What have we learnt about the regulation of phosphate metabolism?

PURPOSE OF REVIEW: 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.

RECENT FINDINGS: 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.

SUMMARY: 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.