Increased Circulatory Level of Biologically Active Full-Length FGF-23 in Patients with Hypophosphatemic Rickets/Osteomalacia

Abstract

Hypophosphatemic rickets/osteomalacia with inappropriately low serum 1,25-dihidroxyvitamin D level is commonly observed in X-linked hypophosphatemic rickets/osteomalacia, autosomal dominant hypophosphatemic rickets/osteomalacia and tumor-induced osteomalacia. Although the involvement of a newly identified factor, FGF-23, in the pathogenesis of ADHR and TIO has been suggested, clinical evidence indicating the role of FGF-23 has been lacking. We have previously shown that FGF-23 is cleaved between Arg(179) and Ser(180), and this processing abolished biological activity of FGF-23 to induce hypophosphatemia. Therefore, sandwich ELISA for biologically active intact human FGF-23 was developed using two kinds of monoclonal antibodies that requires the simultaneous presence of both the N-terminal and C-terminal portion of FGF-23. The serum levels of FGF-23 in healthy adults were measurable and ranged from 8.2 to 54.3 ng/L. In contrast, those in a patient with TIO were over 200 ng/L. After the resection of the responsible tumor, the elevated FGF-23 level returned to normal level within 1 h. The increase of serum concentrations of 1,25-dihidroxyvitamin D and phosphate, and the decrease of serum 24,25-dihydroxyvitamin D followed the change of FGF-23. In addition, the elevated serum FGF-23 levels were demonstrated in most patients with XLH. It is likely that increased serum levels of FGF-23 contributes to the development of hypophosphatemia not only in TIO but also in XLH.

Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets

“…42 In our study population only FGF23-mediated types of HR were identified, but two patients with proven XLHR displayed levels slightly below the upper limit of the normal range of 10-50 pg ml À1 . 43 Normal S-FGF23 levels in genetically verified XLHR has been published in a few cases 43,44 but in the vast majority of HR patients, S-FGF23 levels are elevated, and this significantly more in patients receiving medical treatment. 45,46 Patients with TIO display even higher values of S-FGF23 than the XLHR patients in this study, mean 934 ± 1115 pg ml À1 vs 198 ± 401 pg ml À1 .…”

Fibroblast Growth Factor 23 (FGF23) and Disorders of Phosphate Metabolism

“…In addition, renal transplantation from a healthy donor to a patient with XLH did not correct renal phosphate wasting [29]. It has been shown that serum FGF23 levels in most XLH patients are above the reference range [30, 31]. Serum FGF23 levels in Hyp mice are also elevated, and excess production of FGF23 is found particularly in bone of Hyp mice.…”

Mechanism of FGF23 processing in fibrous dysplasia

“…Various hyperphosphatemic and hypophosphatemic disorders have been shown to be directly related to altered FGF23 levels in the circulation. (1)(2)(3)(4) FGF23 is known to regulate blood Pi by decreasing the expression of the Pi transporter genes, Npt2A and Npt2C, in renal proximal tubule cells, thereby reducing renal ARHR), (9,10) tumor-induced osteomalacia (TIO), (8) and fibrous dysplasia of bone (FD). (11) Conversely, low levels of iFGF23 and elevated levels of cFGF23 are found in familial tumoral calcinosis (FTC) and hyperphosphatemic hyperostosis syndrome (HHS).…”