RESUMO
Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X-linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK-PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first-order absorption, 1-compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK-PD parameters. No other intrinsic factors affected PK or PK-PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fósforo/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Anticorpos Monoclonais Humanizados/farmacocinética , Peso Corporal , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Fatores de Crescimento de Fibroblastos/imunologia , Humanos , Lactente , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Adulto JovemRESUMO
IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Pediatric patients in Japan are diagnosed with IgAN at an early stage of the disease through annual urinary examinations. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) have various roles, including proinflammatory effects, and modulation of several kidney diseases; however, no reports have described their roles in pediatric IgAN. In this study, we performed pathological and immunohistochemical analyses of samples from 14 pediatric IgAN patients. Additionally, gene expression arrays of glomeruli by laser-captured microdissection were performed in hemi-nephrectomized high serum IgA (HIGA) mice, a model of IgA nephropathy, to determine the role of Fn14. Glomeruli with intense Fn14 deposition were observed in 80% of mild IgAN cases; however, most severe cases showed glomeruli with little or no Fn14 deposition. Fn14 deposition was not observed in obvious mesangial proliferation or the crescent region of glomeruli, but was detected strongly in the glomerular tuft, with an intact appearance. In HIGA mice, Fn14 deposition was observed mildly beginning at 11 weeks of age, and stronger Fn14 deposition was detected at 14 weeks of age. Expression array analysis indicated that Fn14 expression was higher in HIGA mice at 6 weeks of age, increased slightly at 11 weeks, and then decreased at 26 weeks when compared with controls at equivalent ages. These findings suggest that Fn14 signaling affects early lesions but not advanced lesions in patients with IgAN. Further study of the TWEAK/Fn14 pathway will contribute to our understanding of the progression of IgAN.
Assuntos
Fatores de Crescimento de Fibroblastos/imunologia , Glomerulonefrite por IGA/imunologia , Adolescente , Animais , Biomarcadores/sangue , Criança , Feminino , Humanos , Japão , Masculino , CamundongosRESUMO
OBJECTIVES: X-linked hypophosphatemic rickets (XLH) is a congenital fibroblast growth factor (FGF)23-related metabolic bone disease that is treated with active vitamin D and phosphate as conventional therapies. Complications of these therapies include nephrocalcinosis (NC) caused by excessive urine calcium and phosphate concentrations. Recently, an anti-FGF23 antibody, burosumab, was developed and reported to be effective in poorly-controlled or severe XLH patients. This study aimed to reveal the impact of switching treatments in relatively well-controlled XLH children with the Rickets Severity Scale less than 2.0. METHODS: The effects of the two treatments in eight relatively well-controlled XLH children with a mean age of 10.4 ± 1.9 years were compared retrospectively for the same treatment duration (31 ± 11 months) before and after the baseline. RESULTS: Actual doses of alfacalcidol and phosphate as conventional therapy were 150.9 ± 43.9 ng/kg and 27.5 ± 6.3 mg/kg per day, respectively. Renal echography revealed spotty NC in 8/8 patients, but no aggravation of NC was detected by switching treatments. Switching treatments increased TmP/GFR (p=0.002) and %TRP (p<0.001), and improved the high urine calcium/creatinine ratio to the normal range (p<0.001) although both treatments controlled disease markers equally. Additionally, low intact parathyroid hormone during conventional therapy was increased within the normal range by switching treatments. CONCLUSIONS: Our results suggest that a high dose of alfacalcidol was needed to control the disease, but it caused hypercalciuria and NC. We concluded that switching treatments in relatively well-controlled XLH children improved renal phosphate reabsorption and decreased urine calcium extraction, and may have the potential to prevent NC.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Substituição de Medicamentos/métodos , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Hidroxicolecalciferóis/uso terapêutico , Nefrocalcinose/prevenção & controle , Conservadores da Densidade Óssea/uso terapêutico , Criança , Raquitismo Hipofosfatêmico Familiar/patologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/imunologia , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic dysfunction and neuro-inflammation. The fibroblast growth factor 21 (FGF21) plays an important role in the regulation of both phenomena and is a major hormone of energetic homeostasis. In this study, we aimed to determine the relevance of FGF21 pathway stimulation in a male mouse model of ALS (mutated SOD1-G93A mice) by using a pharmacological agonist of FGF21, R1Mab1. Mice (SOD1-WT and mutant SOD1-G93A) were treated with R1Mab1 or vehicle. Longitudinal data about clinical status (motor function, body weight) and biological parameters (including hormonal, immunological, and metabolomics profiles) were collected from the first symptoms to euthanasia at week 20. Multivariate models were performed to identify the main parameters associated with R1Mab1 treatment and to link them with clinical status, and metabolic pathways involving the discriminant metabolites were also determined. A beneficial clinical effect of R1Mab1 was revealed on slow rotarod (p = 0.032), despite a significant decrease in body weight of ALS mice (p < 0.001). We observed a decrease in serum TNF-α, MCP-1, and insulin levels (p = 0.0059, p = 0.003, and p = 0.01, respectively). At 16 weeks, metabolomics analyses revealed a clear discrimination (CV-ANOVA = 0.0086) according to the treatment and the most discriminant pathways, including sphingolipid metabolism, butanoate metabolism, pantothenate and CoA biosynthesis, and the metabolism of amino acids like tyrosine, arginine, proline, glycine, serine, alanine, aspartate, and glutamate. Mice treated with R1Mab1 had mildly higher performance on slow rotarod despite a decrease on body weight and could be linked with the anti-inflammatory effect of R1Mab1. These results indicate that FGF21 pathway is an interesting target in ALS, with a slight improvement in motor function combined with metabolic and anti-inflammatory effects.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Esclerose Lateral Amiotrófica/tratamento farmacológico , Animais , Anticorpos Monoclonais/uso terapêutico , Quimiocina CCL2/sangue , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/imunologia , Fatores de Crescimento de Fibroblastos/fisiologia , Interleucina-6/sangue , Leptina/sangue , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Resistina/sangue , Teste de Desempenho do Rota-Rod , Transdução de Sinais , Transcriptoma , Fator de Necrose Tumoral alfa/sangueAssuntos
Anticorpos Monoclonais Humanizados/imunologia , Fatores de Crescimento de Fibroblastos/sangue , Adolescente , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Reações Falso-Negativas , Raquitismo Hipofosfatêmico Familiar/sangue , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/imunologia , Humanos , ImunoensaioRESUMO
Hepatocellular carcinoma (HCC) is a common and particularly fatal form of cancer for which very few drugs are effective. The fibroblast growth factor 19 (FGF19) has been viewed as a driver of HCC development and a potential Ab target for developing novel HCC therapy. However, a previously developed anti-FGF19 Ab disrupted FGF19's normal regulatory function and caused severe bile-acid-related side-effects despite of having potent antitumor effects in preclinical models. Here, we developed novel human Abs (G1A8 and HS29) that specifically target the N-terminus of FGF19. Both Abs inhibited FGF19-induced HCC cell proliferation in vitro and significantly suppressed HCC tumor growth in mouse models. Importantly, no bile-acid-related side effects were observed in preclinical cynomolgus monkeys. Fundamentally, our study demonstrates that it is possible to target FGF19 for anti-HCC therapies without adversely affecting its normal bile acid regulatory function, and highlights the exciting promise of G1A8 or HS29 as potential therapy for HCC.
Assuntos
Anticorpos/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/imunologia , Neoplasias Hepáticas/tratamento farmacológico , Animais , Anticorpos/química , Anticorpos/imunologia , Antineoplásicos/química , Antineoplásicos/imunologia , Ácidos e Sais Biliares/sangue , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Modelos Animais de Doenças , Epitopos , Feminino , Fatores de Crescimento de Fibroblastos/química , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Macaca fascicularis , Masculino , CamundongosRESUMO
Collagen peptides can promote wound healing and are closely related to microbiome colonization. We investigated the relationship among collagen peptides, wound healing, and wound microflora colonization by administering the murine wound model with Salmo salar skin collagen peptides (Ss-SCPs) and Tilapia nilotica skin collagen peptides (Tn-SCPs). We analyzed the vascular endothelial growth factor (VEGF), fibroblast growth factors (ß-FGF), pattern recognition receptor (NOD2), antimicrobial peptides (ß-defence14, BD14), proinflammatory (TNF-α, IL-6, and IL-8) and anti-inflammatory (IL-10) cytokines, macrophages, neutrophil infiltration levels, and microbial communities in the rat wound. The healing rates of the Ss-SCP- and Tn-SCP-treated groups were significantly accelerated, associated with decreased TNF-α, IL-6, and IL-8 and upregulated BD14, NOD2, IL-10, VEGF, and ß-FGF. Accelerated healing in the collagen peptide group shows that the wound microflora such as Leuconostoc, Enterococcus, and Bacillus have a positive effect on wound healing (P < 0.01). Other microbiome species such as Stenotrophomonas, Bradyrhizobium, Sphingomonas, and Phyllobacterium had a negative influence and decreased colonization (P < 0.01). Altogether, these studies show that collagen peptide could upregulate wound NOD2 and BD14, which were implicated in microflora colonization regulation in the wound tissue and promoted wound healing by controlling the inflammatory reaction and increasing wound angiogenesis and collagen deposition.
Assuntos
Colágeno/química , Proteínas de Peixes/química , Microbiota/efeitos dos fármacos , Proteína Adaptadora de Sinalização NOD2/genética , Peptídeos/administração & dosagem , Pele/química , Ferimentos e Lesões/fisiopatologia , beta-Defensinas/genética , Administração Cutânea , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Ciclídeos , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Masculino , Camundongos , Proteína Adaptadora de Sinalização NOD2/imunologia , Peptídeos/química , Ratos , Ratos Sprague-Dawley , Salmo salar , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/imunologia , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/imunologia , Ferimentos e Lesões/microbiologia , beta-Defensinas/imunologiaRESUMO
Acute graft-versus-host disease (aGVHD) and kidney injury are the major complications after allogeneic hematopoietic stem cell transplantation (HSCT). Although the underlying mechanisms for the development of these complications are not yet fully understood, it has been proposed that emergence of aGVHD contributes to the development of kidney injury after HSCT. We have shown previously that aGVHD targets the kidney in a biphasic manner: at the onset, inflammatory genes are up-regulated, while when aGVHD becomes established, donor lymphocytes infiltrate the kidney. Here, we characterize renal manifestations at the onset of aGVHD. Mice receiving allogeneic bone marrow and spleen cells displayed symptoms of aGVHD and elevated serum levels of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) within 4 days. There was concurrent kidney injury with the following characteristics: (1) elevated expression of the kidney injury biomarker, neutrophil gelatinase-associated lipocalin (NGAL), (2) accumulation of hetero-lysosomes in proximal tubule epithelial cells, and (3) reductions in αKlotho mRNA and protein and increased serum levels of fibroblast growth factor 23 (Fgf23), phosphate and urea. This situation resembled acute renal injury caused by bacterial lipopolysaccharide. We conclude that the onset of aGVHD is associated with kidney injury involving down-regulation of αKlotho, a sight that may inspire novel therapeutic approaches.
Assuntos
Injúria Renal Aguda/imunologia , Transplante de Medula Óssea/efeitos adversos , Glucuronidase/metabolismo , Doença Enxerto-Hospedeiro/complicações , Injúria Renal Aguda/sangue , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/patologia , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/imunologia , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/imunologia , Humanos , Interferon gama/sangue , Interferon gama/imunologia , Rim , Proteínas Klotho , Lipocalina-2/análise , Lipocalina-2/metabolismo , Masculino , Camundongos , Transplante Homólogo/efeitos adversos , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The importance of the postprandial state has been acknowledged, since hyperglycemia and hyperlipidemia are linked with several chronic systemic low-grade inflammation conditions. Humans spend more than 16 h per day in the postprandial state and the postprandial state is acknowledged as a complex interplay between nutrients, hormones and diet-derived metabolites. The purpose of this review is to provide insight into the physiology of the postprandial inflammatory response, the role of different nutrients, the pro-inflammatory effects of metabolic endotoxemia and the anti-inflammatory effects of bile acids. Moreover, we discuss nutritional strategies that may be linked to the described pathways to modulate the inflammatory component of the postprandial response.
Assuntos
Ácidos e Sais Biliares/imunologia , Ácidos e Sais Biliares/metabolismo , Endotoxemia/metabolismo , Inflamação/metabolismo , Nutrientes/metabolismo , Complemento C3/metabolismo , Dieta Mediterrânea , Dieta Ocidental , Fatores de Crescimento de Fibroblastos/imunologia , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Lipopolissacarídeos/sangue , Doenças Metabólicas/dietoterapia , NF-kappa B/metabolismo , Fenômenos Fisiológicos da Nutrição , Estresse Oxidativo , Período Pós-Prandial , Espécies Reativas de Oxigênio , Receptores Citoplasmáticos e Nucleares/imunologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/imunologia , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Exercise is considered to be the best approach to improve quality of life, and together with a healthy and adequate dietary pattern, exercise represents the best strategy to reduce the risk of chronic metabolic and inflammatory diseases, such as those related to obesity. The regularity and intensity of exercise is modulated at the molecular level in the skeletal muscle by two protein kinases, the mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), which act as sensors of external stimuli, showing the energy status of muscular fibers. The mTOR pathway is activated by insulin and amino acid availability, and its metabolic actions culminate in increased protein synthesis and reduced autophagy, leading to an increase in muscle mass. In contrast, AMPK activation induces a transcriptional program aimed to increase the mitochondrial content in skeletal muscle, transforming fast-twitch glycolytic fibers to slow-twitch oxidative fibers and increasing resistance to fatigue. In addition, inadequate exercise training induces imbalance in the immune response, generating excessive inflammation and/or immunosuppression. The purpose of this review is to summarize recent studies that provide insight into dietary protein interventions and/or amino acid supplementation that may improve outcomes after exercise by modulating 1) mTOR and AMPK activation during early exercise recovery, leading to increased muscle protein synthesis or increased oxidative capacity; 2) undesirable inflammatory responses; and 3) fibroblast growth factor 21 (FGF21) levels that may have relevant implications in skeletal muscle metabolism, particularly during the exercise recovery and performance of obese subjects.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aminoácidos/metabolismo , Proteínas Alimentares/metabolismo , Exercício Físico/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Imunidade/imunologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/imunologia , Aminoácidos/imunologia , Proteínas Alimentares/imunologia , Suplementos Nutricionais , Fatores de Crescimento de Fibroblastos/imunologia , Humanos , Músculo Esquelético/imunologia , Músculo Esquelético/metabolismo , Aptidão Física/fisiologia , Serina-Treonina Quinases TOR/imunologiaRESUMO
Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease is independently associated with all-cause mortality. Since inflammation is characteristic of chronic kidney disease and associates with increased plasma FGF23 we examined whether inflammation directly stimulates FGF23. In a population-based cohort, plasma tumor necrosis factor (TNF) was the only inflammatory cytokine that independently and positively correlated with plasma FGF23. Mouse models of chronic kidney disease showed signs of renal inflammation, renal FGF23 expression and elevated systemic FGF23 levels. Renal FGF23 expression coincided with expression of the orphan nuclear receptor Nurr1 regulating FGF23 in other organs. Antibody-mediated neutralization of TNF normalized plasma FGF23 and suppressed ectopic renal Fgf23 expression. Conversely, TNF administration to control mice increased plasma FGF23 without altering plasma phosphate. Moreover, in Il10-deficient mice with inflammatory bowel disease and normal kidney function, plasma FGF23 was elevated and normalized upon TNF neutralization. Thus, the inflammatory cytokine TNF contributes to elevated systemic FGF23 levels and also triggers ectopic renal Fgf23 expression in animal models of chronic kidney disease.
Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Doenças Inflamatórias Intestinais/imunologia , Insuficiência Renal Crônica/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Animais , Linhagem Celular , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/imunologia , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Doenças Inflamatórias Intestinais/sangue , Interleucina-10/deficiência , Interleucina-10/genética , Rim/imunologia , Rim/patologia , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Cultura Primária de Células , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologiaRESUMO
In response to environmental and nutrient stress, adipose tissues must establish a new homeostatic state. Here we show that cold exposure of obese mice triggers an adaptive tissue remodeling in visceral adipose tissue (VAT) that involves extracellular matrix deposition, angiogenesis, sympathetic innervation, and adipose tissue browning. Obese VAT is predominated by pro-inflammatory M1 macrophages; cold exposure induces an M1-to-M2 shift in macrophage composition and dramatic changes in macrophage gene expression in both M1 and M2 macrophages. Antibody-mediated CSF1R blocking prevented the cold-induced recruitment of adipose tissue M2 macrophages, suggesting the role of CSF1R signaling in the process. These cold-induced effects in obese VAT are phenocopied by an administration of the FGF21-mimetic antibody, consistent with its action to stimulate sympathetic nerves. Collectively, these studies illuminate adaptive visceral adipose tissue plasticity in obese mice in response to cold stress and antibody-based metabolic therapy.
Assuntos
Adaptação Fisiológica , Anticorpos/farmacologia , Resposta ao Choque Frio , Gordura Intra-Abdominal/fisiologia , Animais , Movimento Celular , Fatores de Crescimento de Fibroblastos/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Camundongos , Camundongos Obesos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Células Estromais/fisiologiaRESUMO
BACKGROUND: Studies using mouse models have revealed that mast cell progenitors are recruited from the blood circulation to the lung during acute allergic airway inflammation. The discovery of a corresponding human mast cell progenitor population in the blood has enabled to study the relation of circulating mast cell progenitors in clinical settings. OBJECTIVES: To explore the possible association between the frequency of mast cell progenitors in the blood circulation and allergic asthma, we assessed the relation of this recently identified cell population with asthma outcomes and inflammatory mediators in allergic asthmatic patients and controls. METHODS: Blood samples were obtained, and spirometry was performed on 38 well-controlled allergic asthmatic patients and 29 controls. The frequency of blood mast cell progenitors, total serum IgE and 180 inflammation- and immune-related plasma proteins were quantified. RESULTS: Allergic asthmatic patients and controls had a similar mean frequency of blood mast cell progenitors, but the frequency was higher in allergic asthmatic patients with reduced FEV1 and PEF (% of predicted) as well as in women. The level of fibroblast growth factor 21 (FGF-21) correlated positively with the frequency of mast cell progenitors, independent of age and gender, and negatively with lung function. The expression of FcεRI on mast cell progenitors was higher in allergic asthmatic patients and correlated positively with the level of total IgE in the controls but not in the asthmatic patients. CONCLUSION: Elevated levels of circulating mast cell progenitors are related to reduced lung function, female gender and high levels of FGF-21 in young adults with allergic asthma.
Assuntos
Asma/sangue , Fatores de Crescimento de Fibroblastos/sangue , Mediadores da Inflamação/sangue , Mastócitos/metabolismo , Células-Tronco/metabolismo , Adolescente , Adulto , Asma/imunologia , Feminino , Fatores de Crescimento de Fibroblastos/imunologia , Humanos , Mediadores da Inflamação/imunologia , Masculino , Mastócitos/imunologia , Células-Tronco/imunologiaRESUMO
The most common heritable disorder of renal phosphate wasting, X-linked hypophosphataemia (XLH), was discovered to be caused by inactivating mutations in the phosphate regulating gene with homology to endopeptidases on the X-chromosome (PHEX) gene in 1995. Although the exact molecular mechanisms by which PHEX mutations cause disturbed phosphate handling in XLH remain unknown, focus for novel therapies has more recently been based upon the finding that the bone-produced phosphaturic hormone fibroblast growth factor-23 is elevated in XLH patient plasma. Previous treatment strategies for XLH were based upon phosphate repletion plus active vitamin D analogues, which are difficult to manage, fail to address the primary pathogenesis of the disease, and can have deleterious side effects. A novel therapy for XLH directly targeting fibroblast growth factor-23 via a humanized monoclonal antibody (burosumab-twza/CRYSVITA, henceforth referred to just as burosumab) has emerged as an effective, and recently approved, pharmacological treatment for both children and adults. This review will provide an overview of the clinical manifestations of XLH, the molecular pathophysiology, and summarize its current treatment.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Biomarcadores/sangue , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/genética , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/imunologia , Predisposição Genética para Doença , Humanos , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fenótipo , Resultado do Tratamento , Regulação para CimaRESUMO
Hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder of ectopic calcification due to deficiency of or resistance to intact fibroblast growth factor 23 (iFGF23). Inactivating mutations in FGF23, N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO (KL) have been reported as causing HFTC/HHS. We present what we believe is the first identified case of autoimmune hyperphosphatemic tumoral calcinosis in an 8-year-old boy. In addition to the classical clinical and biochemical features of hyperphosphatemic tumoral calcinosis, the patient exhibited markedly elevated intact and C-terminal FGF23 levels, suggestive of FGF23 resistance. However, no mutations in FGF23, KL, or FGF receptor 1 (FGFR1) were identified. He subsequently developed type 1 diabetes mellitus, which raised the possibility of an autoimmune cause for hyperphosphatemic tumoral calcinosis. Luciferase immunoprecipitation systems revealed markedly elevated FGF23 autoantibodies without detectable FGFR1 or Klotho autoantibodies. Using an in vitro FGF23 functional assay, we found that the FGF23 autoantibodies in the patient's plasma blocked downstream signaling via the MAPK/ERK signaling pathway in a dose-dependent manner. Thus, this report describes the first case, to our knowledge, of autoimmune hyperphosphatemic tumoral calcinosis with pathogenic autoantibodies targeting FGF23. Identification of this pathophysiology extends the etiologic spectrum of hyperphosphatemic tumoral calcinosis and suggests that immunomodulatory therapy may be an effective treatment.
Assuntos
Autoanticorpos , Doenças Autoimunes , Calcinose , Fatores de Crescimento de Fibroblastos , Hiperostose Cortical Congênita , Hiperfosfatemia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Calcinose/sangue , Calcinose/imunologia , Calcinose/patologia , Criança , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/imunologia , Humanos , Hiperostose Cortical Congênita/sangue , Hiperostose Cortical Congênita/imunologia , Hiperostose Cortical Congênita/patologia , Hiperfosfatemia/sangue , Hiperfosfatemia/imunologia , Hiperfosfatemia/patologia , Sistema de Sinalização das MAP Quinases/imunologia , MasculinoRESUMO
AIMS: The proarrhythmic effect of fibroblast growth factor 23 (FGF23) was observed in patients with end stage kidney disease (ESKD). However, there is no data on the role of FGF23 and soluble Klotho (sKlotho) in the pathogenesis of atrial fibrillation (AF) beyond ESKD. The aim of the study was to assess the peripheral vein and left atrial (LA) serum levels of FGF23 and sKlotho along with calcium-phosphates parameters in patients with AF undergoing percutaneous radiofrequency pulmonary vein isolation (PVI). METHODS AND RESULTS: Sixty-nine consecutive patients (mean age: 55.8⯱â¯9.7â¯years, F/M: 26/43, CHA2DS2-Vasc: 1.7⯱â¯1.1) with paroxysmal/persistent AF undergoing PVI were included into the study. Blood samples were taken during PVI - baseline from the peripheral vein, then from the LA immediately after a septal puncture. RESULTS: There were significant differences in the concentrations of peripheral and LA serum sKlotho, intact FGF23 (iFGF23), calcium and phosphates; peripheral FGF23, calcium and phosphates levels were significantly higher, and sKlotho levels were significantly lower than the LA concentrations. Serum sKlotho levels correlated with the CHADS2-VASc score (râ¯=â¯0.254, pâ¯=â¯0.034) and glucose level (râ¯=â¯0.300, pâ¯=â¯0.005). Serum sKlotho gradient (LA - peripheral vein) correlated with the baseline AF burden in the Holter monitoring (râ¯=â¯-0.389, pâ¯=â¯0.003). PVI efficacy was confirmed in 52 (75%) patients. There was a significant difference in the iFGF23 gradient between patients with AF and without AF (80.3 vs. -47.6â¯pg/ml, pâ¯=â¯0.009) in the six-month follow-up. A receiver operating characteristic (ROC) analysis revealed that an iFGF23 gradient >28.7â¯pg/ml (AUCâ¯=â¯0.742, pâ¯=â¯0.002) was a predictor for AF recurrence. CONCLUSIONS: There is a gradient between the LA and peripheral vein in the markers of calcium-phosphate metabolism in patients undergoing PVI. Lower sKlotho and higher iFGF23 serum levels are associated with episodes of AF. Serum iFGF23 gradient is a potent predictor for the recurrence of AF.
Assuntos
Fibrilação Atrial/sangue , Fatores de Crescimento de Fibroblastos/sangue , Glucuronidase/sangue , Fibrilação Atrial/imunologia , Fibrilação Atrial/patologia , Fibrilação Atrial/terapia , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/imunologia , Seguimentos , Glucuronidase/imunologia , Humanos , Proteínas Klotho , Masculino , Pessoa de Meia-IdadeRESUMO
Immunosuppression may occur for a number of reasons related to an individual's frailty, debility, disease or from therapeutic iatrogenic intervention or misadventure. A large percentage of morbidity and mortality in immunodeficient populations is related to an inadequate response to infectious agents with slow response to antibiotics, enhancements of antibiotic resistance in populations, and markedly increased prevalence of acute inflammatory response, septic and infection related death. Given known relationships between intracellular calcium ion concentrations and cytotoxicity and cellular death, we looked at currently available data linking blockade of calcium ion channels and potential decrease in expression of sepsis among immunosuppressed patients. Notable are relationships between calcium, calcium channel, vitamin D mechanisms associated with sepsis and demonstration of antibiotic-resistant pathogens that may utilize channels sensitive to calcium channel blocker. We note that sepsis shock syndrome represents loss of regulation of inflammatory response to infection and that vitamin D, parathyroid hormone, fibroblast growth factor, and klotho interact with sepsis defense mechanisms in which movement of calcium and phosphorus are part of the process. Given these observations we consider that further investigation of the effect of relatively inexpensive calcium channel blockade agents of infections in immunosuppressed populations might be worthwhile.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/imunologia , Doenças Transmissíveis/tratamento farmacológico , Hospedeiro Imunocomprometido , Sepse/tratamento farmacológico , Cálcio/imunologia , Cálcio/metabolismo , Canais de Cálcio/genética , Doenças Transmissíveis/genética , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/mortalidade , Resistência Microbiana a Medicamentos/genética , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/imunologia , Regulação da Expressão Gênica , Glucuronidase/genética , Glucuronidase/imunologia , Humanos , Proteínas Klotho , Hormônio Paratireóideo/genética , Hormônio Paratireóideo/imunologia , Fósforo/imunologia , Fósforo/metabolismo , Risco , Sepse/genética , Sepse/imunologia , Sepse/mortalidade , Análise de Sobrevida , Vitamina D/imunologia , Vitamina D/metabolismoRESUMO
The high serum fibroblast growth factor 23 (FGF23) levels in patients with acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with increased morbidity and mortality. Mice with folic acid-induced AKI had an increase in bone FGF23 mRNA expression together with an increase in serum FGF23 and several circulating cytokines including interleukin-6 (IL-6). Dexamethasone partially prevented the increase in IL-6 and FGF23 in the AKI mice. IL-6 knock-out mice fed an adenine diet to induce CKD failed to increase bone FGF23 mRNA and had a muted increase in serum FGF23 levels, compared with the increases in wild-type mice with CKD. Therefore, IL-6 contributes to the increase in FGF23 observed in CKD. Hydrodynamic tail injection of IL-6/soluble IL-6 receptor (sIL-6R) fusion protein hyper IL-6 (HIL-6) plasmid increased serum FGF23 levels. Circulating sIL-6R levels were increased in both CKD and AKI mice, suggesting that IL-6 increases FGF23 through sIL-6R-mediated trans-signaling. Renal IL-6 mRNA expression was increased in mice with either AKI or CKD, suggesting the kidney is the source for the increased serum IL-6 levels in the uremic state. HIL-6 also increased FGF23 mRNA in calvaria organ cultures and osteoblast-like UMR106 cells in culture, demonstrating a direct effect of IL-6 on FGF23 expression. HIL-6 increased FGF23 promoter activity through STAT3 phosphorylation and its evolutionarily conserved element in the FGF23 promoter. Thus, IL-6 increases FGF23 transcription and contributes to the high levels of serum FGF23 in both acute and chronic kidney disease.
Assuntos
Injúria Renal Aguda/imunologia , Fatores de Crescimento de Fibroblastos/metabolismo , Interleucina-6/metabolismo , Insuficiência Renal Crônica/imunologia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Adenina/toxicidade , Animais , Osso e Ossos/patologia , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/imunologia , Ácido Fólico/toxicidade , Glucocorticoides/uso terapêutico , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/imunologia , Rim/imunologia , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/imunologia , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Receptores de Interleucina-6/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Transcrição Gênica/imunologiaRESUMO
In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/imunologia , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Cálcio/metabolismo , Método Duplo-Cego , Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Homeostase , Humanos , Masculino , Placebos , Resultado do TratamentoRESUMO
Although humans with X-linked hypophosphatemia (XLH) and the Hyp mouse, a murine homolog of XLH, are known to develop degenerative joint disease, the exact mechanism that drives the osteoarthritis (OA) phenotype remains unclear. Mice that overexpress high-molecular-weight fibroblast growth factor (FGF) 2 isoforms (HMWTg mice) phenocopy both XLH and Hyp, including OA with increased FGF23 production in bone and serum. Because HMWTg cartilage also has increased FGF23 and there is cross-talk between FGF23-Wnt/ß-catenin signaling, the purpose of this study was to determine if OA observed in HMWTg mice is due to FGF23-mediated canonical Wnt signaling in chondrocytes, given that both pathways are implicated in OA pathogenesis. HMWTg OA joints had decreased Dkk1, Sost, and Lrp6 expression with increased Wnt5a, Wnt7b, Lrp5, Axin2, phospho-GSK3ß, Lef1, and nuclear ß-catenin, as indicated by immunohistochemistry or quantitative PCR analysis. Chondrocytes from HMWTg mice had enhanced alcian blue and alkaline phosphatase staining as well as increased FGF23, Adamts5, Il-1ß, Wnt7b, Wnt16, and Wisp1 gene expression and phospho-GSK3ß protein expression as indicated by Western blot, compared with chondrocytes of vector control and chondrocytes from mice overexpressing the low-molecular-weight isoform, which were protected from OA. Canonical Wnt inhibitor treatment rescued some of those parameters in HMWTg chondrocytes, seemingly delaying the initially accelerated chondrogenic differentiation. FGF23 neutralizing antibody treatment was able to partly ameliorate OA abnormalities in subchondral bone and reduce degradative/hypertrophic chondrogenic marker expression in HMWTg joints in vivo. These results demonstrate that osteoarthropathy of HMWTg is at least partially due to FGF23-modulated Wnt/ß-catenin signaling in chondrocytes.