RESUMO
Osteocytes regulate bone turnover and mineralization in chronic kidney disease. As osteocytes are derived from osteoblasts, alterations in osteoblast function may regulate osteoblast maturation, osteocytic transition, bone turnover, and skeletal mineralization. Thus, primary osteoblast-like cells were cultured from bone chips obtained from 24 pediatric ESKD patients. RNA expression in cultured cells was compared with RNA expression in cells from healthy individuals, to RNA expression in the bone core itself, and to parameters of bone histomorphometry. Proliferation and mineralization rates of patient cells were compared with rates in healthy control cells. Associations were observed between bone osteoid accumulation, as assessed by bone histomorphometry, and bone core RNA expression of osterix, matrix gla protein, parathyroid hormone receptor 1, and RANKL. Gene expression of osteoblast markers was increased in cells from ESKD patients and signaling genes including Cyp24A1, Cyp27B1, VDR, and NHERF1 correlated between cells and bone cores. Cells from patients with high turnover renal osteodystrophy proliferated more rapidly and mineralized more slowly than did cells from healthy controls. Thus, primary osteoblasts obtained from patients with ESKD retain changes in gene expression ex vivo that are also observed in bone core specimens. Evaluation of these cells in vitro may provide further insights into the abnormal bone biology that persists, despite current therapies, in patients with ESKD.
Assuntos
Osso e Ossos/fisiopatologia , Calcificação Fisiológica , Proliferação de Células , Expressão Gênica , Falência Renal Crônica , Osteoblastos/fisiologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Adolescente , Osso e Ossos/patologia , Proteínas de Ligação ao Cálcio/genética , Células Cultivadas , Distúrbio Mineral e Ósseo na Doença Renal Crônica/genética , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Falência Renal Crônica/genética , Falência Renal Crônica/patologia , Masculino , Osteoblastos/patologia , Fosfoproteínas/genética , Ligante RANK/genética , RNA/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Receptores de Calcitriol/genética , Transdução de Sinais/genética , Trocadores de Sódio-Hidrogênio/genética , Fator de Transcrição Sp7 , Fatores de Transcrição/genética , Vitamina D3 24-Hidroxilase/genética , Proteína de Matriz GlaRESUMO
Cardiovascular disease is the leading cause of death in pediatric patients with chronic kidney disease (CKD), and vascular calcifications start early in the course of CKD. Based on the growing body of evidence that alterations of bone and mineral metabolism and the therapies designed to treat the skeletal consequences of CKD are linked to cardiovascular calcifications, the Kidney Disease, Improving Global Outcomes (KDIGO) working group redefined renal osteodystrophy as a systemic disorder of mineral and bone metabolism due to CKD, and this newly defined disorder is now known as "chronic kidney disease-mineral bone disorder (CKD-MBD)". Elevated fibroblast growth factor 23 (FGF23), a bone-derived protein, is the first biochemical abnormality to be associated with CKD-MBD, and high FGF23 levels correlate with increased cardiovascular morbidity and mortality, suggesting that bone is central to both initiating and perpetuating the abnormal mineral metabolism and vascular disease in CKD. The current standard therapies for CKD-MBD affect FGF23 levels differently; non-calcium-based binders with or without concurrent use of dietary phosphate restriction reduce FGF23 levels, while calcium-based binders seem to either increase or have no effect on FGF23 levels. Active vitamin D sterols increase FGF23 levels, whereas therapy with calcimimetics decreases FGF23 levels. Thus, the appropriate therapy that will minimize the rise in FGF23 and prevent cardiovascular morbidity remains to be defined.
