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

Parathyroid hormone‐related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia

“…29,30 However, to our knowledge only a limited number of cases of solid tumors have been reported to be associated with elevated serum levels of IL-6. 15 The current study data suggest that IL-6 as well as PTH-rP play a role in TIH in lung carcinoma. We assume that increased serum levels of IL-6 are the result of overproduction of IL-6 by lung tumors as reported previously in squamous carcinoma cases.…”

“…We assume that increased serum levels of IL-6 are the result of overproduction of IL-6 by lung tumors as reported previously in squamous carcinoma cases. 15 Although it has been reported that IL-6 production is stimulated by PTH-rP, 31 we believe that the production of IL-6 in lung carcinoma is independent of PTH-rP, because IL-6 has no correlation with bone metastasis such as PTH-rP does. Thus, it is suggested that IL-6 independently causes TIH and additively or synergistically enhances it in cooperation with PTH-rP.…”

Adult T-cell Leukemia with Hypercalcemia-induced Metastatic Calcification in the Lungs Due to Production of Parathyroid Hormone-related Protein.

“…The humoral factor, PTHrP produced by tumor cells in ATL, is believed to play an important role in the development of hypercalcemia by stimulating osteoclastic bone resorption (9,15,18,(22)(23)(24)(25). PTHrP gene expression in HTLV-Iinfected T cells has been reportedly induced through transactivation by the tax gene in vitro (26 additional substances such as interleukin-loc, 1 (3, 2 and prostaglandin E, (27)(28)(29)(30)(31)(32)(33). In the present case, the elevated serum PTHrP level was probably involved mainly in the mechanism of hypercalcemia.…”

Bone resorption activity of osteolytic metastatic lung and breast cancers

“…In the situation of humeral hypercalcemia of malignancy, cancer cells release factors that induce bone resorption systemically. The causative factors had been extensively investigated, and it was reported that parathyroid hormone related protein (PTHrP) plays a central role with partial role of interleukin-1 (IL-1) and transforming growth factor-a (TGF-a) [1,15,21,33]. In another clinical situation, tumor cells or the surrounding cells in bone marrow produce factors that lead to local bone destruction and result in structural weakness of bone.…”