Evidence for a bone-kidney axis regulating phosphate homeostasis

Abstract

A novel circulation phosphaturic hormone is postulated to regulate systemic phosphate homeostasis. Two new studies reveal that the phosphaturic factor FGF-23 is increased in hypophosphatemic subjects with McCune-Albright syndrome and that secreted frizzled-related protein-4 (sFRP-4), a factor produced by tumors derived from subjects with tumor-induced osteomalacia, also has phosphaturic activity. It remains to be established whether FGF-23 and sFRP-4 represent two distinct phosphatonins or are somehow integrated in a novel phosphate-regulating bone-kidney axis.

Figure 1

A bone-kidney axis regulating renal phosphate handling and skeletal mineralization. A phosphaturic hormone, phosphatonin, stimulates renal phosphate excretion. Osteoblasts in bone may be the source of phosphatonin. Increased release of phosphatonin leads to autocrine effects to regulate bone mineralization of ECM and systemic effects to cause phosphaturia.

Figure 2

Osteoblasts express components necessary for coordinating mineralization of ECM and phosphate handling by the kidney. FGF-23 secreted from osteoblasts under the control of PHEX and possibly G_sα-dependent pathways has systemic actions to regulate renal phosphate handling as well as potential autocrine effects to regulate osteoblast-mediated bone mineralization. The LRP-Wnt signaling pathway in osteoblasts regulates bone mass and, in conjunction with PHEX and FGF-23, may also participate in coordinating renal phosphate conservation to meet the needs of osteoblast-mediated mineralization.