Transient modulation of calcium and parathyroid hormone stimulates bone formation.

Intermittent administration of parathyroid hormone can stimulate bone formation. Parathyroid hormone is a natural hormone that responds to serum calcium levels. In this study, we examined whether a transient increase and/or decrease in the serum calcium can stimulate bone formation. Using a mathematical model previously developed, we first predicted the effects of administration of parathyroid hormone, neutralizing parathyroid hormone antibody, calcium, and EGTA (calcium chelator) on the serum concentration of parathyroid hormone and calcium. The model predicted that intermittent injection of parathyroid hormone and ethylene glycol tetraacetic acid transiently elevated the serum parathyroid hormone, while that of parathyroid hormone antibody and calcium transiently reduced parathyroid hormone in the serum. In vitro analysis revealed that parathyroid hormone's transient changes (both up and down) elevated activating transcription factor 4-mediated osteocalcin expression. In the mouse model of osteoporosis, both intermittent administration of calcium and ethylene glycol tetraacetic acid showed tendency to increase bone mineral density of the upper limb (ulna and humerus) and spine, but the effects varied in a region-specific manner. Collectively, the study herein supports a common bone response to administration of calcium and its chelator through their effects on parathyroid hormone.

Model-Based Analysis of FGF23 Regulation in Chronic Kidney Disease.

The mechanism of FGF23 action in calcium/phosphorus metabolism of patients with chronic kidney disease (CKD) was studied using a mathematical model and clinical data in a public domain. We have previously built a physiological model that describes interactions of PTH, calcitriol, and FGF23 in mineral metabolism encompassing organs such as bone, intestine, kidney, and parathyroid glands. Since an elevated FGF23 level in serum is a characteristic symptom of CKD patients, we evaluate herein potential metabolic alterations in response to administration of a neutralizing antibody against FGF23. Using the parameters identified from available clinical data, we observed that a transient decrease in the FGF23 level elevated the serum concentrations of PTH, calcitriol, and phosphorus. The model also predicted that the administration reduced a urinary output of phosphorous. This model-based prediction indicated that the therapeutic reduction of FGF23 by the neutralizing antibody did not reduce phosphorus burden of CKD patients and decreased the urinary phosphorous excretion. Thus, the high FGF23 level in CKD patients was predicted to be a failure of FGF23-mediated phosphorous excretion. The results herein indicate that it is necessary to understand the mechanism in CKD in which the level of FGF23 is elevated without effectively regulating phosphorus.

Evaluation of the role of FGF23 in mineral metabolism.

Fibroblast growth factor 23 (FGF23) has recently been identified as a critical regulatory factor in phosphate (P) metabolism. Although the exact molecular mechanism of FGF23 synthesis through sensing the concentration of P is yet to be determined, experimental and clinical data indicate the influential role of FGF23 in P and calcium (Ca) homeostasis. Here, we extended our previous mathematical model in calcium regulation and examined the conceivable roles of FGF23 in mineral metabolism. We assumed that the level of FGF23 was controlled through the concentrations of P and calcitriol in serum, and its actions such as lowering of the renal threshold for P, inhibition of the production of calcitriol in the kidney tubule, and inhibition of the production of parathyroid hormone (PTH) were included. Comparisons between the models with and without FGF23 demonstrate a complex interplay of FGF23 with calcitriol and PTH. In consistent with the model, our in vitro experimentation indicates that expression of FGF23 is activated in the presence of P though a G-protein linked receptor. We expect that further efforts on modeling and experimental evaluation would contribute to diagnosing patients with metabolic diseases such as osteoporosis and chronic kidney diseases, and developing FGF23-linked treatment strategies.

A mathematical model of the diluting power of the cortical thick ascending limb of the loop of Henle.

A mathematical model is presented that describes the ionic transport across the cortical thick ascending limb (cTAL) of the Henle's loop, taking into account its tubular geometry. A comprehensive description of the cTAL is given for the first time in terms of potential, ion concentrations and ion fluxes along the tubule. For given ion concentrations at the entrance of the tubule, the model simulates steady-state profiles and allows the fitting of existing experimentally measured values at its exit. Moreover, the model expands the potentialities of experiments in situ and enables testing the effect of different perturbations induced by drugs or mutation-altering transport activity. One of the main insights given by this model is the increase of the lumenal electrical potential from the entrance to the exit of the tubule with a profile determined by the transepithelial electrical potential difference and by the chemical gradients along the lumen, both reflecting transepithelial salt transport. Furthermore, model and experimental results are consistent, showing that when the TAL is perfused at high rates with a diluted NaCl solution in relation to the bath, the transepithelial electrical potential difference increases from 6.7 to 23.0 mV and the potential difference across the basolateral barrier changes very little. The model predicts that the same static head is obtained independently of the NaCl concentration at the entrance of the tubule. A final important insight concerns the lowest reported NaCl concentrations (20-30 mM) at the exit of the tubule, which is controlled by a very tight epithelium, where the back-leak is substantially reduced.