Journal of Biological Chemistry
Volume 285, Issue 48, 26 November 2010, Pages 37427-37435
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Cell Biology
Receptor Activator of NF-κB (RANK) Cytoplasmic IVVY535–538 Motif Plays an Essential Role in Tumor Necrosis Factor-α (TNF)-mediated Osteoclastogenesis*

https://doi.org/10.1074/jbc.M110.149484Get rights and content
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Tumor necrosis factor-α (TNF) enhances osteoclast formation and activity leading to bone loss in various pathological conditions, but its precise role in osteoclastogenesis remains controversial. Although several groups showed that TNF can promote osteoclastogenesis independently of the receptor activator of NF-κB (RANK) ligand (RANKL), others demonstrated that TNF-mediated osteoclastogenesis needs permissive levels of RANKL. Here, we independently reveal that although TNF cannot stimulate osteoclastogenesis on bone slices, it can induce the formation of functional osteoclasts on bone slices in the presence of permissive levels of RANKL or from bone marrow macrophages (BMMs) pretreated by RANKL. TNF can still promote the formation of functional osteoclasts 2 days after transient RANKL pretreatment. These data have confirmed that TNF-mediated osteoclastogenesis requires priming of BMMs by RANKL. Moreover, we investigated the molecular mechanism underlying the dependence of TNF-mediated osteoclastogenesis on RANKL. RANK, the receptor for RANKL, contains an IVVY535–538 motif that has been shown to play a vital role in osteoclastogenesis by committing BMMs to the osteoclast lineage. We show that TNF-induced osteoclastogenesis depends on RANKL to commit BMMs to the osteoclast lineage and RANKL regulates the lineage commitment through the IVVY motif. Mechanistically, the IVVY motif controls the lineage commitment by reprogramming osteoclast genes into an inducible state in which they can be activated by TNF. Our findings not only provide important mechanistic insights into the action of RANKL in TNF-mediated osteoclastogenesis but also establish that the IVVY motif may serve as an attractive therapeutic target for bone loss in various bone disorders.

Bone
Gene Expression
Osteoclast Acidification
TRAF
Tumor Necrosis Factor (TNF)
IVVY Motif
RANKL
Osteoporosis

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*

This work was supported by National Institutes of Health Grant AR47830 through the NIAMS (to X. F.). This work was also supported by a National Institutes of Health/NIAMS graduate research supplement to AR47830 (to J. J.), a Within Our Reach innovative basic research grant from Research and Education Foundation of American College of Rheumatology (to X. F.), and National Institutes of Health/NIAMS University of Alabama at Birmingham Core Center for Basic Skeletal Research (CCBSR) Grant 5P30 AR046031.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.