INTERLEUKIN-6 ENHANCES HYPERCALCEMIA AND BONE-RESORPTION MEDIATED BY PARATHYROID HORMONE-RELATED PROTEIN IN-VIVO

Tumors frequently induce the multifunctional cytokine IL-6, which has been linked to several paraneoplastic syndromes, most notably cachexia . IL-6 stimulates osteoclast formation, causes mild hypercalcemia, and is produced by bone cells in vitro upon exposure to systemic hormones . Since IL-6 is produced together with parathyroid hormone-related pro tein (PTH-rP) in some patients with cancer, we tested the hypothesis t hat production of IL-6 potentiates the effects of PTH-rP on Ca2+ homeo stasis and osteoclastic bone resorption and examined potential mechani sms for these interactions in vivo. Chinese hamster ovarian (CHO) cell s stably transfected with cDNAs for IL-6 (CHO/IL-6) and PTH-rP sense ( CIIO/PTH-rP) or antisense (CHO/PTH-rP AS) were inoculated intramuscula rly into nude mice. Experimental groups included CHO/IL-6 plus CHO/PTH -rP; CHO/IL-6 plus CHO/PTH-rP AS; CHO/IL-6 alone; and CHO/PTH-rP alone . Blood ionized Ca2+ was measured on days 0, 7, 10, 12, and 13. Three different developmental stages in the osteoclast lineage were examined at day 13: the early multipotential precursor, granulocyte macrophage colony-forming units (CFU-GM); more mature mononuclear osteoclast pre cursors, assessed by their capacity to form tartrate-resistant acid ph osphatase-positive multinucleated cells in marrow cultures; and mature osteoclasts, assessed by histomorphometry, IL-6 increased CFU-GM but not bone resorption or Ca2+. In contrast, PTH-rP induced hypercalcemia and bone resorption and increased multinucleated osteoclasts and more mature precursors cells; but not CFU-GM. However, mice treated with b oth IL-6 and PTH-rP had very marked hypercalcemia and osteoclastosis a s well as an increase in the number of both CFU-GM: and mature osteocl ast precursors. These data demonstrate that IL-6 enhances PTH-rP-media ted hypercalcemia and bone resorption, most likely by increasing the p ool of early osteoclast precursors that in turn can differentiate to m ature osteoclasts. We conclude that IL-6 stimulatory effects on osteoc last precursors may enhance the effects of other bone resorption facto rs that act at later stages in the osteoclast lineage.