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1.
Cancer Sci ; 111(5): 1750-1760, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32061104

RESUMO

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 , Camundongos
2.
Kidney Int ; 96(4): 890-905, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31301888

RESUMO

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/imunologia
3.
Clin Exp Allergy ; 49(6): 874-882, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30892731

RESUMO

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/imunologia
4.
Br J Clin Pharmacol ; 85(6): 1188-1198, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30207609

RESUMO

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 Cima
5.
Kidney Int ; 94(2): 315-325, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29861060

RESUMO

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/imunologia
6.
Cytokine ; 111: 106-111, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30138898

RESUMO

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€¯9.7 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 (r = 0.254, p = 0.034) and glucose level (r = 0.300, p = 0.005). Serum sKlotho gradient (LA - peripheral vein) correlated with the baseline AF burden in the Holter monitoring (r = -0.389, p = 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. -47.6 pg/ml, p = 0.009) in the six-month follow-up. A receiver operating characteristic (ROC) analysis revealed that an iFGF23 gradient >28.7 pg/ml (AUC = 0.742, p = 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-Idade
7.
J Inherit Metab Dis ; 41(5): 865-876, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29460029

RESUMO

X-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia. This case-note review documents the clinical features and the complications of treatment in 59 adults (19 male, 40 female) with XLH. XLH is associated with a large number of private mutations; 37 different mutations in the PHEX gene were identified in this cohort, 14 of which have not been previously reported. Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40 years. Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common. The rarity of the disease and the large number of variants make it difficult to discern specific genotype-phenotype relationships. A new treatment, an anti-FGF23 antibody, that may affect the natural history of the disease is currently being investigated in clinical trials.


Assuntos
Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/terapia , Doenças Genéticas Ligadas ao Cromossomo X , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/imunologia , Estudos de Associação Genética , Perda Auditiva/etiologia , Humanos , Laminectomia , Masculino , Pessoa de Meia-Idade , Nefrocalcinose/etiologia , Osteotomia , Ensaios Clínicos Controlados Aleatórios como Assunto , Doenças Estomatognáticas/etiologia , Adulto Jovem
8.
Int J Mol Sci ; 19(9)2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30134544

RESUMO

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/metabolismo
9.
J Cell Physiol ; 232(3): 610-616, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27306296

RESUMO

High molecular weight FGF2 transgenic mice (HMWTg) phenocopy the Hyp mouse, homolog of human X-linked hypophosphatemic rickets with phosphate wasting and abnormal fibroblast growth factor (FGF23), fibroblast growth factor receptor (FGFR), Klotho and mitogen activated protein kinases (MAPK) signaling in kidney. In this study, we assessed whether short-term (24 h) in vivo administration of FGF23 neutralizing antibody (FGF23Ab) could rescue hypophosphatemia and impaired FGFR signaling in kidneys of HMWTg male mice. Bone mineral density and bone mineral content in 1-month-old HMWTg mice were significantly reduced compared with Control/VectorTg mice. Serum FGF23 was significantly increased in HMWTg compared with VectorTg. Serum phosphate was significantly reduced in HMWTg and was rescued by FGF23Ab. Serum parathyroid hormone (PTH) was significantly increased in HMWTg but was not reduced by FGF23Ab. 1, 25(OH)2 D was inappropriately normal in serum of HMWTg and was significantly increased in both Vector and HMWTg by FGF23Ab. Analysis of HMWTg kidneys revealed significantly increased mRNA expression of the FGF23 co-receptor Klotho, transcription factor mRNAs for early growth response-1 transcription factor (Egr-1), and c-fos were all significantly decreased by FGF23Ab. A significant reduction in the phosphate transporter Npt2a mRNA was also observed in HMWTg kidneys, which was increased by FGF23Ab. FGF23Ab reduced p-FGFR1, p-FGFR3, KLOTHO, p-ERK1/2, C-FOS, and increased NPT2A protein in HMWTg kidneys. We conclude that FGF23 blockade rescued hypophosphatemia by regulating FGF23/FGFR downstream signaling in HMWTg kidneys. Furthermore, HMWFGF2 isoforms regulate PTH expression independent of FGF23/FGFR signaling. J. Cell. Physiol. 232: 610-616, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/imunologia , Hipofosfatemia/tratamento farmacológico , Hipofosfatemia/metabolismo , Rim/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Animais , Anticorpos Neutralizantes/farmacologia , Densidade Óssea , Sistema Enzimático do Citocromo P-450/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Fator de Crescimento de Fibroblastos 23 , Glucuronidase/metabolismo , Hipofosfatemia/patologia , Proteínas Klotho , Camundongos Transgênicos , Modelos Biológicos , Peso Molecular , Fosforilação , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Curr Opin Nephrol Hypertens ; 25(4): 333-42, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27219044

RESUMO

PURPOSE OF REVIEW: This review examines the role of fibroblast growth factor-23 (FGF-23) in mineral metabolism, innate immunity and adverse cardiovascular outcomes. RECENT FINDINGS: FGF-23, produced by osteocytes in bone, activates FGFR/α-Klotho (α-Kl) complexes in the kidney. The resulting bone-kidney axis coordinates renal phosphate reabsorption with bone mineralization, and creates a counter-regulatory feedback loop to prevent vitamin D toxicity. FGF-23 acts to counter-regulate the effects of vitamin D on innate immunity and cardiovascular responses. FGF-23 is ectopically expressed along with α-Kl in activated macrophages, creating a proinflammatory paracrine signaling pathway that counters the antiinflammatory actions of vitamin D. FGF-23 also inhibits angiotensin-converting enzyme 2 expression and increases sodium reabsorption in the kidney, leading to hypertension and left ventricular hypertrophy. Finally, FGF-23 is purported to cause adverse cardiac and impair neutrophil responses through activation of FGFRs in the absence of α-Kl. Although secreted forms of α-Kl have FGF-23 independent effects, the possibility of α-Kl independent effects of FGF-23 is controversial and requires additional experimental validation. SUMMARY: FGF-23 participates in a bone-kidney axis regulating mineral homeostasis, proinflammatory paracrine macrophage signaling pathways, and in a bone-cardio-renal axis regulating hemodynamics that counteract the effects of vitamin D.


Assuntos
Osso e Ossos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hipertensão/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Imunidade Inata/imunologia , Rim/metabolismo , Enzima de Conversão de Angiotensina 2 , Animais , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/imunologia , Glucuronidase/metabolismo , Homeostase , Humanos , Minerais/metabolismo , Osteócitos/metabolismo , Peptidil Dipeptidase A/metabolismo , Fosfatos/metabolismo , Transdução de Sinais , Sódio/metabolismo , Vitamina D/metabolismo
11.
Clin Calcium ; 26(2): 269-76, 2016 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-26813507

RESUMO

FGF23-related hypophosphatemic rickets is basically treated with active vitamin D and phosphorus. The treatment goals are to minimize bone deformity and improve adult height in children, and to relieve pain and decrease osteomalacia in adult. However, since they do not target the underlying molecular defect, bone deformity can worsen during growth and adult height is suboptimal restricted. Many adult patients suffer from enthesopathy leading to symptoms such as spinal cord compression and debilitating pain. At present, no treatment is effective in preventing or revenging this complication. The recently developed anti-FGF23 antibody may potentially be a more fundamental treatment.


Assuntos
Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/terapia , Fatores de Crescimento de Fibroblastos/fisiologia , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Calcitriol/administração & dosagem , Criança , Raquitismo Hipofosfatêmico Familiar/complicações , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/biossíntese , Fatores de Crescimento de Fibroblastos/imunologia , Fraturas Espontâneas/etiologia , Fraturas Espontâneas/prevenção & controle , Humanos , Hidroxicolecalciferóis/administração & dosagem , Procedimentos Ortopédicos , Compressão da Medula Espinal/etiologia , Compressão da Medula Espinal/prevenção & controle
13.
Clin Calcium ; 25(1): 37-44, 2015 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-25530521

RESUMO

Fibroblast growth factor 23 (FGF23) is a hormone mainly produced by osteocytes and regulates phosphate and vitamin D metabolism by binding to Klotho-FGF receptor complex. Most diseases previously called vitamin D-resistant rickets/osteomalacia or familial hypophosphatemic rickets/osteomalacia have been shown to be caused by excess actions of FGF23. Therefore, several methods to inhibit the actions of FGF23 are now considered as new treatment methods for these FGF23-related hypophosphatemic diseases. It has been reported that anti-FGF23 antibody increases serum phosphate in patients with FGF23-related hypophosphatemic disease.


Assuntos
Osso e Ossos/metabolismo , Cálcio/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hipofosfatemia/tratamento farmacológico , Animais , Anticorpos/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/imunologia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/imunologia , Humanos , Hipofosfatemia/imunologia
14.
Curr Opin Nephrol Hypertens ; 23(4): 346-51, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24848934

RESUMO

PURPOSE OF REVIEW: The review is intended to provide an update on the expanding knowledge regarding diseases caused by the excess actions of fibroblast growth factor 23 (FGF23) and also on the new therapeutic measures for these diseases, with an emphasis on the anti-FGF23 antibody. RECENT FINDINGS: FGF23 decreases serum phosphate and 1,25-dihydroxyvitamin D levels. After the cloning of FGF23, several hypophosphatemic diseases, including tumor-induced osteomalacia and X-linked hypophosphatemic rickets (XLHR), were shown to be caused by excess actions of FGF23. In addition, recent studies indicated that mutations in the family with sequence similarity 20, member C (FAM20C), HRAS and NRAS genes, also caused FGF23-related hypophosphatemic diseases. The inhibition of FGF23 production or activity is, theoretically, an ideal treatment for these hypophosphatemic diseases. The C-terminal fragment of FGF23, inhibitors of FGF receptor and extracellular signal-regulated kinase, and anti-FGF23 antibody were shown to inhibit FGF23 actions both in vitro and in vivo. A phase I clinical trial of anti-FGF23 antibody has shown that this antibody increases serum phosphate in patients with XLHR. SUMMARY: These recent findings confirm that FGF23 has a pivotal role in phosphate metabolism. The inhibition of FGF23 production or activity is promising as a new therapy for FGF23-related hypophosphatemic diseases. Further studies are clearly necessary to establish the clinical utility and long-term safety of these measures.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/metabolismo , Hipofosfatemia/tratamento farmacológico , Hipofosfatemia/genética , Fatores Imunológicos/uso terapêutico , Animais , Caseína Quinase I/genética , Proteínas da Matriz Extracelular/genética , Raquitismo Hipofosfatêmico Familiar/sangue , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/terapia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/imunologia , Humanos , Hipofosfatemia/sangue , Neoplasias/complicações , Osteomalacia/etiologia , Osteomalacia/terapia , Fosfatos/sangue
15.
Clin Calcium ; 24(8): 1217-22, 2014 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-25065874

RESUMO

Tumor-induced osteomalacia (TIO) is a disease caused by fibroblast growth factor 23 (FGF23) secreted from the causative tumor. This disease is cured by complete surgical removal of the tumor. However, there are several difficult cases in which the responsible tumors cannot be found, are incompletely removed, or relapse after the surgery. Anti-FGF23 antibody is being studied as a novel therapy for FGF23-related hypophosphatemic diseases. The efficacy of anti-FGF23 antibodies were confirmed using a murine model of X-linked hypophosphatemic rickets (XLHR) , which is the most common heritable form of FGF23-related hypophosphatemic disease. In addition, results of phase I study of single injection of humanized anti-FGF23 antibody for adult patients with XLHR were recently published and the safety and effectiveness of this antibody was shown. This antibody therapy may be useful for patients with TIO with similar pathogenesis to that of XLHR.


Assuntos
Anticorpos/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/metabolismo , Fatores de Crescimento de Fibroblastos/imunologia , Neoplasias de Tecido Conjuntivo/terapia , Osteomalacia/tratamento farmacológico , Animais , Raquitismo Hipofosfatêmico Familiar/imunologia , Fator de Crescimento de Fibroblastos 23 , Humanos , Hipofosfatemia/etiologia , Neoplasias de Tecido Conjuntivo/imunologia , Osteomalacia/etiologia , Osteomalacia/imunologia , Síndromes Paraneoplásicas
16.
Bull Exp Biol Med ; 155(5): 655-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24288732

RESUMO

Structural and immunophenotypical characteristics of macrophages, associated with their polarization in the M1 and M2 directions of differentiation and activation, were studied in different morphological types of BCG granulomas by the expression of GM-CSF, IFN-γ, and FGFb cytokines and CD36 and CD16/32 differentiation clusters. The proportion of IFN-γ and FGFb macrophage subpopulations changed over the course of granuloma formation, which led to accumulation of FGFb macrophages in the granulomas. These data indicated that the formation of macrophage granulomas and their subsequent transformation into epithelioid-cell granulomas were associated with dynamic quantitative changes in the subpopulations of macrophages with the morphofunctional characteristics of M1 and M2 phenotypes, determining the antibacterial and destructive potential of granulomas. These data are useful for understanding the contribution of functional polarization of macrophages to the pathogenesis of tuberculous infection and, presumably, its complications.


Assuntos
Granuloma/patologia , Macrófagos/patologia , Mycobacterium bovis/crescimento & desenvolvimento , Baço/patologia , Tuberculose/patologia , Animais , Antígenos CD36/genética , Antígenos CD36/imunologia , Diferenciação Celular , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/imunologia , Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Granuloma/imunologia , Imunofenotipagem , Interferon gama/genética , Interferon gama/imunologia , Macrófagos/classificação , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fenótipo , Receptores de IgG/genética , Receptores de IgG/imunologia , Baço/imunologia , Tuberculose/imunologia
17.
Clin Calcium ; 23(10): 1469-75, 2013 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-24076645

RESUMO

In the last decade, Fibroblast growth factor (FGF) 23 has been shown to be a causative factor of hypophosphatemic rickets/osteomalacia, and considered as potential therapeutic target for this disease. Now the most attention is paid to FGF23 blockades as a new category of therapy that may replace the current supplementation of phosphate and active vitamin D. In this chapter, pharmacological actions of the FGF23-neutralizing antibodies in murine hypophosphatemic rickets/osteomalacia model are reviewed. In addition, other types of FGF23 blockades are also briefly discussed.


Assuntos
Anticorpos Neutralizantes/farmacologia , Fatores de Crescimento de Fibroblastos/imunologia , Raquitismo Hipofosfatêmico/imunologia , Animais , Anticorpos Neutralizantes/sangue , Modelos Animais de Doenças , Fator de Crescimento de Fibroblastos 23 , Glucuronidase/metabolismo , Humanos , Proteínas Klotho , Fosfatos/sangue , Raquitismo Hipofosfatêmico/metabolismo
18.
Biochem Biophys Res Commun ; 420(3): 666-70, 2012 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-22450330

RESUMO

Phosphate in manure of monogastric animals pollutes the environment if improperly applied to soil. Strategies that reduce phosphate inputs into animal production systems reduce environmental pollution. Using a novel vaccine to fibroblast growth factor-23 (FGF-23), we induced neutralizing antibodies that reduced the phosphate requirement of growing chickens. Breeding hens were injected with a FGF-23 peptide (AFLPGMNP) conjugate. Antibody was passively transferred from hen to chick and chick response to deficient dietary phosphate intake was determined. Chicks without passive anti-FGF-23 antibody had a 43% and 21% reduction in blood phosphate and bone ash, respectively, when fed a phosphate deficient diet and compared to chicks fed a phosphate replete diet (P<0.05). Chicks with circulating anti-FGF-23 antibodies fed the phosphate deficient diet had plasma phosphate and bone ash that did not differ from chicks fed the phosphate replete diet (P>0.05). Neutralization of FGF-23 offers a new approach to reduce phosphate requirements of farmed animals and may provide a new means to reduce phosphate pollution related to animal farming.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal/imunologia , Anticorpos/imunologia , Galinhas/crescimento & desenvolvimento , Poluentes Ambientais/análise , Fatores de Crescimento de Fibroblastos/imunologia , Esterco/análise , Necessidades Nutricionais , Fosfatos/análise , Ração Animal , Animais , Galinhas/sangue , Galinhas/metabolismo , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/química , Humanos , Fosfatos/sangue , Fosfatos/metabolismo , Estrutura Secundária de Proteína
19.
Adv Exp Med Biol ; 728: 158-70, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22396168

RESUMO

Fibroblast growth factor (FGF) 23 is a hormone that acts to decrease phosphate, 1,25-dihydroxyvitamin D and parathyroid hormone levels in circulation. Particularly, appropriate actions of FGF23 are essential for maintaining physiological phosphate and vitamin D metabolism. Therefore, either gain or loss of function of FGF23 can impair these homeostatic regulations, causing several metabolic bone diseases. The measurement of circulating levels of FGF23 in patients with various types of hypophosphatemic rickets and/or osteomalacia has revealed that several of them are FGF23-dependent diseases, highlighting a novel therapeutic concept that the inhibition of the excess activity of FGF23 could be beneficial for patients with these diseases. Indeed, preliminary studies with a mouse disease model have validated this concept. On the other hand, replacement therapy with recombinant FGF23 may be applied to the disease caused by loss of function of FGF23. Although these concepts still need to be proven with more detailed analyses, the latest knowledge on the FGF23-related diseases and the development of methods to appropriately regulate FGF23 actions may synergistically create novel therapeutic maneuvers.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Terapia de Alvo Molecular/métodos , Animais , Anticorpos Neutralizantes/imunologia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/imunologia , Terapia de Reposição Hormonal , Humanos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia
20.
J Clin Pharmacol ; 62(1): 87-98, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34352114

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 Jovem
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