What have we learnt about the regulation of phosphate metabolism?

The search for hormones which specifically regulate phosphate metabolism has fuelled recent tantalizing studies. These studies have been motivated by diseases involving renal phosphate wasting, including tumor-induced osteomalacia, X-linked hypophosphatemic rickets, and autosomal dominant hypophosphatemia. This review focuses on likely candidate 'phosphatonins' and their possible physiological significance.

Candidate phosphatonins include fibroblast growth factor 23, matrix extracellular phosphoglycoprotein, stanniocalcin, and Frizzled-related protein 4. Fibroblast growth factor 23 has emerged as the prime candidate explaining pathophysiology of these diseases. FGF-23 is expressed in most tumors in tumor-induced osteomalacia. Serum fibroblast growth factor 23 is increased in most patients with X-linked hypophosphatemic rickets and tumor-induced osteomalacia. Injection of recombinant fibroblast growth factor 23 induces phosphaturia, hypophosphatemia, and suppression of 1,25-dihydroxyvitamin D in animals. Many unanswered questions remain, including the relationship between PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) mutations and elevated fibroblast growth factor 23. It is also not clear whether these candidate phosphatonins play a role in phosphate or vitamin D metabolism in healthy humans, or that this role is endocrine. The most compelling evidence derives from the fibroblast growth factor 23-knockout mouse which shows hyperphosphatemia and increased serum 1,25-dihydroxyvitamin D. A physiologically relevant phosphatonin should explain renal adaptation to variable dietary phosphate intake. The tissue source and determinants of serum fibroblast growth factor 23 are unknown.

Pathophysiological and animal studies serve as a logical foundation on which to base further questions of human physiology. The definition of what is or is not a phosphatonin may need to be refined. There is a need to return to 'old-fashioned' human physiology studies to place recent findings in perspective.