Comparative study of inhibitory effects by murine interferon ? and a new bisphosphonate (alendronate) in hypercalcemic, nude mice bearing human tumor (LJC-1-JCK)

Abstract

The inhibitory effect of murine interferon gamma (muIFN gamma) on humoral hypercalcemia in nude mice bearing lower-jaw cancer (LJC-1-JCK), in which parathyroid-hormone(PTH)-related protein is responsible for causing humoral hypercalcemia by activating bone resorption, was examined in comparison with that of a new bisphosphonate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate). muIFN gamma was injected into tumor-bearing nude mice for 5 days before the establishment of hypercalcemia. The increase of plasma calcium concentration was delayed and this effect continued for more than 6 days even after the injection was stopped. Alendronate markedly suppressed hypercalcemia in tumor-bearing nude mice but this inhibitory effect continued for less than 6 days. Neither muIFN gamma nor alendronate affected the tumor volume or serum PTH-related protein concentration. Injection of muIFN gamma into mice for 3 days almost completely abolished the formation of multinucleated osteoclast-like cells from bone marrow cells in vitro, whereas injection of alendronate into mice had no effect. These findings suggested that muIFN gamma suppressed the formation of osteoclasts, resulting in the prolonged decrease of plasma calcium concentration in hypercalcemic tumor-bearing nude mice, whereas alendronate is cytotoxic to functionally mature osteoclasts and inhibited osteoclastic bone resorption, resulting in a marked decrease in the plasma calcium concentration in tumor-bearing hypercalcemic nude mice.

IFN-γ directly inhibits TNF-α-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions

“…It has been reported that bone resorption in cases of collagen-induced arthritis in IFN-␥-deficient mice was accelerated [25]. Furthermore, IFN-␥ has been found to decrease serum calcium and osteoclastic bone resorption in vivo [35,36]. These results suggest that IFN-␥ inhibits bone resorption in vivo.…”

IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

“…This is underscored by experiments showing that T cell-deficient nude mice fail to undergo bone loss following rIFN-γ administration. IFN-γ-induced bone loss was reversed by T cell reconstitution and is consistent with the fact that IFN-γ has been shown to stimulate bone resorption only in humans or experimental models possessing a normal T cell lineage (14)(15)(16)42), while the vast majority of previous studies concluding that IFN-γ is a bone-sparing cytokine made use of the nude mouse model and/or T cell-depleted in vitro cultures (12,13). Interestingly, Takayanagi et al reported that IFN-γ represses bone resorption in a T cell-replete model, but the only in vivo data presented in the report were derived from calvariae from prepubertal mice (7).…”

“…Silencing of IFN-γ receptor (IFN-γR) signaling led to a more rapid onset of collagen-induced arthritis and bone resorption (11). Furthermore, IFN-γ was found to decrease serum calcium and osteoclastic bone resorption in vivo in nude mice (12,13), suggesting that IFN-γ is a bone-sparing cytokine in vivo. In contrast, observations in humans and rodents suggest that IFN-γ promotes bone resorption and causes bone loss in a variety of pathological conditions.…”

Estrogen deficiency and bone loss: an inflammatory tale

“…Furthermore, IFN-γ is reported to be efficacious in the treatment of osteopetrosis through restoration of bone resorption in humans (64) and rodents (65). In contrast, others have reported that IFN-γ exerts potent antiosteoclastogenic effects in vitro (51), that silencing of IFN-γ receptor signaling leads to more rapid onset of collageninduced arthritis and bone resorption (66), and that IFN-γ decreases serum calcium concentration and osteoclastic bone resorption in nude mice (67,68).…”