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Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease.
Kidney Int. 2016 07; 90(1):77-89.KI

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+Show Affiliations

Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL)-Instituto Biosanitario de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN del ISCIII, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27165819

Citation

Carrillo-López, Natalia, et al. "Direct Inhibition of Osteoblastic Wnt Pathway By Fibroblast Growth Factor 23 Contributes to Bone Loss in Chronic Kidney Disease." Kidney International, vol. 90, no. 1, 2016, pp. 77-89.
Carrillo-López N, Panizo S, Alonso-Montes C, et al. Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease. Kidney Int. 2016;90(1):77-89.
Carrillo-López, N., Panizo, S., Alonso-Montes, C., Román-García, P., Rodríguez, I., Martínez-Salgado, C., Dusso, A. S., Naves, M., & Cannata-Andía, J. B. (2016). Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease. Kidney International, 90(1), 77-89. https://doi.org/10.1016/j.kint.2016.01.024
Carrillo-López N, et al. Direct Inhibition of Osteoblastic Wnt Pathway By Fibroblast Growth Factor 23 Contributes to Bone Loss in Chronic Kidney Disease. Kidney Int. 2016;90(1):77-89. PubMed PMID: 27165819.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease. AU - Carrillo-López,Natalia, AU - Panizo,Sara, AU - Alonso-Montes,Cristina, AU - Román-García,Pablo, AU - Rodríguez,Isabel, AU - Martínez-Salgado,Carlos, AU - Dusso,Adriana S, AU - Naves,Manuel, AU - Cannata-Andía,Jorge B, Y1 - 2016/03/24/ PY - 2015/07/17/received PY - 2015/12/23/revised PY - 2016/01/14/accepted PY - 2016/5/12/entrez PY - 2016/5/12/pubmed PY - 2017/10/3/medline KW - FGF23 KW - bone KW - chronic kidney disease KW - hyperparathyroidism KW - phosphate KW - uremia SP - 77 EP - 89 JF - Kidney international JO - Kidney Int VL - 90 IS - 1 N2 - 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. SN - 1523-1755 UR - https://www.unboundmedicine.com/medline/citation/27165819/Direct_inhibition_of_osteoblastic_Wnt_pathway_by_fibroblast_growth_factor_23_contributes_to_bone_loss_in_chronic_kidney_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0085-2538(16)00314-8 DB - PRIME DP - Unbound Medicine ER -