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This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: 295/2/E254    most recent 90201.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Liu, S. Articles by Quarles, L. D. PubMed PubMed Citation Articles by Liu, S. Articles by Quarles, L. D.

Pathogenic role of Fgf23 in Dmp1-null mice

¹The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; and ²Department of Biomedical Sciences, Baylor College of Dentistry, Dallas, Texas

Submitted 30 January 2008 ; accepted in final form 13 June 2008

Autosomal recessive hypophosphatemic rickets (ARHR), which is characterized by renal phosphate wasting, aberrant regulation of 1-hydroxylase activity, and rickets/osteomalacia, is caused by inactivating mutations of dentin matrix protein 1 (DMP1). ARHR resembles autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH), hereditary disorders respectively caused by cleavage-resistant mutations of the phosphaturic factor FGF23 and inactivating mutations of PHEX that lead to increased production of FGF23 by osteocytes in bone. Circulating levels of FGF23 are increased in ARHR and its Dmp1-null mouse homologue. To determine the causal role of FGF23 in ARHR, we transferred Fgf23 deficient/enhanced green fluorescent protein (eGFP) reporter mice onto Dmp1-null mice to create mice lacking both Fgf23 and Dmp1. Dmp1^–/– mice displayed decreased serum phosphate concentrations, inappropriately normal 1,25(OH)₂D levels, severe rickets, and a diffuse form of osteomalacia in association with elevated Fgf23 serum levels and expression in osteocytes. In contrast, Fgf23^–/– mice had undetectable serum Fgf23 and elevated serum phosphate and 1,25(OH)₂D levels along with severe growth retardation and focal form of osteomalacia. In combined Dmp1^–/–/Fgf23^–/–, circulating Fgf23 levels were also undetectable, and the serum levels of phosphate and 1,25(OH)₂D levels were identical to Fgf23^–/– mice. Rickets and diffuse osteomalacia in Dmp1-null mice were transformed to severe growth retardation and focal osteomalacia characteristic of Fgf23-null mice. These data suggest that the regulation of extracellular matrix mineralization by DMP1 is coupled to renal phosphate handling and vitamin D metabolism through a DMP1-dependent regulation of FGF23 production by osteocytes.

fibroblastic growth factor 23; dentin matrix protein 1; autosomal recessive hypophosphatemic rickets; hypophosphatemia; osteomalacia; phosphate homeostasis