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.

Interactions of sclerostin with FGF23, soluble klotho and vitamin D in renal transplantation

“…We know that sKlotho interacts with Wnt pathway by either inhibiting Wnt ligands [35] or by upregulating Wnt inhibitors [36], thus allowing to accept the present correlation, which reinforces the potential clinical significance of sKlotho in renal patients as a marker of the dialogue between bone and the kidney.…”

Fractures in patients with CKD—diagnosis, treatment, and prevention: a review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis and Transplantation

“…131 Excessive FGF23 also contributes to bone loss in CKD via a klotho-dependent mechanism and the stimulation of the osteoblast Wnt inhibitor Dkk1. 132 Therefore, inactivation of the Wnt/b-catenin signaling pathway by the altered phosphate/FGF23/Klotho axis may provide another autocrine/paracrine mechanism favoring bone loss in CKD-MBD.…”

Electrolyte and Acid-Base Disorders in Chronic Kidney Disease and End-Stage Kidney Failure

“…For patients with tertiary hyperparathyroidism (autonomous PTH production), therapeutic options are limited to cinacalcet or subtotal parathyroidectomy [112]. Recent findings regarding the role of Wnt/beta catenin pathway inhibition in the development of CKD-MBD [113,114] is exciting, offering another potential for future therapeutic targeting.…”