Abstract
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.
Highlights
Rafts are specialized membrane microdomains enriched in glycosphingolipids, cholesterol, and glycosylphosphatidylinositol (GPI)1-anchored proteins [1, 2]
That mice deficient in RANKL, RANK, or TRAF6 commonly show osteopetrotic phenotype due to defective osteoclastic bone resorption points out the particular importance of TRAF6 for RANK signaling in osteoclasts [17,18,19,20,21]
Our findings demonstrate that raft expression increases during the osteoclastogenesis and that TRAF6 is recruited to rafts by RANKL stimulation in osteoclasts
Summary
Rafts are specialized membrane microdomains enriched in glycosphingolipids, cholesterol, and glycosylphosphatidylinositol (GPI)1-anchored proteins [1, 2]. 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. In Raw264.7 cells induced to differentiate to osteoclasts in the presence of RANKL, similar patterns of increase were observed in the expression of flotillin, TRAF6, and Src (Fig. 1B).
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