GENES REGULATED BY PHOSPHATE-INDUCED PARATHYROID CELL PROLIFERATION IN ORGAN CULTURE : ANALYSIS USING OLIGO-DNA MICROARRAY

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A patient with hypophosphatemic osteomalacia, who was treated with high phosphate, developed tertiary hyperparathyroidism. Gene analysis of the four hyperparathyroid glands revealed several gene mutations, suggesting that high phosphate concentration stimulated parathyroid growth, accompanied by monoclonal proliferation of parathyroid (Reference(1)).To clarify phosphate-induced cell proliferation of parathyroid gland, we established organ culture of parathyroid tissue obtained from patient with primary (I°-)or secondary hyperparathyroidism (II°-HPT). In this organ culture, intact PTH was actively secreted for more than 1 month. When parathyroid tissue were cultured with high phosphate medium, intact PTH secretion was increased and cell proliferation was also stimulated, thus reproducing clinical features of parathyroid glands in patients with II°-HPT。Gene analyses by oligo-DNA microarray, which can analyze whole human genes at a single run (41000genes) revealed that parathyroid cells express abundantly collagens, proteins for cell adhesion and morphogenesis, signal transductions, dopamine receptor D4, prion, etc. Furthermore, parathyroid-specific genes such as PTH, chromogranin-A, calcium-sensing receptor, and vitamin D receptor were also significantly expressed. When parathyroid cells were cultured with high-phosphate medium, more than 100 genes including PTH were increased more than 100%., and parathyroid cells obtained from patients with II°-HPT proliferated to a greater extent than those from I°-HPT. Growth factors which are reported to be involved in parathyroid cell proliferation, such as FGF-2,IGF-1,or TGF-α, did not increase in response to high-phosphate medium, suggesting parathyroid cells proliferate via unknown-pathway. By analyzing microarray at earlier points, we are investigating what signals are the first to stimulate proliferation of parathyroid cells in response to high phosphate concentrations.