Parathyroid Hormone-Related Protein and Interleukinla 1α Synergistically Stimulate Bone Resorptionin Vitroand Increase the Serum Calcium Concentration in Micein Vivo*

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Abstract
To elucidate the mechanism of humoral hypercalcemia elicited by human esophageal carcinoma cells (EC-GI), which constitutively produced interleukin-lα (IL-lα) and PTHlike factor, the effects of IL-lα and PTH-related protein (PTHrP) on bone resorption in vitro and on serum calcium concentrations in vivo were investigated. Nude mice transplanted with EC-GI cells invariably developed hypercalcemia, although their urinary cAMP excretion remained within the normal range. IL-lα or PTH-rP-(l-34) stimulated 45Ca release from prelabeled fetal mouse forearm bones in a concentration-dependent manner, and when combined, IL-lα and PTH-rP-(l-34) synergistically stimulated bone resorption in vitro. Injection of PTHrP-( l-34) into mice three times a day for 2 days increased the serum calcium concentration in a dose-dependent manner. Continuous infusion of IL-lα occasionally increased the serum calcium concentration. Simultaneous administration of IL-lα at rates of 1-2.7 μg/day and PTH-rP-(l-34) at doses of 15-30 μg/ day synergistically increased the serum calcium concentration in vivo. These findings suggest that PTH-rP and IL-l± produced by the tumor cells were synergistically responsible for the humoral hypercalcemia observed in both the original patient and the tumor-bearing nude mice, and that at least two bone-resorbing factors [PTH-rP and another nonadenylate cyclase-stimulating bone-resorbing factor(s)] are active in patients with malignancyassociated hypercalcemia, in whom nephrogenous cAMP excretion is neither increased nor decreased. (Endocrinology124: 2172–2178, 1989)