RESUMO
Despite numerous investigations on the influence of fibroblast growth factor 23 (FGF23), α-Klotho and FGF receptor-1 (FGFR1) on osteoporosis (OP), there is no clear consensus. Mendelian randomization (MR) analysis was conducted on genome-wide association studies (GWASs)-based datasets to evaluate the causal relationship between FGF23, α-Klotho, FGFR1 and OP. The primary endpoint was the odds ratio (OR) of the inverse-variance weighted (IVW) approach. Furthermore, we stably transfected FGF23-mimic or siRNA-FGF23 into human bone marrow mesenchymal stem cells (hBMSCs) in culture and determined its cell proliferation and the effects on osteogenic differentiation. Using MR analysis, we demonstrated a strong correlation between serum FGF23 levels and Heel- and femoral neck-BMDs, with subsequent ORs of 0.919 (95% CI: 0.860-0.983, p = 0.014) and 0.751 (95% CI: 0.587-0.962; p = 0.023), respectively. The expression levels of FGF23 were significantly increased in femoral neck of patients with OP than in the control cohort (p < 0.0001). Based on our in vitro investigation, after overexpression of FGF23, compared to the control group, the BMSC's proliferation ability decreased, the expression level of key osteogenic differentiation genes (RUNX2, OCN and OSX) significantly reduced, mineralized nodules and ALP activity significantly decreased. After silencing FGF23, it showed a completely opposite trend. Augmented FGF23 levels are causally associated with increased risk of OP. Similarly, FGF23 overexpression strongly inhibits the osteogenic differentiation of hBMSCs, thereby potentially aggravating the pathological process of OP.
Assuntos
Diferenciação Celular , Proliferação de Células , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Células-Tronco Mesenquimais , Osteogênese , Osteoporose , Humanos , Fator de Crescimento de Fibroblastos 23/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Proliferação de Células/genética , Diferenciação Celular/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas Klotho/metabolismo , Feminino , Glucuronidase/genética , Glucuronidase/metabolismo , Densidade Óssea/genética , Masculino , Pessoa de Meia-Idade , Colo do Fêmur/metabolismo , Colo do Fêmur/patologiaRESUMO
El propósito del estudio fue determinar la frecuencia de los genotipos de los receptores de vitamina D y de estrógeno y su relación con la densidad mineral ósea en mujeres sanas pre y perimenopáusicas de la ciudad de Córdoba y alrededores. Los genotipos se determinaron con la técnica de reacción en cadena de la polimerasa y análisis de los polimorfismos de longitud de fragmentos de restricción. Se usaron como restrictasas Bsm I y Fok I para el gen del receptor de vitamina D y Pvu II y Xba I para el gen del receptor de estrógeno. Se reclutaron y agruparon por edad doscientos diez mujeres pre y peri-menopáusicas. Sus niveles séricos de Ca y de hormona paratiroidea fueron similares, pero los de fósforo y b-Cross Laps disminuyeron con la edad. La densidad mineral ósea de cuello femoral disminuyó después de los 30 años. Las frecuencias genotípicas de ambos receptores fueron similares a aquéllas de otras mujeres caucásicas. No hubo asociación entre los genotipos de los receptores y la densidad mineral ósea. Los análisis de interacción entre ambos genes no evidenciaron influencia sobre la densidad mineral ósea, utilizándose edad, talla e índice de masa corporal como covariables. Los estilos de vida y hábitos de fumar y beber alcohol tampoco afectaron la densidad mineral ósea. En conclusión, estos datos no sostienen la hipótesis de que los genotipos de los receptores de vitamina D y de estrógeno influencian la densidad mineral ósea de columna lumbar y cuello femoral en mujeres sanas pre y perimenopáusicas de esta región de Argentina.
The aim of this study was to determine the frequency of vitamin D receptor and estrogen receptor genotypes and their relationship with the lumbar spine or femoral neck bone mineral density in healthy pre and perimenopausal women from Córdoba (Argentina) and adjacent areas. Genotypes were assessed by restriction fragment length polymorphism-polymerase chain reaction technique. Bsm I and Fok I for vitamin D receptor gene and XbaI and PvuII for estrogen receptor gene were used as restrictases. Two hundred and ten healthy pre and perimenopausal women were recruited and analyzed by age. Calcemia and serum parathyroid hormone did not change, but serum P and b-CrossLaps decreased with age. Femoral neck bone mineral density decreased significantly after 30 years old. Vitamin D receptor and estrogen receptor genotype frequencies were similar to those from other Caucasian women. No association between vitamin D receptor and estrogen receptor genotypes with the lumbar spine or femoral neck bone mineral density has been detected. Analysis of interaction between vitamin D receptor and estrogen receptor genes using covariates such as age, height and body mass index did not show any influence of the combination of those genotypes on bone mineral density. Lifestyle, smoking and alcohol intake had no effect on lumbar spine and femoral neck bone mineral density. To conclude, these data do not support the hypothesis that vitamin D receptor and estrogen receptor genotypes influence on lumbar spine and femoral neck bone mineral density in healthy pre and perimenopausal women from this area of Argentina.