Insulin-like growth factors (IGF) I and II utilize different calcium signaling pathways in a primary human parathyroid cell culture model

Wong, C. K., Lai, T., Holly, M. P., Wheeler, M. H., Stewart, Claire E. and Farndon, J. R. (2006) Insulin-like growth factors (IGF) I and II utilize different calcium signaling pathways in a primary human parathyroid cell culture model. World Journal of Surgery, 30 (3). pp. 333-345. ISSN 1432-2323

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Abstract

Background In most cell types, influx of calcium (Ca2+) induces a growth or secretory response. The opposite occurs in parathyroid (PTH), cells where there is an inverse relationship between intracellular Ca2+ concentration and PTH secretion. We have examined the effects of calcium channel and metabolism modulators on insulin-like growth factors (IGFs) in a parathyroid cell culture model. Methods Cell cultures were prepared from 9 patients undergoing operation for hyperparathyroidism. Following adhesion, the cells were transferred to serum-free medium and dosed with IGF I, II ± ethyleneglycol-bis(β-aminoethyl)-N, N, N′,N′-tetraacetic acid (EGTA), nifedipine, nickel, 2-aminoethoxy-diphenylborate (2-APB), or dantrolene. Proliferation (96 hours) was assessed by measuring tritiated thymidine incorporation and PTH release (1 and 3 hours) assayed by IRMA. Results Both IGF I and II increased DNA synthesis to 162.8% ± 10.6% (SEM) and 131.1% ± 7.7%, respectively (P < 0.05). EGTA at 0.2 mmol (ionized Ca2+ 0.2mmol) did not affect the response to both IGFs. EGTA at 2 mmol (ionized Ca2+ 0 mmol) reduced the DNA synthesis of IGF I and II to 29% and 26%, respectively (P < 0.05). Nifedipine and nickel (nonspecific Ca2+ channel blocker) were equally potent in negating the mitogenic effects of both IGFs. 2-APB (IP3R blocker) reduced the basal DNA synthesis to 51.3% ± 8.4% but had no effect on either IGF. Dantrolene (ryanodine receptor blocker) negated IGF II induced mitogenisis (74.2% ± 6.7%) and partially inhibited IGF I mitogenesis (123% ± 6%) (P < 0.05). The rate of PTH secretion was greater after IGF II stimulation than after IGF I stimulation. Conclusions IGFs I and II induce mitogenesis by different calcium signaling pathways. These data suggest that parathyroid cells may utilize different calcium signaling pathways to distinguish growth factors and serum calcium changes.