Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo

J. De La Mata, H. L. Uy, Theresa Guise, B. Story, B. F. Boyce, G. R. Mundy, G. David Roodman

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2846-2852
Number of pages7
JournalJournal of Clinical Investigation
Volume95
Issue number6
StatePublished - 1995
Externally publishedYes

Fingerprint

Parathyroid Hormone-Related Protein
Hypercalcemia
Bone Resorption
Interleukin-6
Osteoclasts
Cricetulus
Granulocyte-Macrophage Progenitor Cells
Paraneoplastic Syndromes
Cachexia
Nude Mice

Keywords

  • cytokine
  • interleukin-6
  • malignancy
  • osteoclast
  • parathyroid hormone-related protein

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo. / De La Mata, J.; Uy, H. L.; Guise, Theresa; Story, B.; Boyce, B. F.; Mundy, G. R.; Roodman, G. David.

In: Journal of Clinical Investigation, Vol. 95, No. 6, 1995, p. 2846-2852.

Research output: Contribution to journalArticle

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AU - De La Mata, J.

AU - Uy, H. L.

AU - Guise, Theresa

AU - Story, B.

AU - Boyce, B. F.

AU - Mundy, G. R.

AU - Roodman, G. David

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