Mode of action of interleukin-6 on mature osteoclasts. Novel interactions with extracellular Ca2+ sensing in the regulation of osteoclastic bone resorption.
We describe a physiologically significant mechanism through which interleukin-6 (IL-6) and a rising ambient Ca2+ interact to regulate osteoclastic bone resorption. VOXEL-based confocal microscopy of nonpermeabilized osteoclasts incubated with anti- IL-6 receptor antibodies revealed intense, strictly peripheral plasma membrane fluorescence. IL-6 receptor expression in single osteoclasts was confirmed by in situ reverse transcriptase PCR histochemistry. IL-6 (5 ng/l to 10 microg/l), but not IL-11 (10 and 100 microg/l), reversed the inhibition of osteoclastic bone resorption induced by high extracellular Ca2+ (15 mM). The IL-6 effect was abrogated by excess soluble IL-6 receptor (500 microg/l). Additionally, IL-6 (5 pg/l to 10 microg/l) inhibited cytosolic Ca2+ signals triggered by high Ca2+ or Ni2+. In separate experiments, osteoclasts incubated in 10 mM Ca2+ or on bone released more IL-6 than those in 1.25 mM Ca2+. Furthermore, IL-6 mRNA histostaining was more intense in osteoclasts in 10 or 20 mM Ca2+ than cells in 1.25 mM Ca2+. Similarly, IL-6 receptor mRNA histostaining was increased in osteoclasts incubated in 5 or 10 mM Ca2+. Thus, while high Ca2+ enhances IL-6 secretion, the released IL-6 attenuates Ca2+ sensing and reverses inhibition of resorption by Ca2+. Such an autocrine-paracrine loop may sustain osteoclastic activity in the face of an inhibitory Ca2+ level generated locally during resorption.
Adebanjo
O A
OA
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, USA.
Moonga
B S
BS
Yamate
T
T
Sun
L
L
Minkin
C
C
Abe
E
E
Zaidi
M
M
D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D017404:In Situ Hybridization, Fluorescence; D017370:Interleukin-11 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins / Q000032:analysis; D009532:Nickel / Q000494:pharmacology; D010010:Osteoclasts / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D019947:Receptors, Interleukin-6 / Q000032:analysis
D017370:Interleukin-11; D015850:Interleukin-6; D008565:Membrane Proteins; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D009532:Nickel; D002118:Calcium