The complexities of organ cross talk in phosphate homeostasis: Time to put phosphate sensing back in the limelight

Phosphate homeostasis is essential in health and disease, and involves four organs, the bone, kidney, small intestine and parathyroid glands. These organs act together to maintain extracellular phosphate concentration, with an intricate process involving phosphate transporters, phosphate sensors, and three circulating hormones. The role of the kidney in phosphate homeostasis is well known, although it is recognized that the cellular mechanisms in murine models and humans is different. Intestinal phosphate transport also appears to differ in humans and rodents, with recent studies demonstrating a dominant role for the paracellular pathway, and the potential involvement of claudin proteins. The existence of phosphate sensing has been acknowledged for decades, however, the underlying molecular mechanisms are poorly understood. At least three phosphate sensor candidates have emerged. PiT2 and FGFR1c both act as phosphate sensors controlling Fibroblast Growth Factor 23 secretion in bone. While the calcium-sensing receptor controls parathyroid hormone secretion in response to extracellular phosphate. All three of the proposed sensors are expressed in the kidney and intestine but their exact function is unknown. Understanding organ interactions and the mechanisms involved in phosphate sensing still needs significant research in order to develop novel approaches for the treatment of phosphate homeostasis disorders.