title: Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease.
abstract: Bone loss and increased fractures are common complications in chronic kidney disease. Because Wnt pathway activation is essential for normal bone mineralization, we assessed whether Wnt inhibition contributes to high-phosphorus-induced mineralization defects in uremic rats. By week 20 after 7/8 nephrectomy, rats fed a high-phosphorus diet had the expected high serum creatinine, phosphorus, parathyroid hormone, and fibroblast growth factor 23 (FGF23) levels and low serum calcium. There was a 15% reduction in tibial mineral density and a doubling of bone cortical porosity compared to uremic rats fed a normal-phosphorus diet. The decreases in tibial mineral density were preceded by time-dependent increments in gene expression of bone formation (Osteocalcin and Runx2) and resorption (Cathepsin K) markers, which paralleled elevations in gene expression of the Wnt inhibitors Sfrp1 and Dkk1 in bone. Similar elevations of Wnt inhibitors plus an increased phospho-β-catenin/β-catenin ratio occurred upon exposure of the osteoblast cell line UMR106-01 either to uremic serum or to the combination of parathyroid hormone, FGF23, and soluble Klotho, at levels present in uremic serum. Strikingly, while osteoblast exposure to parathyroid hormone suppressed the expression of Wnt inhibitors, FGF23 directly inhibited the osteoblastic Wnt pathway through a soluble Klotho/MAPK-mediated process that required Dkk1 induction. Thus, the induction of Dkk1 by FGF23/soluble Klotho in osteoblasts inactivates Wnt/β-catenin signaling. This provides a novel autocrine/paracrine mechanism for the adverse impact of high FGF23 levels on bone in chronic kidney disease.
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Carrillo-López
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Panizo
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alonso-Montes
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Román-García
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rodríguez
authors.affiliation: Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL)-Instituto Biosanitario de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-Salgado
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Dusso
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Naves
authors.affiliation: Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain; Departmento de Medicina, Universidad de Oviedo, Oviedo, Asturias, Spain. Electronic address: cannata@hca.es.
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Cannata-Andía
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002113:Calcification, Physiologic; D002118:Calcium / Q000097:blood; D056657:Cathepsin K / Q000378:metabolism; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D003649:Decalcification, Pathologic / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D005966:Glucuronidase / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood / Q000378:metabolism; D016226:Phosphorus, Dietary / Q000009:adverse effects; D016062:Porosity; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000378:metabolism; D013977:Tibia / Q000378:metabolism / Q000473:pathology; D014511:Uremia / Q000150:complications / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000097:blood; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D015415:Biomarkers; D002118:Calcium; D056657:Cathepsin K; D050659:Core Binding Factor Alpha 1 Subunit; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D036341:Intercellular Signaling Peptides and Proteins; D000090265:Klotho Proteins; D008565:Membrane Proteins; D015675:Osteocalcin; D010281:Parathyroid Hormone; D010758:Phosphorus; D016226:Phosphorus, Dietary; D051153:Wnt Proteins; D051176:beta Catenin; C531384:Dkk1 protein, rat; C000717427:FGF23 protein, human; C493717:Runx2 protein, rat; C500646:Sfrp1 protein, rat; D000094742:Secreted Frizzled-Related Proteins; C534133:Ctsk protein, rat
keywords: FGF23; bone; chronic kidney disease; hyperparathyroidism; phosphate; uremia