title: Dual-specificity phosphatases are implicated in severe hyperplasia and lack of response to FGF23 of uremic parathyroid glands from rats.
abstract: Phosphate load accelerates the progression of secondary hyperparathyroidism (sHPT). In advanced stages of sHPT, there is a marked hyperplasia and resistance to classical regulatory endocrine factors such as calcium, calcitriol, or fibroblast growth factor 23 (FGF23), which suppresses PTH secretion by an ERK-dependent mechanism. Nephrectomized rats were fed with a high- or normal-phosphorus diet for different periods of time to induce sHPT. Biochemical parameters, parathyroid gland microarrays, quantitative real-time PCR, and immunohistochemistry (ERK/phospho-ERK) were performed. To test the role of dual-specificity phosphatases (Dusp) on parathyroid gland regulation, normal parathyroid glands were cultured with FGF23 and Dusp. Uremic rats fed with a high-phosphorus diet showed more severe sHPT, higher serum FGF23 levels and mortality, and decreased parathyroid Klotho gene expression. In all stages of sHPT, parathyroid microarrays displayed a widespread gene expression down-regulation; only a few genes were overexpressed, among them, Dusp5 and -6. In very severe sHPT, a significant reduction in phospho-ERK (the target of Dusp) and a significant increase of Dusp5 and -6 gene expression were observed. In ex vivo experiments with parathyroid glands, Dusp partially blocked the effect of FGF23 on PTH secretion, suggesting that Dusp might play a role in parathyroid regulation. The overexpression of Dusp and the inactivation of ERK found in the in vivo studies together with the ex vivo results might be indicative of the defense mechanism triggered to counteract hyperplasia, a mechanism that can also contribute to the resistance to the effect of FGF23 on parathyroid gland observed in advanced forms of chronic kidney disease.
authors.affiliation: Servicio de Metabolismo Óseo y Mineral, Instituto Reina Sofía de Investigaciones Nefrológicas, Hospital Universitario Central de Asturias, 33006 Oviedo, Asturias, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Román-García
authors.forename: Natalia
authors.initials: N
authors.lastname: Carrillo-López
authors.forename: Manuel
authors.initials: M
authors.lastname: Naves-Díaz
authors.forename: Isabel
authors.initials: I
authors.lastname: Rodríguez
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Cannata-Andía
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D054637:Dual-Specificity Phosphatases / Q000378:metabolism* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D020869:Gene Expression Profiling; D005966:Glucuronidase / Q000378:metabolism; D006962:Hyperparathyroidism, Secondary / Q000235:genetics / Q000378:metabolism; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010280:Parathyroid Glands / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016226:Phosphorus, Dietary / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D014511:Uremia / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology
chemical_list: C505605:Fgf23 protein, rat; D016226:Phosphorus, Dietary; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D054637:Dual-Specificity Phosphatases; D005966:Glucuronidase; D000090265:Klotho Proteins