MODE OF ACTION OF INTERLEUKIN-6 ON MATURE OSTEOCLASTS - NOVEL INTERACTIONS WITH EXTRACELLULAR CA2-RESORPTION( SENSING IN THE REGULATION OF OSTEOCLASTIC BONE)

We describe a physiologically significant mechanism through which inte rleukin-6 (IL-6) and a rising ambient Ca2+ interact to regulate osteoc lastic bone resorption. VOXEL-based confocal microscopy of nonpermeabi lized osteoclasts incubated with anti-IL-6 receptor antibodies reveale d intense, strictly peripheral plasma membrane fluorescence. IL-6 rece ptor expression in single osteoclasts was confirmed by in situ reverse transcriptase PCR histochemistry. IL-6 (5 ng/l to 10 mu g/l), but not IL-11 (10 and 100 mu g/l), reversed the inhibition of osteoclastic bo ne resorption induced by high extracellular Ca2+ (15 mM). The IL-6 eff ect was abrogated by excess soluble IL-6 receptor (500 mu g/l). Additi onally, IL-6 (5 pg/l to 10 mu g/l) inhibited cytosolic Ca2+ signals tr iggered by high Ca2+ or Ni2+. In separate experiments, osteoclasts inc ubated 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 oste oclasts in 10 or 20 mM Ca2+ than cells in 1.25 mM Ca2+. Similarly, IL- 6 receptor mRNA histostaining was increased in osteoclasts incubated i n 5 or 10 mM Ca2+. Thus, while high Ca2+ enhances IL-6 secretion, the released IL-6 attenuates Ca2+ sensing and reverses inhibition of resor ption by Ca2+. Such an autocrine-paracrine loop may sustain osteoclast ic activity in the face of an inhibitory Ca2+ level generated locally during resorption.