IL-4 inhibits bone-resorbing activity of mature osteoclasts by affecting NF-kappa B and Ca2+ signaling.
IL-4 is an important immune cytokine that regulates bone homeostasis. We investigated the molecular mechanism of IL-4 action on bone-resorbing mature osteoclasts. Using a highly purified population of mature osteoclasts, we show that IL-4 dose-dependently inhibits receptor activator of NF-kappaB ligand (RANKL)-induced bone resorption by mature osteoclasts. We detected the existence of IL-4R mRNA in mature osteoclasts. IL-4 decreases TRAP expression without affecting multinuclearity of osteoclasts, and inhibits actin ring formation and migration of osteoclasts. Interestingly, IL-4 inhibition of bone resorption occurs through prevention of RANKL-induced nuclear translocation of p65 NF-kappaB subunit, and intracellular Ca(2+) changes. Moreover, IL-4 rapidly decreases RANKL-stimulated ionized Ca(2+) levels in the blood, and mature osteoclasts in IL-4 knockout mice are sensitive to RANKL action to induce bone resorption and hypercalcemia. Furthermore, IL-4 inhibits bone resorption and actin ring formation by human mature osteoclasts. Thus, we reveal that IL-4 acts directly on mature osteoclasts and inhibits bone resorption by inhibiting NF-kappaB and Ca(2+) signaling.
National Center for Cell Science, University of Pune Campus, Pune 411-007, India.
Latha S
LS
Mangashetti
Shruti M
SM
Khapli
Mohan R
MR
Wani
D000135:Acid Phosphatase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D000328:Adult; D000818:Animals; D001862:Bone Resorption / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002464:Cell Migration Inhibition; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006934:Hypercalcemia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D010010:Osteoclasts / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053246:Receptor Activator of Nuclear Factor-kappa B; D018003:Receptors, Calcitonin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000071681:Tartrate-Resistant Acid Phosphatase; D051996:Transcription Factor RelA
D000199:Actins; D002352:Carrier Proteins; D006023:Glycoproteins; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018003:Receptors, Calcitonin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D051996:Transcription Factor RelA; D015847:Interleukin-4; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase