title: Parathyroid hormone-related protein and interleukin-1 alpha synergistically stimulate bone resorption in vitro and increase the serum calcium concentration in mice in vivo.
abstract: To elucidate the mechanism of humoral hypercalcemia elicited by human esophageal carcinoma cells (EC-GI), which constitutively produced interleukin-1 alpha (IL-1 alpha) and PTH-like factor, the effects of IL-1 alpha and PTH-related protein (PTH-rP) 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-1 alpha or PTH-rP-(1-34) stimulated 45Ca release from prelabeled fetal mouse forearm bones in a concentration-dependent manner, and when combined, IL-1 alpha and PTH-rP-(1-34) synergistically stimulated bone resorption in vitro. Injection of PTH-rP-(1-34) into mice three times a day for 2 days increased the serum calcium concentration in a dose-dependent manner. Continuous infusion of IL-1 alpha occasionally increased the serum calcium concentration. Simultaneous administration of IL-1 alpha at rates of 1-2.7 micrograms/day and PTH-rP-(1-34) at doses of 15-30 micrograms/day synergistically increased the serum calcium concentration in vivo. These findings suggest that PTH-rP and IL-1 alpha 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 malignancy-associated hypercalcemia, in whom nephrogenous cAMP excretion is neither increased nor decreased.
authors.affiliation: Institute of Clinical Endocrinology, Tokyo Women's Medical College, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: Y
authors.initials: Y
authors.lastname: Fujii
authors.forename: K
authors.initials: K
authors.lastname: Kasono
authors.forename: M
authors.initials: M
authors.lastname: Ozawa
authors.forename: H
authors.initials: H
authors.lastname: Imamura
authors.forename: Y
authors.initials: Y
authors.lastname: Kanaji
authors.forename: H
authors.initials: H
authors.lastname: Kurosawa
authors.forename: T
authors.initials: T
authors.lastname: Tsushima
authors.forename: K
authors.initials: K
authors.lastname: Shizume
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000187:drug effects*; D002118:Calcium / Q000097:blood*; D000242:Cyclic AMP / Q000652:urine; D004357:Drug Synergism; D005260:Female; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D009994:Osmolar Concentration; D010281:Parathyroid Hormone / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology; D019379:Teriparatide; D014407:Tumor Cells, Cultured
chemical_list: D007375:Interleukin-1; D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D019379:Teriparatide; D000242:Cyclic AMP; D002118:Calcium