RESUMO
BACKGROUND: Lipoprotein (a) [Lp(a)] is a causal risk factor for cardiovascular diseases, while its role in vascular calcification has not been well-established. Here, we investigated an association of Lp(a) with vascular calcification using population-based and in vitro study designs. METHODS: A total of 2806 patients who received coronary computed tomography were enrolled to assess the correlation of Lp(a) with the severity of coronary artery calcification (CAC). Human aortic smooth muscle cells (HASMCs) were used to explore mechanisms of Lp(a)-induced vascular calcification. RESULTS: In the population study, Lp(a) was independently correlated with the presence and severity of CAC (all pâ¯<â¯0.05). In vitro study showed that cell calcific depositions and alkaline phosphatase (ALP) activity were increased and the expression of pro-calcific proteins, including bone morphogenetic protein-2 (BMP2) and osteopontin (OPN), were up-regulated by Lp(a) stimulation. Interestingly, Lp(a) activated Notch1 signaling, resulting in cell calcification, which was inhibited by the Notch1 signaling inhibitor, DAPT. Lp(a)-induced Notch1 activation up-regulated BMP2-Smad1/5/9 pathway. In contrast, Noggin, an inhibitor of BMP2-Smad1/5/9 pathway, significantly blocked Lp(a)-induced HASMC calcification. Notch1 activation also induced translocation of nuclear factor-κB (NF-κB) accompanied by OPN overexpression and elevated inflammatory cytokines production, while NF-κB silencing alleviated Lp(a)-induced vascular calcification. CONCLUSIONS: Elevated Lp(a) concentrations are independently associated with the presence and severity of CAC and the impact of Lp(a) on vascular calcification is involved in the activation of Notch1-NF-κB and Notch1-BMP2-Smad1/5/9 pathways, thus implicating Lp(a) as a potential novel therapeutic target for vascular calcification.
Assuntos
Lipoproteína(a)/sangue , Calcificação Vascular/sangue , Adulto , Idoso , Proteína Morfogenética Óssea 2/sangue , Estudos de Casos e Controles , Células Cultivadas , China/epidemiologia , Feminino , Humanos , Lipoproteína(a)/fisiologia , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Osteopontina/sangue , Gravidade do Paciente , Receptor Notch1/sangue , Calcificação Vascular/epidemiologia , Calcificação Vascular/patologiaRESUMO
Bone morphogenetic protein (Bmp) signaling is critical for organismal development and homeostasis. To elucidate Bmp2 function in the vascular/hematopoietic lineages we generated a new transgenic mouse line in which ectopic Bmp2 expression is controlled by the Tie2 promoter. Tie2CRE/+;Bmp2tg/tg mice develop aortic valve dysfunction postnatally, accompanied by pre-calcific lesion formation in valve leaflets. Remarkably, Tie2CRE/+;Bmp2tg/tg mice develop extensive soft tissue bone formation typical of acquired forms of heterotopic ossification (HO) and genetic bone disorders, such as Fibrodysplasia Ossificans Progressiva (FOP). Ectopic ossification in Tie2CRE/+;Bmp2tg/tg transgenic animals is accompanied by increased bone marrow hematopoietic, fibroblast and osteoblast precursors and circulating pro-inflammatory cells. Transplanting wild-type bone marrow hematopoietic stem cells into lethally irradiated Tie2CRE/+;Bmp2tg/tg mice significantly delays HO onset but does not prevent it. Moreover, transplanting Bmp2-transgenic bone marrow into wild-type recipients does not result in HO, but hematopoietic progenitors contribute to inflammation and ectopic bone marrow colonization rather than to endochondral ossification. Conversely, aberrant Bmp2 signaling activity is associated with fibroblast accumulation, skeletal muscle fiber damage, and expansion of a Tie2+ fibro-adipogenic precursor cell population, suggesting that ectopic bone derives from a skeletal muscle resident osteoprogenitor cell origin. Thus, Tie2CRE/+;Bmp2tg/tg mice recapitulate HO pathophysiology, and might represent a useful model to investigate therapies seeking to mitigate disorders associated with aberrant extra-skeletal bone formation.
Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Linhagem da Célula , Ossificação Heterotópica/metabolismo , Ossificação Heterotópica/patologia , Receptor TIE-2/metabolismo , Animais , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Valva Aórtica/fisiopatologia , Transplante de Medula Óssea , Proteína Morfogenética Óssea 2/sangue , Calcinose/diagnóstico por imagem , Calcinose/patologia , Calcinose/fisiopatologia , Condrogênese , Células Endoteliais/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Estimativa de Kaplan-Meier , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Musculares/patologia , Ossificação Heterotópica/sangue , Ossificação Heterotópica/diagnóstico por imagem , Osteogênese , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Bone morphogenetic proteins (BMP) are multifunctional proteins. They work as cytokines regulating osteogenesis during fracture healing process. The objectives of this study were to assess changes in BMPs during fracture and their correlations to Fracture's healing. METHODS: Case-Control hospital-based study conducted from January 2018 to January 2019. Demographic data, anthropometric measurements, and blood samples were collected from patients and controls (18-65 years old). Plasma concentrations of selected BMPs and vitamin D were measured using quantitative enzyme linked immunosorbent assay (ELISA). SPSS version 25 was used to calculate frequencies, Pearson correlation tests, chi-square and unpaired t-test. RESULTS: Sixty-five patients with fractures and Sixty-five controls were studied. Means of plasma concentrations were (TGFß1 = 21.07 ng/ml ±8.49 and 19.8 ng/ml ±7.2) (BMP-2 = 76.3 pg/ml ± 156.6 and 55.5 ng/ml ± 127.9) (BMP-7 = 13.02 pg/ml ±43.5 and 64.6pg/ml ±250) (BMP-10 = 8.14 pg/ml ±12.7 and 5.48 pg/ml ±11.3) (Vitamin D mean was 24.94 ng/ml ±13.2 and 26.2 ng/ml ±11.6) in patients and controls, respectively. Forty-five subjects were enrolled into follow up study: 30 males, 15 females. Healing time mean was 4.13± 2.6 months. No significant correlation between BMP-2/BMP-7 with healing time. CONCLUSIONS: BMP-7 was significantly lowers in the plasma of patients that controls (P = 0.042). Low Vitamin D was observed among Sudanese participants.
Assuntos
Proteína Morfogenética Óssea 2/sangue , Proteína Morfogenética Óssea 7/sangue , Proteínas Morfogenéticas Ósseas/sangue , Fraturas Ósseas/sangue , Fator de Crescimento Transformador beta1/sangue , Vitamina D/sangue , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Consolidação da Fratura/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sudão , Adulto JovemRESUMO
Barrett's esophagus (BE) predisposes for the malignant condition of esophageal adenocarcinoma (EAC). Since BE patients have few or no symptoms, most of these patients are not identified and not included in surveillance programs. These BE patients are at risk of developing advanced-stage EAC. At present, non-invasive tests to identify BE patients from the general population are lacking. We and others showed that Bone Morphogenetic Protein 4 (BMP4), and other BMPs are upregulated in BE. We aimed to determine if circulating BMPs can be identified and used as blood biomarkers to identify BE patients at high risk in the general population. In this study, we could detect the different BMPs in the blood of 112 BE patients and 134 age- and sex-matched controls. Concentration levels of BMP2, BMP4, and BMP5 were elevated in BE patients, with BMP2 and BMP5 significantly increased. BMP5 remained significant after multivariate analysis and was associated with an increased risk for BE with an OR of 1.49 (p value 0.01). Per log (pg/mL) of BMP5, the odds of having BE increased by 50%. Future optimization and validation studies might be needed to prove its utility as a non-invasive method for the detection of BE in high-risk populations and screening programs.
Assuntos
Esôfago de Barrett/sangue , Biomarcadores/sangue , Proteína Morfogenética Óssea 5/sangue , Idoso , Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Proteína Morfogenética Óssea 2/sangue , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 4/sangue , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 5/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Bone morphogenetic proteins-2 and -4 (BMPs) have been implicated in left ventricular remodeling (LVR) processes such as an inflammation and fibrogenesis. We hypothesized that this knowledge could be translated into clinics. METHODS: We studied the dynamics of serum levels of BMPs, its correlation with markers of LVR and with parameters of echocardiography in patients (n = 31) during the six-month follow-up period after myocardial infarction (MI). RESULTS: Elevated serum levels of BMPs decreased by the six-month follow-up period. BMP-2 decreased from the first day after MI, and BMP-4 decreased from the Day 14. The elevated level of BMP-2 at Day 1 was associated with a lower level of troponin I, reperfusion time and better left ventricular ejection fraction (LV EF) at the six-month follow-up. Elevated serum level of BMP-4 at Day 1 was associated with a lower level of a soluble isoform of suppression of tumorigenicity 2 (sST2), age and reperfusion time. An elevated level of BMP-2 at the six-month follow-up was associated with higher levels of BMP-4, high-sensitivity C-reactive protein (hCRP) and sST2. High serum level of BMP-2 correlated with high levels of hCRP and matrix metalloproteinase (MMP)-9 on Day 7. High serum level of BMP-4 correlated with low levels of hCRP, MMP-9 at Day 3, sST2 at Day 1 and with decreased LV EF on Day 7. The findings of multivariate analysis support the involvement of BMP-2 in the development of post-infarction LVR. CONCLUSIONS: Our research translates experimental data about the BMPs in the development of adverse LVR into the clinic. Elevated serum levels of BMPs decreased by the end of the six-month period after MI. BMP-2 decreased from the first day and BMP-4 decreased from Day 14. BMP-2 and BMP-4 were associated with the development of LVR. Their correlations with markers of inflammation, degradation of the extracellular matrix, hemodynamic stress and markers of myocardial damage further support our hypothesis. Diagnostic and predictive values of these BMPs at the development of post-infarction LVR in vivo should be investigated further.
Assuntos
Proteína Morfogenética Óssea 2/sangue , Proteína Morfogenética Óssea 4/sangue , Metaloproteinase 9 da Matriz/sangue , Infarto do Miocárdio/sangue , Adulto , Idoso , Biomarcadores/sangue , Proteína C-Reativa/genética , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/genética , Volume Sistólico/genéticaRESUMO
We evaluated whether castration affects bone morphogenetic protein 2 (BMP2) level and the expression of its signaling molecules in Korean cattle bulls. We also checked whether castration affects the expression of muscle fiber type and oxidative and glycolytic enzyme genes. Enzyme-linked immunosorbent assays revealed that steers had higher plasma BMP2 and leptin concentrations than bulls. Quantitative real-time PCR showed that steers had higher mRNA levels of the lysyl oxidase gene, a downstream target of the BMP signaling pathway, in the longissimus thoracis (LT) muscle. Steers had higher adipogenic peroxisome proliferator-activated receptor gamma and lipogenic fatty acid binding protein 4 mRNA levels in the LT than bulls. Steers had lower mRNA levels for several muscle fiber type 1 genes and fiber type 2A myosin heavy chain 2 gene than bulls. Steers had higher mRNA levels of the glycolytic enzyme phosphoglycerate kinase 1 gene than bulls. Transcript levels of oxidative enzyme genes did not differ between bulls and steers. Regression analysis revealed a positive association between plasma BMP2 levels and intramuscular fat (IMF) content in the steer group. These findings suggest that upregulation of the BMP signaling pathway in response to castration induces increased adipogenic gene expression, contributing to the increased IMF deposition observed in castrated animals.
Assuntos
Tecido Adiposo/fisiologia , Proteína Morfogenética Óssea 2/sangue , Músculo Esquelético/fisiologia , Orquiectomia , Transdução de Sinais , Adipogenia , Animais , Bovinos , Glicólise , Leptina/sangue , Masculino , Estresse Oxidativo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Análise de Regressão , República da Coreia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
OBJECTIVE: Anterior cruciate ligament (ACL) injuries which cause knee disabilities remain a clinical challenge due to the compromised tendon-bone repair. Multiple strategies have been proposed to treat the tendon-bone injuries, and the combination of these therapies hold great potential to achieve synergistic effects. MATERIALS AND METHODS: We built PLGA-BMP-2 (bone morphogenetic protein 2) system and confirmed the sustained release of BMP-2 both in vitro and in vivo. We then applied different therapies to treat rat ACL reconstruction. We collected the tissue sample and analyzed the BMP-2 concentration both in serum and in injured sites. We tested the mRNA expression of genes that were related to inflammation, tissue repair and bone formation in damaged tissues. We also analyzed the protein levels of some genes associated with tendon formation and check the function of newly generated bone through biomechanical test. RESULTS: We found that, compared to monotherapies, simultaneous utilization of sustained BMP-2 release and platelet-rich fibrin (PRF) after anterior cruciate ligament reconstruction showed better therapeutic effects on tendon-bone healing in rat. This combined therapy efficiently enhanced the levels of growth factors that favor the angiogenesis and relieved the inflammatory responses in the injured sites. Of note, the combined therapy efficiently promoted the signals associated with bone formation and tendon regeneration. CONCLUSIONS: We demonstrated that the combined therapy with BMP-2 and PRF achieves synergistic effects on tendon-bone healing and holds great potential for the treatment of ACL reconstruction.
Assuntos
Lesões do Ligamento Cruzado Anterior/terapia , Reconstrução do Ligamento Cruzado Anterior/métodos , Proteína Morfogenética Óssea 2/uso terapêutico , Fibrina Rica em Plaquetas/química , Tendões/fisiologia , Animais , Proteína Morfogenética Óssea 2/sangue , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 2/farmacologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Portadores de Fármacos/química , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Osteogênese/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ratos , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Estresse Mecânico , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , CicatrizaçãoRESUMO
OBJECTIVES: Several molecules are involved in the pathogenesis of new bone formation in axial spondyloarthritis (axSpA). The aim of this study was to evaluate the serum levels of BMP-2 and IL-17A in patients with axSpA and their possible correlations with radiographic damage, disease activity, and function. METHODS: AxSpA patients fulfilled the ASAS criteria and with at least New York grade 2 bilateral sacroiliitis and healthy matched controls were enrolled for this study. BASDAI, ASDAS-CRP, BASMI, BASFI and CRP were evaluated as measures of disease activity and function. Spinal damage was assessed using the mSASSS on radiographs performed within 3 months from baseline. Serum concentrations of BMP-2 and IL-17A were assessed using ELISA kit. RESULTS: Sixty patients and 30 healthy subjects satisfying the inclusion criteria were enrolled. In our axSpA group, serum BMP-2 levels [median (25th-75th percentile) of 589.2 (430.24-1017.1) pg/ml] did not statistically differ from controls [518.34 (450.2-1028.2) pg/ml]. However, significant correlations were found between serum BMP-2 levels and radiographic damage assessed by mSASSS, and BMP-2 levels were found to be higher in patients with grade 4 sacroiliitis when compared to patients with lower grade of sacroiliitis. Of note, serum BMP-2 levels significantly inversely correlate with IL-17A levels and CRP, and were found to be lower in patients with higher disease activity. CONCLUSIONS: The results of our study may confirm a possible role of BMP-2 in the pathogenesis of new bone formation in axSpA patients. Furthermore, a link between inflammation and BMP-2 was found.
Assuntos
Proteína Morfogenética Óssea 2/sangue , Interleucina-17/sangue , Osteogênese , Espondilartrite/sangue , Estudos de Casos e Controles , Estudos Transversais , Humanos , Índice de Gravidade de DoençaRESUMO
We induced chronic kidney disease (CKD) with adenine in WT mice, mice with osteocyte-specific deletion of Cyp27b1, encoding the 25-hydroxyvitamin D 1(OH)ase [Oct-1(OH)ase-/-], and mice with global deletion of Cyp27b1 [global-1α(OH)ase-/-]; we then compared extraskeletal calcification. After adenine treatment, mice displayed increased blood urea nitrogen, decreased serum 1,25(OH)2D, and severe hyperparathyroidism. Skeletal expression of Cyp27b1 and of sclerostin and serum sclerostin all increased in WT mice but not in Oct-1α(OH)ase-/- mice or global-1α(OH)ase-/- mice. In contrast, skeletal expression of BMP2 and serum BMP2 rose in the Oct-1α(OH)ase-/- mice and in the global-1α(OH)ase-/- mice. Extraskeletal calcification occurred in muscle and blood vessels of mice with CKD and was highest in Oct-1α(OH)ase-/-mice. In vitro, recombinant sclerostin (100 ng/mL) significantly suppressed BMP2-induced osteoblastic transdifferentiation of vascular smooth muscle A7r5 cells and diminished BMP2-induced mineralization. Our study provides evidence that local osteocytic production of 1,25(OH)2D stimulates sclerostin and inhibits BMP2 production in murine CKD, thus mitigating osteoblastic transdifferentiation and mineralization of soft tissues. Increased osteocytic 1,25(OH)2D production, triggered by renal malfunction, may represent a "primary defensive response" to protect the organism from ectopic calcification by increasing sclerostin and suppressing BMP2 production.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Calcinose/patologia , Calcitriol/metabolismo , Insuficiência Renal Crônica/complicações , Uremia/complicações , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/sangue , Adenina/toxicidade , Animais , Nitrogênio da Ureia Sanguínea , Proteína Morfogenética Óssea 2/sangue , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Calcinose/sangue , Calcinose/etiologia , Calcitriol/sangue , Transdiferenciação Celular , Modelos Animais de Doenças , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Osteócitos/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/induzido quimicamente , Uremia/sangue , Uremia/induzido quimicamenteRESUMO
A number of different serum biomarkers are currently being evaluated for their potential use as diagnostic and prognostic biomarkers in Glioblastoma Multiforme. Amongst these, a vast number of different microRNAs have been studied, that are up-regulated or downregulated in relation to Glioblastoma Multiforme. Different studies have found numerous associations of these different microRNAs with recurrence, Karnofsky Performance Score, Progression Free Survival and Overall Survival. Other than microRNAs, serum Glial Fibrillary Acid Protein, cytokines and YLK-40, as well as a number of other candidate serum biomarkers are being studied.More studies, with larger sample sizes are required before these serum biomarkers can be routinely, and reliably used in clinical practice. Use of serum biomarkers can provide a non-invasive means for diagnosing and monitoring disease.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/sangue , Citocinas/sangue , Glioblastoma/sangue , MicroRNAs/sangue , Proteína Morfogenética Óssea 2/sangue , Neoplasias Encefálicas/mortalidade , Proteína 1 Semelhante à Quitinase-3/sangue , Proteína Glial Fibrilar Ácida/sangue , Glioblastoma/mortalidade , Humanos , Avaliação de Estado de Karnofsky , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Intervalo Livre de Progressão , Taxa de SobrevidaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Oxidative damage to osteoblasts was a key factor in the development of osteoporosis. Er-Xian Decotion (EXD) is widely used in China for the treatment of osteoporosis, which has a variety of antioxidant active ingredients. EXD may be an important source of protection against oxidative damage in osteoblasts, but the anti-osteoporotic active components of EXD is currently unclear. AIM OF THE STUDY: This work established an effective and reliable drug screening method to find main active ingredients in EXD (M-EXD) that can protect osteoblasts against oxidative stress and achieve anti-osteoporosis effects. MATERIALS AND METHODS: H2O2-induced osteoblast cell fishing with UHPLC-QTOF/MS was firstly used to discover the potential active components from EXD. Afterword, the EXD compound-osteoporosis target network was constructed using network pharmacology, thus potentially anti-osteoporosis ingredients were founded, and their combination were defined as the M-EXD. Finally, pharmacology effects of M-EXD was evaluated by ovariectomized rats, prednisolone induced-zebrafish and H2O2-induced osteoblasts. RESULTS: 40 candidate active ingredients in EXD were initially screened out via pathological cell fishing. According to network pharmacology result, M-EXD consisted of 13 ingredients since they had a close relationship with 65 osteoporosis-related targets. Pharmacological evaluation showed that M-EXD significantly ameliorated oxidative stress in H2O2-induced osteoblast model, evidently reversed the activity of ALP, ROS, GSH-px, NO and MDA compared with the model group. M-EXD showed better anti-oxidative activities than individual ingredients, presenting obvious synergetic effects. In osteoporosis rat and zebrafish models, M-EXD also demonstrated good anti-osteoporotic properties by mitigating the osteoporosis bone loss and increasing serum bone morphogenetic protein 2, and reversing osteocalcin expression in bone tissue. It significantly ameliorated oxidative stress in the in-vivo models. Moreover, M-EXD and EXD showed similar anti-osteoporotic and anti-oxidative properties, while the rest components of EXD had no satisfactory anti-osteoporotic efficacy. CONCLUSIONS: Our work successfully identified the main active components in EXD, which could represent the efficacy of EXD on treating osteoporosis, and meanwhile, it also provided an effective strategy to investigate active ingredients from natural medicines, which might be helpful for drug development and application.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Animais , Proteína Morfogenética Óssea 2/sangue , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Peróxido de Hidrogênio/farmacologia , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Peixe-ZebraRESUMO
Various studies have investigated the serum sclerostin and bone morphogenetic protein-2 (BMP-2) levels in patients with ankylosing spondylitis (AS), but the results were inconsistent. The aim of this meta-analysis was to synthetically assess the associations of serum levels of sclerostin and BMP-2 with AS. Multiple electronic databases were searched to locate relevant articles published before November 2018. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. Totally, 21 studies were included. Meta-analysis results showed no significant difference between AS group and control group in serum sclerostin levels (SMD = 0.098, 95% CI - 0.395 to 0.591, p = 0.697). Nevertheless, serum BMP-2 levels in AS patients were higher than that in controls (SMD = 1.184, 95% CI 0.209 to 2.159, p = 0.017). Subgroup analysis demonstrated that European and South American AS patients had lower serum levels of sclerostin than controls. AS patients with age ≥ 40 years, erythrocyte sedimentation rate (ESR) ≤ 20 mm/h and Bath Ankylosing Spondylitis Functional Index (BASFI) < 4 had statistically significant lower serum sclerostin concentrations compared to controls. Chinese and Korean AS patients as well as patients with lower CRP had higher serum BMP-2 levels than controls, and country may be a source of heterogeneity across the studies. No publication bias existed and sensitivity analysis confirmed the stability of results. Serum BMP-2, but not sclerostin levels may be closely related to the development of AS.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/sangue , Proteína Morfogenética Óssea 2/sangue , Proteínas Morfogenéticas Ósseas/sangue , Espondilite Anquilosante/sangue , Povo Asiático , Marcadores Genéticos/fisiologia , Humanos , Índice de Gravidade de DoençaRESUMO
BACKGROUND To investigate the effect of the BMP/Smad signaling pathway on fracture healing and osteogenic ability in senile osteoporotic fracture on humans and rats. MATERIAL AND METHODS Sixty-two patients and well-matched normal controls were enrolled for clinical observation. A rat model of senile osteoporotic fracture was established. Serum BMP2 and Smad4 levels, as well as alkaline phosphatase (ALP) activity, were detected by ELISA. Fracture healing was observed by X-ray radiography and bone formation was analyzed by micro-CT. RESULTS Serum BMP2 and Smad4 levels in patients with senile osteoporotic fracture were significantly lower than those in normal controls (all P<0.01). BMP2 was highly positively correlated with Smad4 in patients with senile osteoporotic fracture (r=0.738). Compared with patients with low serum BMP2 and Smad4 levels, visual analog scale scores decreased, bone mineral density (BMD) increased, and duration of fracture healing was shortened in patients with high levels (all P<0.05). Compared with the Model group, serum BMP2 and Smad4 levels increased, fracture healing was improved, BMD, trabecular bone volume (TBV), tissue volume (TV), bone volume fraction (BV/TV), mean trabecular thickness (Tb. Th), and mean number of trabecular bone (Tb. N) were increased, and ALP activity increased in the BMP2 overexpression group (all P<0.05), while each index in the NC group showed no statistical difference relative to rats in the Model group (all P>0.05). CONCLUSIONS BMP2 overexpression can promote fracture healing and osteogenic ability in senile osteoporotic fractures through activating the BMP/Smad signaling pathway.
Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Consolidação da Fratura , Osteogênese , Fraturas por Osteoporose/metabolismo , Transdução de Sinais , Proteína Smad4/metabolismo , Idoso , Fosfatase Alcalina/sangue , Animais , Densidade Óssea , Proteína Morfogenética Óssea 2/sangue , Calo Ósseo/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Fraturas por Osteoporose/sangue , Fraturas por Osteoporose/fisiopatologia , Ratos , Proteína Smad4/sangueRESUMO
Vascular calcification is a main cause of increased cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. This study aimed to investigate the role of the bone morphogenetic protein (BMP) signaling pathway in the early development of vascular calcification in CKD. A CKD vascular calcification rat model was established by providing rats with a 1.8% high-phosphorus diet and an intragastric administration of 2.5% adenine suspension. The kidney and aortic pathologies were analyzed. Blood biochemical indicators, serum BMP-2 and BMP-4 levels, and aortic calcium content were determined. The expression levels of BMP-2, BMP-4, bone morphogenetic protein receptor-IA (BMPR-IA), and matrix Gla protein (MGP) in aorta were examined by quantitative real-time polymerase chain reaction and immunohistochemistry. Compared with the normal control (Nor) rats, the CKD rats exhibited a significantly decreased body weight and an increased kidney weight as well as abnormal renal function and calcium-phosphorus metabolism. Aortic von Kossa and Alizarin red staining showed massive granular deposition and formation of calcified nodules in aorta at 8 weeks. The aortic calcium content was significantly increased, which was positively correlated with the serum BMP-2 (r = 0.929; P < 0.01) and serum BMP-4 (r = 0.702; P < 0.01) levels in CKD rats. The rat aortic BMP-2 mRNA level in the CKD rats was persistently increased, and the BMP-4 mRNA level was prominently increased at the 4th week, declining thereafter. Strong staining of BMP-2, BMP-4, BMPR-IA, and MGP proteins was observed in the tunica media of the aorta from the 4th week after model induction. In conclusion, activation of the BMP signaling pathway is involved in the early development of vascular calcification in CKD. Therefore, elevated serum BMP-2 and BMP-4 levels may serve as serum markers for CKD vascular calcification.
Assuntos
Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 4/genética , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Regulação para Cima/genética , Calcificação Vascular/complicações , Calcificação Vascular/genética , Animais , Aorta/metabolismo , Aorta/patologia , Peso Corporal , Proteína Morfogenética Óssea 2/sangue , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/sangue , Proteína Morfogenética Óssea 4/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio , Ensaio de Imunoadsorção Enzimática , Proteínas da Matriz Extracelular , Rim/patologia , Rim/fisiopatologia , Masculino , Tamanho do Órgão , Proteinúria/complicações , Proteinúria/genética , Ratos Sprague-Dawley , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/urina , Calcificação Vascular/fisiopatologia , Calcificação Vascular/urina , Proteína de Matriz GlaRESUMO
Blockage of bone morphogenetic protein (BMP) signaling is required for differentiation of neurons and oligodendrocytes from neural stem cells (NSCs). Sera of untreated relapsing-remitting multiple sclerosis (RR-MS) patients expressed significantly higher levels of BMP-2 compared to sera of healthy controls. BMP-2 levels correlated with BMP-4 and -5 levels only in sera of untreated MS patients. Furthermore, sera of untreated patients inhibited the neuronal differentiation of RA-treated P19 cells, which was associated with induction of phospho-SMAD signaling pathway. These results suggest that BMP-2 sera levels may play a role in the failure of remyelination and neuro-regeneration in RR-MS.
Assuntos
Proteína Morfogenética Óssea 2/sangue , Proteína Morfogenética Óssea 4/sangue , Proteína Morfogenética Óssea 5/sangue , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/patologia , Células-Tronco Neurais/metabolismo , Adolescente , Adulto , Citocinas/sangue , Avaliação da Deficiência , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Células-Tronco Neurais/efeitos dos fármacos , Oligodendroglia/metabolismo , Transdução de Sinais/fisiologia , Proteínas Smad/metabolismo , Estatística como Assunto , Adulto JovemRESUMO
Bone morphogenetic proteins (BMPs) regulate diverse cellular responses during embryogenesis and in adulthood including cell differentiation, proliferation, and death in various tissues. In the adult pituitary, BMPs participate in the control of hormone secretion and cell proliferation, suggesting a potential endocrine/paracrine role for BMPs, but some of the mechanisms are unclear. Here, using a bioactivity test based on embryonic cells (C3H10T1/2) transfected with a BMP-responsive element, we sought to determine whether pituitary cells secrete BMPs or BMP antagonists. Interestingly, we found that pituitary-conditioned medium contains a factor that inhibits action of BMP-2 and -4. Combining surface plasmon resonance and high-resolution mass spectrometry helped pinpoint this factor as thrombospondin-1 (TSP-1). Surface plasmon resonance and co-immunoprecipitation confirmed that recombinant human TSP-1 can bind BMP-2 and -4 and antagonize their effects on C3H10T1/2 cells. Moreover, TSP-1 inhibited the action of serum BMPs. We also report that the von Willebrand type C domain of TSP-1 is likely responsible for this BMP-2/4-binding activity, an assertion based on sequence similarity that TSP-1 shares with the von Willebrand type C domain of Crossveinless 2 (CV-2), a BMP antagonist and member of the chordin family. In summary, we identified for the first time TSP-1 as a BMP-2/-4 antagonist and presented a structural basis for the physical interaction between TSP-1 and BMP-4. We propose that TSP-1 could regulate bioavailability of BMPs, either produced locally or reaching the pituitary via blood circulation. In conclusion, our findings provide new insights into the involvement of TSP-1 in the BMP-2/-4 mechanisms of action.
Assuntos
Proteína Morfogenética Óssea 2/antagonistas & inibidores , Proteína Morfogenética Óssea 4/antagonistas & inibidores , Modelos Moleculares , Hipófise/metabolismo , Elementos de Resposta , Trombospondina 1/metabolismo , Animais , Animais Endogâmicos , Proteína Morfogenética Óssea 2/sangue , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/sangue , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Linhagem Celular , Células Cultivadas , Biologia Computacional , Feminino , Genes Reporter , Humanos , Camundongos , Hipófise/citologia , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Carneiro Doméstico , Trombospondina 1/química , Trombospondina 1/isolamento & purificaçãoRESUMO
OBJECTIVE: This study aimed to assess the association between plasma bone morphogenetic protein-2 (BMP-2) level and in-stent restenosis in patients with coronary artery disease. METHODS: A total of 96 patients who underwent percutaneous coronary intervention (PCI) and were followed up after PCI were enrolled in this study. 47 patients diagnosed with in-stent restenosis (ISR) were recruited to ISR group and 49 patients without ISR were recruited to Control group according to the results of coronary angiography (CAG). Baseline characteristic data were collected, and plasma BMP-2 level was evaluated. The results were analyzed using logistic regression. RESULTS: There were 47 patients in the ISR group and 49 patients in the Control group. Plasma levels of BMP-2 were higher in the ISR group than in the non-ISR group [20.96 (18.44, 27.05) pg/ml vs. 29.53 (25.03, 34.07) pg/ml, P<0.01]. Furthermore, the ISR group had significantly longer stent lengths and lower stent diameters than the Control group (P<0.01 and P<0.01, respectively). In multivariate analysis, BMP-2 level, diabetes, stent length and stent diameter were independently associated with ISR [odds ratio (OR)=1.11, 95% confidence interval (CI)=1.03-1.18, P<0.01; OR=4.75, 95% CI=(1.44-15.61), P=0.01; OR=1.06, 95% CI=(1.02-1.11), P<0.01; and OR=0.15, 95% CI=(0.02-0.95), P=0.04, respectively]. CONCLUSIONS: Increased BMP-2 levels were independently associated with ISR in patients with coronary artery disease. Plasma BMP-2 may be useful in predicting ISR.
Assuntos
Proteína Morfogenética Óssea 2/sangue , Doença da Artéria Coronariana/sangue , Reestenose Coronária/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/cirurgia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária PercutâneaRESUMO
BACKGROUND: The healing process of bone fracture requires a well-controlled multistage and sequential order beginning immediately after the injury. However, complications leading to nonunion exist, creating serious problems and costs for patients. Transforming growth factor-beta 1 (TGF-ß1) and bone morphogenic protein 2 (BMP-2) are two major growth factors involved in human bone fracture healing by promoting various stages of bone ossification. In this study, we aimed to determine the role of these factors during the fracture healing of human long bones and assess their impacts on nonunion condition. MATERIALS AND METHODS: We performed a comprehensive analysis of plasma TGF-ß1 and BMP-2 levels in blood samples from 10 patients with proved nonunion and 10 matched patients with normal union following a predetermined time schedule. The concentrations of TGF-ß1 and BMP-2 were measured at each time point using a solid-phase ELISA. RESULTS: TGF-ß1 and BMP-2 levels were detectable in all patients. For all patients, a maximal peak for TGF-ß1 was found at 3-week. In normal union group, TGF-ß1 showed a maximal peak at 2-week while nonunion group had a delayed maximal peak at 3-week. Plasma levels of BMP-2 for all patients and for normal union group reached a maximal peak at 1-week, but nonunion group showed a delayed maximal peak at 2-week. In general, plasma TGF-ß1 or BMP-2 level was not significantly different between normal union and nonunion groups. CONCLUSION: The expression levels of TGF-ß1 and BMP-2 appeared to be delayed in nonunion patients which could play an important role in developing an early marker of fracture union condition and facilitate improved patient's management.
Assuntos
Proteína Morfogenética Óssea 2/sangue , Consolidação da Fratura/genética , Consolidação da Fratura/fisiologia , Fraturas Ósseas/genética , Fraturas Ósseas/fisiopatologia , Fraturas Mal-Unidas/diagnóstico , Fraturas Mal-Unidas/genética , Expressão Gênica , Fator de Crescimento Transformador beta1/sangue , Adulto , Biomarcadores/sangue , Proteína Morfogenética Óssea 2/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Fator de Crescimento Transformador beta1/fisiologia , Adulto JovemRESUMO
CONTEXT: Few potential candidate genes coding for type I and II receptors of transforming growth factor beta signaling pathway and the serotonin transporter have been associated with pulmonary hypertension (PH). The latter being a phenotype for high altitude pulmonary edema (HAPE), these genes are hypothesized to be crucial markers to investigate under the hypobaric hypoxic environment of high altitude. AIMS: We hence aimed to investigate bone-morphogenetic protein-2 (BMP2), bone morphogenetic protein receptor type-II (BMPR-2), activin receptor-like kinase-1 (ALK-1), serotonin transporter (5-HTT) and serotonin (5-HT) for their contribution, individually/epistatically, to clinical endpoints by altering downstream signaling molecules. METHODS AND MATERIALS: In a case-control design, interactions between/among polymorphisms of BMPR-2, ALK-1 and 5-HTT were screened in 200 HAPE-patients (HAPE-p) and 200 HAPE-free sojourners (HAPE-f). Plasma biomarker BMP-2 and 5-HT were estimated. The relative gene expression was also witnessed in 20 humans/10 rats followed by correlation analyses. RESULTS: The genotype/allele models revealed the prevalence of BMPR-2 rs6717924A-rs4303700A-rs1048829A; ALK-1 rs11169953T-rs3759178C-rs706816C and 5-HTT rs6354C in HAPE (P≤0.05). Multifactor dimensionality reduction for interactions among genes revealed a 4-locus model of BMPR-2 rs6717924G/A; ALK-1 rs11169953C/T-rs706816T/C and 5-HTT rs6354A/C as the best disease predicting (P≤0.001); whereas HapEvolution analysis confirmed the alleles rs6717924A, rs4303700A and rs6354C as the best interacting (P≤0.01). Plasma levels of BMP-2 and 5-HT were elevated in HAPE (P≤0.0001). The expression of BMP-2, ALK-1, 5-HT, 5-HTT was elevated and of BMPR-2 decreased in humans and rats (P≤0.05). The risk alleles BMPR-2 rs6717924A-rs4303700G-rs1048829A; ALK-1 rs11169953T-rs706816C and 5-HTT rs6354C correlated inversely with arterial oxygen saturation (SaO2) and positively with mean arterial pressure (MAP), BMP-2 and 5-HT in HAPE. Likewise, haplotypes BMPR-2 GGGCGAAAA, AAATAGGGA and ALK-1 CCTCAAAG, CCTTAAAG correlated with clinical markers and biomarkers (P≤0.01). BMP-2 and 5-HT correlated positively with MAP and negatively with SaO2 (P≤0.01). CONCLUSIONS: The genetic-interactions among BMPR-2, ALK-1, and 5-HTT polymorphisms, elevated BMP-2 and 5-HT levels and differential gene expression substantiated the strong genetic contribution in HAPE pathophysiology.
Assuntos
Receptores de Activinas Tipo II/genética , Doença da Altitude/genética , Proteína Morfogenética Óssea 2/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Hipertensão Pulmonar/genética , Hipóxia/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Receptores de Activinas Tipo II/metabolismo , Alelos , Altitude , Doença da Altitude/metabolismo , Doença da Altitude/fisiopatologia , Animais , Pressão Arterial , Proteína Morfogenética Óssea 2/sangue , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Estudos de Casos e Controles , Epistasia Genética , Haplótipos , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Modelos Genéticos , Redução Dimensional com Múltiplos Fatores , Polimorfismo Genético , Ratos , Ratos Wistar , Serotonina/sangue , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Although Bone morphogenetic protein-2 (BMP-2) is a known mediator of bone regeneration and vascular calcification, to date no study has investigated the relationship between BMP-2 and type 2 diabetes mellitus (T2DM) and its possible role in coronary artery disease (CAD). The purpose of this study is to evaluate the relationship of BMP-2 with atherosclerosis and calcification in patients with T2DM. METHODS: 124 subjects were enrolled in this study: 29 patients with T2DM and CAD; 26 patients with T2DM and without CAD; 36 patients with CAD and without T2DMand 34 without T2DM or CAD (control group). Severity of coronary lesions was assessed using coronary angiography and intravascular ultrasound (IVUS). Plasma BMP-2 levels were quantified using a commercially available ELISA kit. RESULTS: Compared to the control group, the mean plasma BMP-2 level was significantly higher in T2DM patients with or without CAD (20.1 ± 1.7 or 19.3 ± 1.5 pg/ml, vs 17.2 ± 3.3 pg/ml, P < 0.001). In a multivariable linear regression analysis, both T2DM and CAD were significantly and positively associated with BMP-2 (Estimate, 0.249; standard error (SE), 0.063; p <0.0001; Estimate, 0.400; SE, 0.06; p < 0.0001). Plasma BMP-2 was also strongly correlated with glycosylated hemoglobin A1c (HbA1c) (Spearman ρ = -0.31; p = 0.0005). SYNTAX score was also significantly associated with BMP-2 (Spearman ρ = 0.46; p = 0.0002). Using the results from IVUS, plasma BMP-2 levels were shown to positively correlate with plaque burden (Spearman ρ = 0.38, P = 0.002) and plaque calcification (Spearman ρ =0.44, P = 0.0003) and to negatively correlate with lumen volume (Spearman ρ =0.31, P = 0.01). CONCLUSIONS: Our study demonstrates that patients with T2DM had higher circulating levels of BMP-2 than normal controls. Plasma BMP-2 levels correlated positively with plaque burden and calcification in patients with T2DM.