Effect of Osteocyte-Ablation on Inorganic Phosphate Metabolism: Analysis of Bone–Kidney–Gut Axis

Abstract

In response to kidney damage, osteocytes increase the production of several hormones critically involved in mineral metabolism. Recent studies suggest that osteocyte function is altered very early in the course of chronic kidney disease. In the present study, to clarify the role of osteocytes and the canalicular network in mineral homeostasis, we performed four experiments. In Experiment 1, we investigated renal and intestinal Pi handling in osteocyte-less (OCL) model mice [transgenic mice with the dentin matrix protein-1 promoter-driven diphtheria toxin (DT)-receptor that were injected with DT]. In Experiment 2, we administered granulocyte colony-stimulating factor to mice to disrupt the osteocyte canalicular network. In Experiment 3, we investigated the role of osteocytes in dietary Pi signaling. In Experiment 4, we analyzed gene expression level fluctuations in the intestine and liver by comparing mice fed a high Pi diet and OCL mice. Together, the findings of these experiments indicate that osteocyte ablation caused rapid renal Pi excretion (P < 0.01) before the plasma fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) levels increased. At the same time, we observed a rapid suppression of renal Klotho (P < 0.01), type II sodium phosphate transporters Npt2a (P < 0.01) and Npt2c (P < 0.05), and an increase in intestinal Npt2b (P < 0.01) protein. In OCL mice, Pi excretion in feces was markedly reduced (P < 0.01). Together, these effects of osteocyte ablation are predicted to markedly increase intestinal Pi absorption (P < 0.01), thus suggesting that increased intestinal Pi absorption stimulates renal Pi excretion in OCL mice. In addition, the ablation of osteocytes and feeding of a high Pi diet affected FGF15/bile acid metabolism and controlled Npt2b expression. In conclusion, OCL mice exhibited increased renal Pi excretion due to enhanced intestinal Pi absorption. We discuss the role of FGF23–Klotho on renal and intestinal Pi metabolism in OCL mice.

Fibroblast Growth Factor 15/19: From Basic Functions to Therapeutic Perspectives

“…In fact, dietary Pi restriction up-regulates FGF15 expression in mouse ileum, but not in VDR-deficient mice (145). Conversely, high Pi-fed mice have significantly lower transcript levels of FGF15 in the ileum (146).…”

Osteometabolism: Metabolic Alterations in Bone Pathologies

“…In 2013 Sato et al reported that the absence of osteocytes leads to lymphopenia and revealed that osteocytes are the important regulators of fat metabolism and lymphopoiesis [ 73 ]. It has been observed that in osteocyte-deficient mice, the absorption of inorganic phosphate (pi) increases in the intestine, which further stimulates the pi excretion from the renal system [ 74 ]. In addition, a study revealed that by expressing resistin, osteoclasts induce insulin resistance and suggest that suppression of osteoclasts generation could be a potential therapeutic strategy for insulin resistance [ 75 ].…”

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

“…Although cathepsin K is mainly required for osteoclastic bone resorption, osteocytes also release cathepsin K and regulate mechanotransduction ( 70 ). Osteocytes release FGF23, dentin matrix acidic phosphoprotein 1 (DMP1), PHEX, and MEPE, and act as endocrine cells to regulate phosphate metabolism ( 1 , 71 – 73 ). Osteocytes release sclerostin to control bone mineralization via the modulation of DMP1, PHEX, MEPE, and FGF-23 expression ( 74 , 75 ).…”