title: Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo.
abstract: 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 protein (PTH-rP) in some patients with cancer, we tested the hypothesis that production of IL-6 potentiates the effects of PTH-rP on Ca2+ homeostasis and osteoclastic bone resorption and examined potential mechanisms for these interactions in vivo. Chinese hamster ovarian (CHO) cells stably transfected with cDNAs for IL-6 (CHO/IL-6) and PTH-rP sense (CHO/PTH-rP) or antisense (CHO/PTH-rP AS) were inoculated intramuscularly 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 precursors, assessed by their capacity to form tartrate-resistant acid phosphatase-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 both IL-6 and PTH-rP had very marked hypercalcemia and osteoclastosis as well as an increase in the number of both CFU-GM and mature osteoclast precursors. These data demonstrate that IL-6 enhances PTH-rP-mediated hypercalcemia and bone resorption, most likely by increasing the pool of early osteoclast precursors that in turn can differentiate to mature osteoclasts. We conclude that IL-6 stimulatory effects on osteoclast precursors may enhance the effects of other bone resorption factors that act at later stages in the osteoclast lineage.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio 78284, USA.
authors.forename: J
authors.initials: J
authors.lastname: de la Mata
authors.forename: H L
authors.initials: HL
authors.lastname: Uy
authors.forename: T A
authors.initials: TA
authors.lastname: Guise
authors.forename: B
authors.initials: B
authors.lastname: Story
authors.forename: B F
authors.initials: BF
authors.lastname: Boyce
authors.forename: G R
authors.initials: GR
authors.lastname: Mundy
authors.forename: G D
authors.initials: GD
authors.lastname: Roodman
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001862:Bone Resorption / Q000139:chemically induced*; D016466:CHO Cells; D002100:Cachexia / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006934:Hypercalcemia / Q000139:chemically induced*; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism*; D010010:Osteoclasts / Q000502:physiology; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D002118:Calcium