Pseudohypoparathyroidism (PHP) refers to disorders that are elicited by coding and non-coding mutations in GNAS, a complex gene locus encoding the α-subunit of stimulatory G protein (Gsα) and splice variants thereof. The complexity of the GNAS locus is reflected by several alternatively spliced sense and antisense transcripts, a parent-specific methylation pattern and consequently transcription from only one parental allele for all mRNAs, except for the mRNA encoding Gsα. PHP can be divided into two major groups that are caused either by heterozygous mutations in exons affecting Gsα (PHP type Ia: PHP-Ia) or by deletions of presumably regulatory regions affecting GNAS (PHP type Ib: PHP-Ib). The former group comprises besides PHP-Ia, pseudo-PHP (pPHP), and progressive osseous heteroplasia (POH). The phenotypes of these disorders are quite different and depend on the kind of mutation and whether it is inherited maternally or paternally. For example, PHP-Ia develops after maternal inheritance of a Gsα mutation, while paternal inheritance of the same mutation leads to pPHP or POH. Similarly, maternal inheritance of a deletion in STX16, the gene encoding syntaxin 16, up-stream of GNAS leads to PHP-Ib, while inheritance of the same mutation from a male does not result in an obvious phenotype. In most familial cases of PHP-Ib, there is a loss of methylation affecting only exon A/B thus leading to active A/B transcription from both parental alleles, thereby suppressing Gsα transcription in the renal cortex and causing PTH-resistance.

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Pseudohypoparathyroidism (PHP) is composed of PHP-Ia and PHP-Ib. The former is characterized by multiple hormone resistance including parathyroid hormone associated with Albright hereditary osteodystrophy (AHO); but in the latter, AHO is not complicated. In the natural course of PHP-Ia, the time of onset, the degree of hypocalcemia and associated symptoms vary among patients. Since the symptoms of AHO, including brachydactyly, are often ambiguous, the criteria for clinical differential diagnosis between these two types are required. In our 10 cases of sporadic PHP-Ib, no patient had subcutaneous calcification. Currently, however, genetic analysis on the DNA methylation is necessary for the definite diagnosis. All of the 10 cases of sporadic PHP-Ib had complete methylation in NESP55 as well as complete demethylation in the AS and 1A regions of the GNAS gene, while the region of the abnormal methylation in XL were varied among the patients. There was no clear correlation among skewed X-inactivation, abnormal DNA methylation pattern, clinical phenotypes and other complications.

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The overview on X-linked hypophosphatemia (XLH) was presented by summarizing the current findings on the relationships between PHEX and FGF23 as well as on the homeostasis of extracellular phosphorus and vitamin D metabolism. There are urgent needs in the identification of phosphatonin. Concerning FGF23, its expression mechanisms, physiological roles, as well as the intracellular signaling pathway should be clarified.

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X-linked hypophosphatemia (XLH) is a hypophosphatemic rachitic disorder, which occurs in one of 20,000 live births. The disease phenotype is quite variable, and many patients do not have profound signs or symptoms including rickets. Thus, XLH is sometimes called "XLH rickets without rickets". Such phenotypic variability makes a genetic examination of potentially affected patients inevitable for definite diagnosis. In most of the patients, hypophosphatemia, elevated serum alkaline phosphatase, and a lowered level of active vitamin D, as well as abnormalities in the bone mineralization, are seen. In hyp-mice, the model mouse of XLH, a hormonal abnormality that affects the Npt2 protein mediates the abnormal Na-dependent Pi transport in the renal tubules. The defect in vitamin D metabolism is the result of diminished 25(OH)D-1α-hydroxylase activity due to a post-transcriptional abnormality. There is a genetic abnormality of the PHEX gene causal of XLH. PHEX codes a protein from the cell membrane-bound endopeptidase family, which causes hypophosphatemia by decreasing the Npt2 in the kidneys; however, the localization of PHEX is limited to the bones and teeth. To clarify the pathophysiology of XLH, therefore, identification of the mechanism by which the diseased gene functions is urgently required.

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Fibroblast growth factor 23 (FGF23) was identified as a causative factor of autosomal dominant hypophosphatemic rickets (ADHR) and tumor-induced osteomalacia (TIO). Continuous administration of FGF23 by transplanting the FGF23-expressing CHO cells reproduced typical features observed in TIO patients, such as hypophosphatemia, low serum 1,25-dihydroxyvitamin D level, and osteomalacia in nude mice. A series of in vivo studies have shown that FGF23 can reduce sodium dependent phosphate co-transporter (NaPi2a) protein amount and 1α-hydroxylase mRNA level, and increase 24-hydroxylase mRNA levels in kidney. Fgf23 knockout mice demonstrated severe hyperphosphatemia, significant elevation in serum 1,25-dihydroxyvitamin D level and abnormal skeletal development. In addition, vitamin D treatment or dietary phosphate loading have been shown to stimulate FGF23 production. These evidences suggest that FGF23 plays an essential role in regulating phosphate and vitamin D metabolisms in normal physiology. On the other hand, the elevation of serum FGF23 levels in patients with X-linked hypophosphatemic rickets (XLH) has suggested important roles of FGF23 in developing XLH as well as ADHR and TIO. In our recent preliminary study, administration of anti-FGF23 neutralizing antibody ameliorated hypophosphatemia and rachitic bone characters in Hyp mice. These findings indicate a pathological contribution of FGF23 in development of XLH and may provide new insights to its therapy.

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Achondroplasia (ACHs) and thanatophoric dysplasia (TD) are representative diseases of micromelic short stature that are elicited by a constitutively activated FGFR3 caused by point-mutation in the receptor molecule. Based on the mutated point in the receptor, there are several types of diseases of which the severity varies. In the chondrogenic cell line (ATDC5), the signaling cascade in the fibroblast growth factor 3 (FGFR3) was silenced by a overexpression of the mutated FGFR3 that resulted in decreased expression of the mRNA of the parathyroid hormone-related peptide (PTHrP); and also apoptosis was induced. The expression levels of PTHrP were inversely correlated with the severity of the disease; and the replacement of PTHrP prevented the apoptotic changes in the cell lines. In the following studies, however, we selected rhPTH that possesses a high homology and had been clinically used in the treatment of osteoporosis. In the organ culture, rhPTH remarkably elongated the proximal and distal cartilages of the ACH transgenic mice (ACHtg) and expressed collagen X similarly to the wild mice. An in vivo study of rhPTH significantly increased the growth of the long bones of ACHtg in comparison with those of the control (saline). The future prospects of parathyroid hormone (PTH) therapy of ACH are to be discussed.

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