of osteoclasts by inhibiting the activation of the NF-κB pathway.


Assuntos
Reabsorção Óssea/metabolismo , Cistatinas/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Osteoporose/metabolismo , Animais , Densidade Óssea/genética , Reabsorção Óssea/genética , Cistatinas/genética , Bases de Dados Genéticas , Proteínas I-kappa B/metabolismo , Integrina beta3/metabolismo , Masculino , Proteínas de Neoplasias/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Osteocalcina/sangue , Osteoclastos/enzimologia , Osteogênese/genética , Osteoporose/induzido quimicamente , Osteoporose/enzimologia , Osteoporose/genética , Osteoprotegerina/metabolismo , Fosfodiesterase I/sangue , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Ligante RANK/metabolismo , RNA Interferente Pequeno , Ratos , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Fosfatase Ácida Resistente a Tartarato/sangue , Regulação para Cima
10.
Eur J Pharmacol ; 859: 172519, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31271743

RESUMO

Juvenile Paget disease (JPD1), an autosomal-recessive disorder, is characterized by extremely rapid bone turnover due to osteoprotegerin deficiency. Its extra-skeletal manifestations, such as hypertension and heart failure, suggest a pathogenesis with shared skeletal and cardiovascular system components. In spite of this, the effects of anti-hypertensive drugs on bone morphometry remain unknown. We administered an angiotensin II type 1 receptor blocker, olmesartan (5 mg/kg/day) to 8-week-old male mice lacking the osteoprotegerin gene, with and without 1 µg/kg/min of angiotensin II infusion for 14 days. Olmesartan treatment decreased systolic blood pressure, and echocardiography showed increased left ventricular systolic contractility. Three-dimensional micro-computed tomography scans demonstrated that olmesartan treatment increased trabecular bone volume (sham, +176%; angiotensin II infusion, +335%), mineral density (sham, +150%; angiotensin II infusion, +313%), and trabecular number (sham, +407%; angiotensin II infusion, +622%) in the tibia. Olmesartan increased cortical mineral density (sham, +19%; angiotensin II infusion, +24%), decreased the cortical bone section area (sham, -16%; angiotensin II infusion, -18%), decreased thickness (sham, -18%; angiotensin II infusion, -31%), and decreased the lacunar area (sham, -41%; angiotensin II infusion, -27%) in the tibia. Similar trend was observed in the femur. Moreover, olmesartan decreased angiotensin II-induced increases in tartrate-resistant acid phosphatase concentrations in plasma, but it affected neither type I procollagen N-terminal propeptides, nor the receptor activator of nuclear factor kappa-B ligand. Our data suggest that blockade of the angiotensin II type 1 receptor improves bone vulnerability, and helps to maintain the heart's structural integrity in osteoprotegerin-deficient mice.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Densidade Óssea/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/fisiopatologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Fêmur/efeitos dos fármacos , Fêmur/patologia , Fêmur/fisiopatologia , Hipertrofia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Osteíte Deformante/metabolismo , Osteíte Deformante/patologia , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Ligante RANK/sangue , Sístole/efeitos dos fármacos , Sístole/fisiologia , Fosfatase Ácida Resistente a Tartarato/sangue
11.
Biochem Biophys Res Commun ; 515(4): 538-543, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31176486

RESUMO

Chronic inflammatory responses have profound effects on the differentiation and activity of both the bone-forming osteoblasts and bone-resorbing osteoclasts. Importantly, inflammatory bone diseases characterized by clinical osteolysis promote bone resorption and decrease bone formation by uncoupling the process in favor of excess resorption. Notch signaling regulates osteoclast development and thus its manipulation has the potential to suppress resorptive potential. Here, we have utilized a genetic model of Notch inhibition in osteoclasts by expression of dnMAML to prevent formation of transcriptional complex essential for downstream Notch signaling. Using this model and LPS as a tool for experimental inflammatory osteolysis, we have demonstrated that dnMAML-expressing osteoclasts exhibited significantly lower maturation and resorption/functional potential ex vivo using TRAP staining and calcium phosphate coated surfaces. Moreover, we observed that while LPS stimulated the formation of wildtype osteoclasts pre-treated with RANKL, dnMAML expression produced resistance to osteoclast maturation after LPS stimulation. Genetically, Notch-inhibited animals showed a significantly lower TRAP and CTX-1 levels in serum after LPS treatment compared to the control groups in addition to a marked reduction in osteoclast surfaces in calvaria sections. This report provides evidence for modulation of Notch signaling activity to protect against inflammatory osteolysis. Taken together, the findings of this study will help guide the development of Notch signaling-based therapeutic approaches to prevent bone loss.


Assuntos
Lipopolissacarídeos/farmacologia , Osteoclastos/citologia , Osteólise/prevenção & controle , Receptores Notch/deficiência , Transdução de Sinais , Animais , Colágeno Tipo I/sangue , Colágeno Tipo I/deficiência , Feminino , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Peptídeos/sangue , Peptídeos/deficiência , Ligante RANK/farmacologia , Receptores Notch/biossíntese , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fosfatase Ácida Resistente a Tartarato/sangue , Fosfatase Ácida Resistente a Tartarato/deficiência , Fosfatase Ácida Resistente a Tartarato/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Genética
12.
J Bone Miner Metab ; 37(6): 1075-1082, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31214836

RESUMO

INTRODUCTION: Recent clinical studies demonstrated the favorable effects of calcium-free phosphate binders on mortality and vascular calcification in hemodialysis (HD) patients. The aim of the present study was to investigate the effects of a calcium-free phosphate binder, lanthanum carbonate (LC), on bone metabolic markers and bone mineral density (BMD), compared with those of calcium carbonate (CC), in subjects new to HD. MATERIALS AND METHODS: The present study included 65 subjects from our previous randomized controlled trial (LC group, N = 31; CC group, N = 34). We investigated the effects of LC on serum intact parathyroid hormone (iPTH), osteocalcin (OC), bone-specific alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRACP-5b), sclerostin levels, and BMD, compared with those of CC in patients new to HD at baseline and at 12 and 18 months. RESULTS: Serum OC levels at 18 months were significantly higher in the LC group than in the CC group. During the study period, serum BAP and TRACP-5b and iPTH levels tended to be higher in the LC group than in the CC group. At 18 months, the percentage of low bone turnover, based on a serum BAP cutoff value, was significantly lower in the LC group than in the CC group. There were no significant differences in the lumbar and femoral BMD between the two groups. CONCLUSIONS: The results of the present study suggest that LC has potential in preventing low bone turnover, in comparison to CC, in patients new to HD.


Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/fisiologia , Lantânio/farmacologia , Diálise Renal , Idoso , Biomarcadores/sangue , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Cálcio/sangue , Carbonato de Cálcio/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteocalcina/sangue , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Insuficiência Renal Crônica/sangue , Fosfatase Ácida Resistente a Tartarato/sangue
13.
Sci Rep ; 9(1): 6787, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086225

RESUMO

Calcium and nutrients are transferred from mothers to fetuses or infants during pregnancy or lactation, respectively, promoting metabolic changes in the mother, many uncharacterized. To evaluate these changes, we undertook two parallel studies. In one we analyzed fourteen clinical cases of vertebral fragility fractures, at or before three months after partum, in mothers who breastfed their infants. In the other, we enrolled 79 additional pregnant subjects, some who chose to breastfeed and others who did not, and analyzed changes in bone metabolic status starting between 34 and 36 weeks of gestation and ending one month after partum. In the larger group, bone-resorbing and bone-forming parameters such as serum TRACP5b and osteocalcin, respectively, significantly increased after partum. Among parameters that changed after partum, serum PTH and the bone-resorbing markers serum TRACP5b and urine NTX were significantly higher in mothers who only breastfed infants compared to mothers who fed infants formula or a mix of both. However, bone-forming parameters were comparable between breastfeeding and non-breast-feeding groups after partum, suggesting that elevated bone-resorption occurs only in the breastfeeding group. Radiographic analysis after partum demonstrated that no subject among the 79 analyzed showed vertebral fractures, even those who breastfed exclusively. Among fracture cases analyzed, subjects exhibited significantly lower bone mineral density than did non-fracture cases in breastfeeding-only subjects. We conclude that bone metabolic status significantly changes over the period between pregnancy and post-partum lactation, and that low bone mineral density seen in a small subset of breastfeeding-only cases likely causes post-partum vertebral fragility fractures.


Assuntos
Densidade Óssea , Osso e Ossos/metabolismo , Aleitamento Materno , Fraturas Ósseas , Lactação/metabolismo , Adulto , Biomarcadores/metabolismo , Cálcio/sangue , Colágeno Tipo I/urina , Feminino , Humanos , Pessoa de Meia-Idade , Mães , Osteocalcina/sangue , Hormônio Paratireóideo/sangue , Peptídeos/urina , Gravidez , Fosfatase Ácida Resistente a Tartarato/sangue , Adulto Jovem
14.
J Biol Regul Homeost Agents ; 33(2): 557-562, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30973000

RESUMO

In order to investigate the diagnostic value of serum levels of tartrate-resistant acid phosphatase 5b (TRACP5b) in patients with bone tumors, enzyme linked immunosorbent assay (ELISA) was used to com¬pare serum levels of TRACP5b and alkaline phosphatase (ALP) in bone tumor patients (experimental group, 80 cases) and healthy controls (control group, 36 cases). It was found that the serum level of TRACP5b in the experimental group was significantly higher than that in the control group. In addition, the sensitivity and specificity of serum TRACP5b were higher than those of serum ALP in the diagnosis of bone tumors. Fur¬thermore, the serum level of TRACP5b was positively correlated with that of ALP. Therefore, it was conclud¬ed that the serum level of TRACP5b may be used as a sensitive indicator of bone tumors, and the sensitivity and specificity of TRACP5b are even higher than those of ALP in the diagnosis of bone tumors.


Assuntos
Fosfatase Alcalina/sangue , Neoplasias Ósseas/diagnóstico , Fosfatase Ácida Resistente a Tartarato/sangue , Biomarcadores , Neoplasias Ósseas/sangue , Estudos de Casos e Controles , Humanos
15.
Ann Hum Biol ; 46(4): 330-334, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30995879

RESUMO

Background: Osteoporosis in women is a serious health problem. The relationships between biochemical markers of bone turnover and bone mineral density (BMD) in women have been reported, but no study has examined relationships between tartrate-resistant acid phosphatase-5b (TRACP-5b) or bone-specific alkaline phosphatase (BAP) and bone mass measured by quantitative ultrasound (QUS) in Japanese post-menopausal women. Aim: To investigate the serum TRACP-5b and BAP levels and to determine their associations with the heel stiffness index measured by QUS in post-menopausal women. Subjects and methods: The subjects were 510 post-menopausal women who were invited to participate in periodic health examinations in 2011-2013 (the Unzen Study). The heel stiffness index (bone mass) was measured by QUS. Serum samples were collected and TRACP-5b and BAP levels were measured. Results: Multiple regression analysis showed that a higher log (TRACP-5b) was correlated with a lower stiffness index (p = 0.014) and log (BAP) was not correlated with stiffness index after adjusting for covariates (p = 0.136). Conclusion: Higher rates of bone resorption are associated with a lower stiffness index in Japanese post-menopausal women. These results may indicate that high bone resorption affects bone mass more than bone formation, resulting in a low bone mass.


Assuntos
Fosfatase Alcalina/sangue , Remodelação Óssea/fisiologia , Indicadores Básicos de Saúde , Calcanhar/diagnóstico por imagem , Vida Independente , Fosfatase Ácida Resistente a Tartarato/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Cidades , Feminino , Calcanhar/fisiopatologia , Humanos , Japão , Pessoa de Meia-Idade
16.
Clin Nephrol ; 91(4): 222-230, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30862350

RESUMO

INTRODUCTION: Renal osteodystrophy (ROD) develops early in chronic kidney disease (CKD) and progresses with loss of kidney function. While intact parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (1,25D), and fibroblast growth factor-23 (FGF-23) levels are usually considered the primary abnormalities in ROD development, the role of serum activin A elevations in CKD and its relationships to ROD have not been explored. The aims of this study were to evaluate serum activin A at different CKD stages, and to establish the relationships between activin A, bone biomarkers, and bone histomorphometric parameters. MATERIALS AND METHODS: 104 patients with CKD stages 2 - 5D underwent bone biopsies. We measured in the serum activin A, BSAP, DKK1, FGF-23, α-Klotho, intact PTH, sclerostin, TRAP-5b, and 1,25D. Biochemical results were compared across CKD stages and with 19 age-matched controls with normal kidney function. RESULTS: Median activin A levels were increased in all stages of CKD compared to controls from 544 pg/mL in CKD 2 (431 - 628) to 1,135 pg/mL in CKD 5D (816 - 1,456), compared to 369 pg/mL in controls (316 - 453, p < 0.01). The increase of activin A in CKD 2 (p = 0.016) occurred before changes in the other measured biomarkers. Activin A correlated with intact PTH and FGF-23 (r = 0.65 and 0.61; p < 0.01) and with histomorphometric parameters of bone turnover (BFR/BS, Acf, ObS/BS and OcS/BS; r = 0.47 - 0.52; p < 0.01). These correlations were comparable to those found with intact PTH and FGF-23. CONCLUSION: Serum activin A levels increase starting at CKD 2 before elevations in intact PTH and FGF-23. Activin A correlates with bone turnover similar to intact PTH and FGF-23. These findings suggest a role for activin A in early development of ROD.


Assuntos
Ativinas/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Insuficiência Renal Crônica/sangue , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteínas Morfogenéticas Ósseas/sangue , Remodelação Óssea , Estudos de Casos e Controles , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Marcadores Genéticos , Taxa de Filtração Glomerular , Glucuronidase/sangue , Humanos , Subunidades beta de Inibinas , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX5/sangue , Hormônio Paratireóideo/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Índice de Gravidade de Doença , Fosfatase Ácida Resistente a Tartarato/sangue , Vitamina D/análogos & derivados , Vitamina D/sangue
17.
Am J Hum Biol ; 31(3): e23240, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30897260

RESUMO

OBJECTIVES: A number of basic questions about bone biology have not been answered, including population differences in bone turnover. In part, this stems from the lack of validated minimally invasive biomarker techniques to measure bone formation and resorption in field-based population-level research. The present study addresses this gap by validating a fingerprick dried blood spot (fDBS) assay for tartrate-resistant acid phosphatase 5b (TRACP-5b), a well-defined biomarker of bone resorption and osteoclast number. METHODS: We adapted a commercially available enzyme-linked immunosorbent assay (ELISA) kit from MyBiosource for the quantitative determination of TRACP-5b levels in serum and plasma for use with DBS. We used a rigorous process of assay modification and validation, including the use of a matched set of 189 adult plasma, fDBS, and venous DBS (vDBS) samples; parameters evaluated included precision, reliability, and analyte stability. RESULTS: Plasma and DBS TRACP-5b concentrations showed a linear relationship. There were no systematic differences in TRACP-5b levels in fDBS and vDBS, indicating no significant differences in TRACP-5b distribution between capillary and venous blood. Parallelism and spike-and-recovery results indicated that matrix factors in DBS do not interfere with measurement of TRACP-5b levels from DBS using the validated kit. Intra- and interassay CVs were 5.0% and 12.1%, respectively. DBS samples should preferably be stored frozen but controlled room temperature storage for up to a month may be acceptable. CONCLUSIONS: This DBS-based ELISA assay adds to the methodological toolkit available to human biologists and will facilitate research on bone turnover in population studies.


Assuntos
Reabsorção Óssea/sangue , Teste em Amostras de Sangue Seco/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Fosfatase Ácida Resistente a Tartarato/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Teste em Amostras de Sangue Seco/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
J Bone Miner Metab ; 37(5): 805-814, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30706148

RESUMO

This study evaluated the preventative effects of metformin (Met) on glucocorticoid (GC)-induced osteoporosis in a rat model, compared with alendronate (Aln). Twenty-eight 3-month-old female Sprague-Dawley rats were randomly assigned into four groups: normal control (Ctr), methylprednisolone (MP, 13 mg/kg/day, sc, 5 days per week), MP plus Aln orally (1 mg/kg/day), and MP plus Met orally (200 mg/kg/day). After 9 weeks, serum bone metabolic biochemistry, bone densitometry and histomorphometry were performed. The GC-induced osteoporosis model was characterized by decreased osteocalcin, increased tartrate-resistant acid phosphatase-5b (TRAP-5b), and decreased bone mineral density (BMD) in the femur and fifth lumbar vertebra (L5). Histomorphometrically, MP significantly decreased trabecular bone volume, decreased bone formation and increased bone resorption in proximal metaphysis, compared with the controls. Aln and Met increased the BMDs of femur (0.305 ± 0.011 vs. 0.280 ± 0.012, P < 0.05; 0.304 ± 0.019 vs. 0.280 ± 0.012, P < 0.05) and L5 (0.399 ± 0.029 vs. 0.358 ± 0.022, P < 0.05; 0.397 ± 0.022 vs. 0.358 ± 0.022, P < 0.05), compared with the model group. Met increased osteocalcin and decreased TRAP-5b, but Aln only decreased TRAP-5b, compared with model group. In histomorphometry of tibial proximal metaphysis, Aln and Met increased trabecular bone volume (39.21 ± 2.46 vs. 30.98 ± 5.83, P < 0.05; 38.97 ± 5.56 vs. 30.98 ± 5.83, P < 0.05), while Met increased the bone formation dynamic parameters and decreased bone resorption dynamic parameters, but Aln just decreased bone resorption dynamic parameters, compared with model group significantly. These findings suggest that metformin prevents GC-induced bone loss by suppressing bone resorption and stimulating bone formation in trabecular bone. The action mode of metformin was different from alendronate, which only suppressed bone resorption.


Assuntos
Glucocorticoides/efeitos adversos , Metformina/uso terapêutico , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Alendronato/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Feminino , Fêmur/efeitos dos fármacos , Fêmur/fisiologia , Fêmur/fisiopatologia , Lipídeos/sangue , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Vértebras Lombares/fisiopatologia , Metformina/farmacologia , Metilprednisolona/farmacologia , Osteocalcina/sangue , Osteoporose/sangue , Osteoporose/fisiopatologia , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Fosfatase Ácida Resistente a Tartarato/sangue
19.
Poult Sci ; 98(6): 2562-2569, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668765

RESUMO

Bone volumes and quality are related to their hormone levels in laying hens. In this study, we investigated letrozole (LZ) induced effects on the physicochemical properties of cortical bone in laying hens. After 9-wk LZ treatment, we observed that LZ could decrease estrogen level in laying hens. As a result, both the plasma tartrate-resistant acid phosphatase and bone Gla protein activities were suppressed significantly. In addition, carbonate substitution was inhibited significantly in humerus and femur confirmed by Raman spectroscopy. Meanwhile, the mineral density and yield load capacities of humerus and femur were improved. This study demonstrated that the high crystallinity and low carbonate substitution were tightly correlated with the relatively enhanced mechanical properties. Moreover, it elucidated biochemical mechanisms of estrogen in regulating mineralogical and mechanical properties of bones in laying hens.


Assuntos
Inibidores da Aromatase/farmacologia , Osso e Ossos/efeitos dos fármacos , Calcificação Fisiológica/efeitos dos fármacos , Letrozol/farmacologia , Animais , Densidade Óssea/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Osso e Ossos/química , Carbonatos/metabolismo , Galinhas/metabolismo , Estrogênios/sangue , Feminino , Osteocalcina/análise , Oviposição/fisiologia , Fosfatase Ácida Resistente a Tartarato/sangue
20.
Eur J Pharmacol ; 846: 38-48, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30658113

RESUMO

Tartrate-resistant acid phosphatase 5a (TRACP5a) is mainly secreted by activated macrophages in chronic inflammation. Serum TRACP5a is associated with symptom distress in lung cancer patients during chemotherapy. Therefore, this study aimed to investigate whether chemotherapy drugs modulate TRACP5a as an inducible marker for symptom distress in lung cancer patients during chemotherapy. In clinical analysis, lung cancer participants completely received the six-cycle chemotherapy process (n = 42). Clinical determinations for TRACP5a, C-reactive protein (CRP), interleukin-6 (IL-6), white blood cells, monocytes, and hemoglobin were analyzed at six time points: BL, C1d8, C2d1, C4d1, C4d8, and Ed28. Meanwhile, five questionnaires for fatigue, sleep disturbance, pain, depression, and confusion were finished before drug treatment. For monocyte-to-macrophage differentiation, THP-1 cells were treated with phorbol 12-myristate 13-acetate (PMA). TRACP5a secretion in THP-1 cells was determined at the following days up to 6 days after 1-day incubation of chemotherapy drugs by dot blotting. Clinical analysis revealed that TRACP5a significantly increased at C1d8 and C4d8, but dropped at C2d1 and Ed28. CRP and IL-6 displayed a broad-range variation, resulting in no significant difference among the assessment time points. In contrast, monocytes decreased at C1d8 and C4d8, but rose again at C2d1 and Ed28. In symptom distress, the changes only in fatigue and sleep disturbance were positively associated with the trend in TRACP5a. In PMA-treated THP-1 cells, TRACP5a significantly increased after stimulation with gemcitabine and paclitaxel. Taken together, induction of TRACP5a by chemotherapy drugs might be generated from monocyte-differentiated macrophages, further causing clinical symptom distress in lung cancer patients.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Macrófagos/metabolismo , Fosfatase Ácida Resistente a Tartarato/metabolismo , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Carcinoma Pulmonar de Células não Pequenas/psicologia , Diferenciação Celular , Confusão/induzido quimicamente , Confusão/metabolismo , Depressão/induzido quimicamente , Depressão/metabolismo , Fadiga/induzido quimicamente , Fadiga/metabolismo , Feminino , Hemoglobinas/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Leucócitos/efeitos dos fármacos , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/psicologia , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Transtornos do Sono-Vigília/induzido quimicamente , Transtornos do Sono-Vigília/metabolismo , Avaliação de Sintomas , Células THP-1 , Fosfatase Ácida Resistente a Tartarato/sangue , Acetato de Tetradecanoilforbol/uso terapêutico
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