FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders.

A subset of human growth hormone (GH)-secreting pituitary tumors contains the gsp oncogene that encodes an activation mutation of the alpha-subunit of the stimulatory GTP-binding protein (G(S) alpha). This study was undertaken to investigate the frequency of the gsp oncogene in GH-secreting pituitary tumors in Korean acromegalic patients and to elucidate the clinical characteristics of these patients to endocrine testing. Direct polymerase chain reaction sequencing revealed the gsp oncogene mutation in 9 out of 21 tumors (43%) at amino acid 201 of the G(S) alpha protein. A single nucleotide mutation in the tumors carrying the gsp oncogene was observed, which replaced an arginine (CGT) in the normal protein with cysteine (TGT) in eight tumors and serine (AGT) in one tumor. The patients with the gsp oncogene mutation (group 1) were older (54 +/- 10 vs 41 +/- 11 years, p = 0.0085) than those without the mutation (group 2). Sex, tumor size and grade, basal GH and prolactin levels, the GH response to oral glucose loading, the GH fluctuation and the paradoxical response to thyrotropin-releasing hormone or gonadotropin-releasing hormone did not differ between the groups. The gsp oncogene was found mostly in somatotroph adenomas. The octreotide-induced GH suppression was significantly higher in group 1 than in group 2 (95 +/- 5% vs 81 +/- 17%, p = 0.0335). The GH response to bromocriptine did not differ between the groups. These results suggest that the G(S) alpha mutations of GH-secreting tumor are observed in Korean acromegalic patients with similar frequency to those of western countries. The patients with gsp oncogene are likely to be older than those without the oncogene, and show excellent response of GH suppression to octreotide.

The gene mutated in autosomal dominant hypophosphatemic rickets (ADHR), a phosphate wasting disorder, has been identified as FGF-23, a protein that shares sequence homology with fibroblast growth factors (FGFs). Patients with ADHR display many of the clinical and laboratory characteristics that are observed in patients with oncogenic hypophosphatemic osteomalacia (OHO), a disorder thought to arise by the secretion of a phosphate wasting factor from different mesenchymal tumors. In the present studies, we therefore investigated whether FGF-23 is a secreted factor and whether it is abundantly expressed in OHO tumors. After transient transfection of OK-E, COS-7, and HEK293 cells with the plasmid encoding full-length FGF-23, all three cell lines efficiently secreted two protein species into the medium that were approximately 32 and 12 kDa upon SDS-PAGE and subsequent Western blot analysis using an affinity-purified polyclonal antibody to FGF-23. Furthermore, Northern blot analysis using total RNA from five different OHO tumors revealed extremely high levels of FGF-23 mRNA, and Western blot analysis of extracts from a sixth tumor detected the 32 kDa FGF-23 protein species. In summary, FGF-23, the gene mutated in ADHR, is a secreted protein and its mRNA is abundantly expressed by several different OHO tumors. Our findings indicate that FGF-23 may be a candidate phosphate wasting factor, previously designated "phosphatonin".

Abstract. To investigate the potential pathophysiologic role of human SRIF receptor gene expression in GH-secreting adenomas in acromegalic patients, we studied the relationship between the SRIF receptor gene expression, endogenous SRIF activity and exogenous response to octreotide in 16 acromagalic patients. Hypothalamic somatostatinergic activity (HSA) was assessed by glucose-induced suppression of TRH-stimulated TSH secretion. As an indicator of somatotrope sensitivity to HSA, glucose-induced suppression of TRH-stimulated GH secretion was determined. For the acute octreotide response, a 100 mg bolus of octreotide was injected intravenously and GH was measured hourly for 6 hr. Pituitary tumor SRIF receptor subtype 2 and 5 (sst2 and sst5) mRNA levels were measured by real-time RT-PCR. Gsp oncogene was also detected by direct PCR sequencing. Sst2 and sst5 mRNA levels were detected in all tumors. Sst2 mRNA levels positively correlated with that of sst5. Sst2 and sst5 mRNA levels did not show any correlation with basal GH values (nadir or peak). Expression of sst2, but not sst5, showed a positive correlation with the GH response to HSA, while the octreotide response positively correlated with the sum of sst2 and sst5 mRNA levels. Individuals with gsp-positive tumors were more responsive to octreotide than those with gsp-negative tumors but sst2 and sst5 mRNA levels did not differ between these two groups. These results suggest common transcriptional and/or post-transcriptonal regulatory mechanisms for these SRIF receptor subtypes within GH-secreting pituitary adenomas. The functional observations suggest that the degree (or level) of sst2 and sst5 expression is critical for the ultimate GH response of somatotropinomas to endogenous SRIF tone and exogenous SRIF analogue therapy. However, sst2 and sst5 mRNA levels are not the only factors mediating the response to SRIF.

Symptomatic hepatic injury develops usually within the first few months of PTU administration with rare frequency, but its clinical course is relatively benign once the drug is withdrawn. However, it may be difficult to predict its development, so all patients should be monitored for rise in LFTs at regular intervals, especially during the early period.

We report a case of oncogenic osteomalacia associated with a phosphaturic mesenchymal tumor in a 31-year-old woman. She was presented with severe generalized bone and muscle pain and was restricted to bed. She lost 20cm in height over the 8 years since she had first noticed a pain in her thigh. A walnut-sized, hard, soft tissue tumor was found very easily beside her lower molar teeth. Radiologic examination revealed a remarkable decrease in bone density and multiple pathologic fractures of spine, femur and phalangeal bones. Severe hypophosphatemia, hyperphosphaturia, low plasma 1,25-dihydroxyvitamin D3 level and high plasma PTH level were disclosed at presentation. Histomorphometric examination revealed an extensive area of unmineralized osteoid and little mineralizing activity. A pharmacologic dose of 1α-hydroxyvitamin D3 or 1,25-dihydroxyvitamin D3 slightly increased the serum phosphate level and renal tubular reabsorption of phosphate, and slightly decreased plasma PTH level without any symptomatic improvement. Histologic examination of the tumor revealed a mixed connective tissue tumor that consisted of central woveh bones and surrounding primitive spindle cells with prominent vascularities. After removal of the tumor, all biochemical, hormonal and radiologic abnormalities disappeared with remarkable symptomatic improvement.

These data suggest that good octreotide responders are more likely to respond to TRH or bromocriptine. Good octreotide responders may include subgroups with different levels of TRH and dopamine receptor expression. A possible relation between octreotide response and the mutation of G alpha s gene should be investigated.

ObjectivesThis study examined the effect of cilostazol, a potent phosphodiesterase inhibitor, on the progression of neuropathies associated with streptozotocininduced diabetes mellitus in Sprague-Dawley rats.MethodsEight weeks after streptozotocin treatment, a pelleted diet containing 0.03% cilostazol (15mg/kg body weight) was given for four weeks. Body weight, blood glucose level, motor nerve conduction velocity(MNCV), myelinated fiber density and size distribution of sciatic nerves were compared between age-matched normal rats (Group 1), control diabetic rats (Group 2) and cilostazol-treated diabetic rats (Group 3).ResultsBody weight was significantly reduced and blood glucose level was significantly increased in diabetic rats (Group 2 and 3) compared to normal rats. MNCV and cAMP content of sciatic nerves were significantly reduced in diabetic rats 12 weeks after streptozotocin treatment. Myelinated fiber size and density were also significantly reduced, and thickening of the capillary walls and duplication of the basement membranes of the endoneural vessels were observed in the diabetic rats. Whereas both body weight and blood glucose level of Group 3 did not differ significantly from those of Group 2, cilostazol treatment significantly increased MNCV and cAMP content of sciatic nerves in Group 3 but not to the levels observed in Group 1. MNCV positively correlated with cAMP content of sciatic nerves (r=0.86; p < 0.001). Cilostazol treatment not only restored myelinated fiber density and size distribution but reversed some of the vascular abnormalities.ConclusionThese findings suggest that a reduced cAMP content in motor nerves may be involved in the development of diabetic neuropathy, and that cilostazol may prevent the progression of diabetic neuropathy by restoring functional impairment and morphological changes of peripheral nerves.