Endocrine functions of bone in mineral metabolism regulation
L. Darryl Quarles
L. Darryl Quarles
Published December 1, 2008
Citation Information: J Clin Invest. 2008;118(12):3820-3828. https://doi.org/10.1172/JCI36479.
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Science in Medicine

Endocrine functions of bone in mineral metabolism regulation

Abstract

Given the dramatic increase in skeletal size during growth, the need to preserve skeletal mass during adulthood, and the large capacity of bone to store calcium and phosphate, juxtaposed with the essential role of phosphate in energy metabolism and the adverse effects of hyperphosphatemia, it is not surprising that a complex systems biology has evolved that permits cross-talk between bone and other organs to adjust phosphate balance and bone mineralization in response to changing physiological requirements. This review examines the newly discovered signaling pathways involved in the endocrine functions of bone, such as those mediated by the phosphaturic and 1,25(OH)2D-regulating hormone FGF23, and the broader systemic effects associated with abnormalities of calcium and phosphate homeostasis.

Authors

L. Darryl Quarles

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Figure 1

Interrelationships among FGF23, PTH, 1,25(OH)2D, and Klotho.

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Interrelationships among FGF23, PTH, 1,25(OH)2D, and Klotho. (A) The...
(A) The PTH/1,25(OH)2D axis. The principal function of the PTH/1,25(OH)2D axis is to regulate calcium homeostasis. Decrements in serum calcium levels stimulate PTH secretion by the PTG, which targets the kidney to reduce urinary calcium excretion, stimulate 1α-hydroxylase activity, and enhance the fractional excretion of phosphate (PO4), and targets bone to increase the efflux of calcium and phosphate. The resulting increase in 1,25(OH)2D targets the gastrointestinal tract to increase dietary absorption of calcium, which suppresses PTH. (B) The FGF23/Klotho axis. FGF23 produced by bone principally targets the kidney, leading to reductions in serum phosphate and 1,25(OH)2D levels by stimulating the fractional excretion of phosphate and reducing 1α-hydroxylase activity. The receptor for FGF23 in the kidney is a Klotho:FGFR1 complex located in the distal tubule. There may be a distal-to-proximal feedback mechanism that mediates the effects of FGF23 on the proximal tubule. FGF23 also decreases the kidney expression of Klotho, which diminishes renal tubular calcium reabsorption via its interactions with transient receptor potential cation channel, subfamily V, member 5 (TRPV5). FGF23 may also directly target the PTG to reduce PTH secretion. FGF23 is the principal phosphaturic hormone and may function to counter the hypercalcemic and hyperphosphatemic effects of excess 1,25(OH)2D through reductions in PTH and elevations in FGF23 levels.