RESUMO
In this study we determined the molecular mechanisms of how homocysteine differentially affects receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) synthesis in the bone. The results showed that oxidative stress induced by homocysteine deranges insulin-sensitive FOXO1 and MAP kinase signaling cascades to decrease OPG and increase RANKL synthesis in osteoblast cultures. We observed that downregulation of insulin/FOXO1 and p38 MAP kinase signaling mechanisms due to phosphorylation of protein phosphatase 2A (PP2A) was the key event that inhibited OPG synthesis in homocysteine-treated osteoblast cultures. siRNA knockdown experiments confirmed that FOXO1 is integral to OPG and p38 synthesis. Conversely homocysteine increased RANKL synthesis in osteoblasts through c-Jun/JNK MAP kinase signaling mechanisms independent of FOXO1. In the rat bone milieu, high-methionine diet-induced hyperhomocysteinemia lowered FOXO1 and OPG expression and increased synthesis of proresorptive and inflammatory cytokines such as RANKL, M-CSF, IL-1α, IL-1ß, G-CSF, GM-CSF, MIP-1α, IFN-γ, IL-17, and TNF-α. Such pathophysiological conditions were exacerbated by ovariectomy. Lowering the serum homocysteine level by a simultaneous supplementation with N-acetylcysteine improved OPG and FOXO1 expression and partially antagonized RANKL and proresorptive cytokine synthesis in the bone milieu. These results emphasize that hyperhomocysteinemia alters the redox regulatory mechanism in the osteoblast by activating PP2A and deranging FOXO1 and MAPK signaling cascades, eventually shifting the OPG:RANKL ratio toward increased osteoclast activity and decreased bone quality.
Assuntos
Fatores de Transcrição Forkhead/fisiologia , Homocisteína/farmacologia , Proteínas do Tecido Nervoso/fisiologia , Osteoblastos/metabolismo , Osteoporose/etiologia , Osteoprotegerina/fisiologia , Ligante RANK/fisiologia , Acetilcisteína , Animais , Células Cultivadas , Feminino , Hiper-Homocisteinemia/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoprotegerina/análise , Proteína Fosfatase 2/metabolismo , Ligante RANK/análise , Ratos , Ratos Sprague-Dawley , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologiaRESUMO
Vascular calcification is an important problem in the patients with diabetes and chronic kidney disease (CKD) , and contributes to the increased risk of cardiovascular events by a variety of mechanisms, including an increase in arterial stiffness by medial calcification or an increase in plaque vulnerability by a specific type of atherosclerotic calcification. Coronary calcification is a marker of atherosclerosis and evaluation of coronary artery calcium (CAC) score by cardiac MDCT has been recognized as the useful strategies to initiate or intensify appropriate treatment to slow the progression of atherosclerosis. Besides the risk of coronary heart disease, CAC has been demonstrated to be associated with the risk of complication during PCI, including arterial perforation and dissection, stent malapposition, and resultant late stent thrombosis. Increasing evidence demonstrates that both types of vascular calcification are active and tightly regulated by a process similar to bone formation.
Assuntos
Doença das Coronárias/etiologia , Placa Aterosclerótica/etiologia , Calcificação Vascular/complicações , Animais , Proteína Morfogenética Óssea 2/fisiologia , Cálcio/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/fisiologia , Vasos Coronários/patologia , Humanos , Camundongos , Osteoprotegerina/fisiologia , Fósforo/metabolismo , Ligante RANK/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/fisiologia , Receptores Notch/fisiologia , Risco , Calcificação Vascular/genéticaRESUMO
En las espondiloartropatías, la marca distintiva del daño esquelético es la neoformación ósea en forma de entesopatía calcificante, axial o periférica, y de anquilosis ósea. Las terapias biológicas que neutralizan el factor de necrosis tumoral se han mostrado eficaces para controlar la actividad inflamatoria de estas enfermedades. Sin embargo, datos procedentes de modelos animales, estudios clínicos de imagen y datos ecográficos parecen indicar que la inflamación y la formación ósea podrían ser procesos independientes y que el control de la inflamación puede no ser suficiente para impedir el desarrollo de anquilosis en estos pacientes. En la diferenciación y la activación del osteoblasto para inducir la formación ósea, la vía Wnt (wingless) y las proteínas morfogenéticas óseas adquieren un especial protagonismo y pueden ser determinantes en el comienzo y la progresión de la osificación entesítica, y convertirse en posibles dianas terapéuticas. Por otro lado, otros hallazgos clínicos, estudios de imagen y de marcadores óseos respaldarían la hipótesis de que la osificación se relaciona con la inflamación como un proceso inicialmente reparador. Se revisan estos hechos y se exponen las últimas teorías que intentan establecer el nexo entre inflamación y formación ósea (AU)
In spondyloarthropathies, the distinctive evidence of skeletal damage is de novo bone formation in the form of an ossifying enthesopathy, be it axial or peripheral, and bony ankylosis. Biologic therapy that neutralize the tumor necrosis factor have shown to be effective controlling the inflammatory activity of these diseases. However, data from animal models, clinical imaging studies and ecographic data seem to indicate that inflammation and bone formation could be independent processes and that control of inflammation might not be enough to impede the development of ankylosis in these patients. In the osteoblasts differentiation and activation that leads to bone formation, the Wnt (wingless) pathway and the bone morphogenic proteins acquire a special role and might be determinant in the onset and progression of enthesopathic ossification, as well as become therapeutic targets. On the other hand, clinical and imaging findings as well as the determination of bone markers support the hypothesis that that ossification is initially related to inflammation as a repair process. These facts are reviewed and the latest theories are exposed, in an attempt to establish a link between inflammation and bone formation (AU)
Assuntos
Humanos , Inflamação/fisiopatologia , Doenças Reumáticas/fisiopatologia , Terapia Biológica , Espondiloartropatias/fisiopatologia , Anquilose/prevenção & controle , Ossificação Heterotópica/prevenção & controle , Proteínas Morfogenéticas Ósseas/fisiologia , Osteoprotegerina/fisiologiaRESUMO
Bone health, characterized by its mass, density, and micro-architectural qualities, is maintained by a balanced system of remodeling. The lack of these qualities, caused by an uncoupling of the remodeling process, leads to bone fragility and an increased risk for fracture. The prime regulator of bone remodeling is the RANK/RANKL/OPG system. The common origin of both bone and immune stem cells is the key to understanding this system and its relationship to the transcription factor nuclear factor kappaB in bone loss and inflammation. Via this coupled osteo-immune relationship, a catabolic environment from heightened proinflammatory cytokine expression and/or a chronic antigen-induced activation of the immune system can initiate a switch-like diversion of osteoprogenitor-cell differentiation away from monocyte-macrophage and osteoblast cell formation and toward osteoclast and adipocyte formation. This disruption in bone homeostasis leads to increased fragility. Dietary and specific nutrient interventions can reduce inflammation and limit this diversion. Common laboratory biomarkers can be used to assess changes in body metabolism that affect bone health. This literature review offers practical information for applying effective strategic nutrition to fracture-risk individuals while monitoring metabolic change through serial testing of biomarkers. As examples, the clinician may recommend vitamin K and potassium to reduce hypercalciuria, _-lipoic acid and N-acetylcysteine to reduce the bone resorption marker N-telopeptide (N-Tx), and dehydroepiandrosterone (DHEA), whey, and milk basic protein (the basic protein fraction of whey) to increase insulin-like growth factor-1 (IGF-1) and create a more anabolic profile.
Assuntos
Biomarcadores/sangue , Osteoporose , Absorciometria de Fóton , Acidose/etiologia , Densidade Óssea , Remodelação Óssea/fisiologia , Proteína C-Reativa/metabolismo , Cálcio/urina , Doença Celíaca/complicações , Desidroepiandrosterona/metabolismo , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Hidrocortisona/sangue , Hiper-Homocisteinemia/complicações , Masculino , Osteoporose/diagnóstico , Osteoporose/metabolismo , Osteoporose/prevenção & controle , Osteoprotegerina/fisiologia , Ligante RANK/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/fisiologia , Doenças da Glândula Tireoide/complicações , Vitamina D/sangue , Vitamina K/sangueRESUMO
Osteoporosis represents an important cause of morbidity in patients with beta-thalassemia major, and its etiology is multifactorial. Thus, the aim of this study was to characterize the possible role of the osteoprotegerin (OPG) and receptor activator of the NF-kappaB ligand (RANKL) system in thalassemia-related bone loss. Serum concentrations of OPG, soluble RANKL (s-RANKL), markers of bone turnover, and lumbar spine bone mineral density (BMD) were measured in random samples of males (n = 29; mean age +/- SEM, 24.26 +/- 1.29 years; range, 13-41 years) and females (n = 31; age, 24.59 +/- 0.95 years; range, 12-34 years) with beta-thalassemia major and in 30 healthy age-, height-, and weight-matched subjects. Thalassemic patients had significantly lower levels of OPG compared with controls (2.54 +/- 0.12 vs. 3.25 +/- 0.122, respectively; P < 0.05) and higher, albeit not statistically significantly, serum levels of s-RANKL (0.350 +/- 0.03 vs. 0.295 +/- 0.046, respectively; P < 0.05). s-RANKL correlated negatively with age (r = -0.3, P < 0.05), and OPG correlated positively with the duration of the interval between the onset of transfusions and chelation therapy (r = 0.52, P < 0.001). Regarding markers of bone metabolism, plasma values of osteocalcin correlated positively with s-RANKL (r = 0.40, P < 0.05) and negatively with OPG/s-RANKL ratio (r = -0.55, P < 0.01). In multiple regression analysis only cross-linked N-teleopeptide of type I collagen (NTX) significantly accounted for BMD. Although the OPG/RANKL system may have some clinical usefulness as a marker of bone turnover in beta-thalassemia, conventional markers of bone turnover more accurately represent changes in the BMD of these patients.
Assuntos
Osteoporose/complicações , Osteoprotegerina/sangue , Receptor Ativador de Fator Nuclear kappa-B/sangue , Talassemia beta/sangue , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Osteoprotegerina/fisiologia , Ligante RANK/sangue , Receptor Ativador de Fator Nuclear kappa-B/fisiologia , Talassemia beta/complicaçõesRESUMO
OBJECTIVE: To assess the effect of osteoprotegerin (OPG) on joint swelling, synovial inflammation and cartilage destruction, periarticular and axial bone volume, and bone turnover in rat antigen-induced arthritis (AIA). DESIGN: Rats were treated with OPG (3 mg/kg/day) at regular intervals from day 1 to day 20 of AIA. Disease activity was evaluated by measurement of joint swelling as well as, joint inflammation and destruction by histology. Bone volume and cellular turnover parameters of secondary spongiosa of the right tibia head and the third lumbar vertebra were evaluated by histomorphometry. Periarticular bone volume of the primary spongiosa at the right tibia head was measured by linear scanning. The findings were compared with those of PBS-treated AIA and healthy animals. RESULT: OPG treatment did not reduce joint swelling or histological signs of inflammation. Cartilage destruction was reduced. However, this effect did not reach statistical significance . In the secondary spongiosa OPG treatment reduced the loss of periarticular bone volume. However, the latter did not reach the level of healthy controls. OPG treatment significantly reduced parameters of bone formation and bone resorption. In the primary spongiosa, OPG-treatment led to a higher amount of mineralized tissue and a greater number of trabeculae compared to PBS-treated animals with AIA or healthy controls. In the axial skeleton, OPG treatment reduced bone formation and bone resorption parameters compared to healthy animals. This treatment had no influence on bone volume. CONCLUSIONS: In periarticular bone of AIA rats, OPG treatment reduced the loss of bone volume and decreased the bone turnover, thus preventing periarticular bone destruction. OPG treatment had no influence on inflammatory process or on cartilage destruction.