Membrane rafts play a crucial role in receptor activator of nuclear factor kappaB signaling and osteoclast function.
Membrane lipid rafts play a key role in immune cell activation by recruiting and excluding specific signaling components of immune cell surface receptors upon the receptor engagement. Despite this, the role of these microdomains in the regulation of osteoclasts as controlled by receptor activator of nuclear factor kappaB (RANK) has yet to be established. In this study, we demonstrate that the raft microdomain expression plays an essential role in osteoclast function and differentiation. Expression of raft component flotillin greatly increased during osteoclast differentiation, whereas engagement of RANK induced the translocation of tumor necrosis factor receptor-associated factor 6 to rafts where Src was constitutively resident. Disruption of rafts blocked TRAF6 translocation and Akt activation by RANK ligand in osteoclasts and further reduced the survival of osteoclasts. Actin ring formation and bone resorption by osteoclasts were also found to require the integrity of rafts. Our observations demonstrate for the first time that RANK-mediated signaling and osteoclast function are critically dependent on the expression and integrity of raft membrane microdomains.
Ha
Hyunil
H
National Research Laboratory for Bone Metabolism, Research Center for Proteineous Materials, and School of Dentistry, Chosun University, Gwangju 501-759, Korea.
Kwak
Han Bok
HB
Lee
Seung Ku
SK
Na
Doe Sun
DS
Rudd
Christopher E
CE
Lee
Zang Hee
ZH
Kim
Hong-Hee
HH
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010010:Osteoclasts / Q000378:metabolism*; D053244:Osteoprotegerin; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D013347:Subcellular Fractions; D048029:TNF Receptor-Associated Factor 6; D013997:Time Factors; D014162:Transfection
D006023:Glycoproteins; D053244:Osteoprotegerin; D011506:Proteins; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D048029:TNF Receptor-Associated Factor 6; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt