Mode of Action of Interleukin-6 on Mature Osteoclasts. Novel Interactions with Extracellular Ca2+ Sensing in the Regulation of Osteoclastic Bone Resorption

doi:10.1083/jcb.142.5.1347

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© The Rockefeller University Press, 0021-9525/1998//1347 $5.00
The Journal of Cell Biology, Volume 142, Number 5, , 1998 1347-1356

Articles

Mode of Action of Interleukin-6 on Mature Osteoclasts. Novel Interactions with Extracellular Ca²⁺ Sensing in the Regulation of Osteoclastic Bone Resorption

Olugbenga A. Adebanjo^*, Baljit S. Moonga^*, Tomoo Yamate, Li Sun^*, Cedric Minkin, Etsuko Abe, and Mone Zaidi^*

^* Center for Osteoporosis and Skeletal Aging, Veterans Affairs Medical Center, and Department of Medicine, Medical College of Pennsylvania–Hahnemann School of Medicine, Philadelphia, Pennsylvania 19104; Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205; and School of Dentistry, University of Southern California, Los Angeles, California 90089

We describe a physiologically significant mechanism throughwhich interleukin-6 (IL-6) and a rising ambient Ca²⁺ interactto regulate osteoclastic bone resorption. VOXEL-based confocalmicroscopy of nonpermeabilized osteoclasts incubated with anti–IL-6 receptor antibodies revealed intense, strictly peripheralplasma membrane fluorescence. IL-6 receptor expression in singleosteoclasts was confirmed by in situ reverse transcriptasePCR histochemistry. IL-6 (5 ng/l to 10 µg/l), but notIL-11 (10 and 100 µg/l), reversed the inhibition of osteoclasticbone resorption induced by high extracellular Ca²⁺ (15 mM).The IL-6 effect was abrogated by excess soluble IL-6 receptor(500 µg/l). Additionally, IL-6 (5 pg/l to 10 µg/l)inhibited cytosolic Ca²⁺ signals triggered by high Ca²⁺ orNi²⁺. In separate experiments, osteoclasts incubated in 10mM Ca²⁺ or on bone released more IL-6 than those in 1.25 mM Ca²⁺. Furthermore, IL-6 mRNA histostaining was more intensein osteoclasts in 10 or 20 mM Ca²⁺ than cells in 1.25 mM Ca²⁺.Similarly, IL-6 receptor mRNA histostaining was increased inosteoclasts incubated in 5 or 10 mM Ca²⁺. Thus, while highCa²⁺ enhances IL-6 secretion, the released IL-6 attenuatesCa²⁺ sensing and reverses inhibition of resorption by Ca²⁺.Such an autocrine–paracrine loop may sustain osteoclasticactivity in the face of an inhibitory Ca²⁺ level generated locally during resorption.

Key Words: IL-6 • Ca²⁺ sensing • Ca²⁺ receptor • osteoporosis • ryanodine receptor

Abbreviations used in this paper: ANOVA, analysis of variance; CSI, corrected staining intensity; DEPC, diethyl pyrocarbonate; DIG, digoxigenin; GA3PD, glyceraldehyde 3-phosphate dehydrogenase; IL-6, interleukin-6; IL-6R, IL-6 receptor; rhIL-6, human recombinant IL-6; RT-PCR, reverse transcriptase PCR; TRAP, tartrate-resistant acid phosphatase.

M. Zaidi acknowledges the support of the National Institutesof Health (RO1-AG14917-02), the Department of Veteran's Affairs,Amgen Pharmaceuticals Inc. (Thousand Oaks, CA), and Merck andCo. (Whitehouse Station, NJ).

Drs. Yamate and Sun are equal contributors to the work.

Address all correspondence to Mone Zaidi, M.D., Ph.D., Geriatrics and Extended Care (11G), VA Medical Center, Woodlands and UniversityAvenues, Philadelphia, PA 19104. Tel.: (215) 823-4400. Fax:(215) 823-6715. E-mail: zaidim{at}auhs.edu

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