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

Abstract

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 μg/l), but not IL-11 (10 and 100 μg/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 μg/l). Additionally, IL-6 (5 pg/l to 10 μg/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.

Proteome Variations in Pancreatic Stellate Cells upon Stimulation with Proinflammatory Factors

“…The protein levels of these three cytokines were actually found repressed by IL6. This result fits well to the fact that IL6 causes a reduction in the cytosolic level of calcium (63). Under certain pathological stimuli, calcium can play a detrimental role in cell death and apoptosis (64).…”

Differential effects of interleukin-6 receptor activation on intracellular signaling and bone resorption by isolated rat osteoclasts

“…Conversely, extracellular Ca 2+ elevation stimulates IL-6 synthesis and secretion. Taken together these findings are compatible with a positive feedback loop that involves IL-6 in the conservation of osteoclast activity (Adebanjo et al 1998). Finally, IL-6 inhibits osteoclast apoptosis, but again through a mechanism that is still unclear (Hughes et al 1995).…”

“…IL-6 stimulates osteoclastic bone resorption by mature rat and human osteoclasts (Ohsaki et al 1992, Ishimi et al 1990, Adebanjo et al 1998. It reduces the sensitivity of mature osteoclasts to elevations in extracellular [Ca 2+ ] (Adebanjo et al 1998).…”

Increased Osteoblastic Activity and Expression of Receptor Activator of NF-κB Ligand in Nonuremic Nephrotic Syndrome

“…Most of these pro-and anti-osteoclastogenic cytokines act primarily through the osteoblasts by altering the levels of RANKL and osteoprotegerin, the balance of which determines overall osteoclast formation. Some cytokines, particularly IL-6, also have direct osteoclastic actions (35). Elevated serum and urinary activity of various cytokines, including IL-1 and IL-6 (19,36), IL-2 and IL-4 (20), and TNF-␣ (21), have been identified in patients with NS, particularly during clinical activity of their disease.…”

“…At first, the higher NTx values were unexpected because they coincided with the decline in AP levels and RANKL expression. However, one third of the remission samples were obtained in patients while they were on cyclosporine, an agent that is capable of exerting a bone-resorbing effect independent of RANKL activation, with IL-6 being a possible mediator of this action (35).…”