title: Molecular basis of requirement of receptor activator of nuclear factor κB signaling for interleukin 1-mediated osteoclastogenesis.
abstract: IL-1, a proinflammatory cytokine, is implicated in bone loss in various pathological conditions by promoting osteoclast formation, survival, and function. Although IL-1 alone can sufficiently prolong osteoclast survival and activate osteoclast function, IL-1-mediated osteoclastogenesis requires the receptor activator of NF-κB (RANK) ligand (RANKL). However, the molecular basis of the dependence of IL-1-mediated osteoclastogenesis on RANKL is not fully understood. Here we show that although IL-1 cannot activate the expression of the osteoclast genes encoding matrix metalloproteinase 9, cathepsin K, tartrate-resistant acid phosphatase, and carbonic anhydrase II in bone marrow macrophages (BMMs), RANKL renders these osteoclast genes responsive to IL-1. We further demonstrate that IL-1 alone fails to induce the expression of nuclear factor of activated T cell cytoplasmic 1 (NFATc1), a master transcriptional regulator of osteoclastogenesis), in BMMs but can up-regulate its expression in the presence of permissive levels of RANKL or with RANKL pretreatment. The RANK IVVY motif, which has been previously shown to commit BMMs to the osteoclast lineage in RANKL- and TNF α-mediated osteoclastogenesis, also plays a crucial role in IL-1-mediated osteoclastogenesis by changing the four osteoclast marker and NFATc1 genes to an IL-1-inducible state. Finally, we show that MyD88, a known critical component of the IL-1 receptor I signaling pathway, plays a crucial role in IL-1-mediated osteoclastogenesis from RANKL-primed BMMs by up-regulating the expression of the osteoclast marker and NFATc1 genes. This study reveals a novel mechanism of IL-1-mediated osteoclastogenesis and supports the promising potential of the IVVY motif to serve as a therapeutic target for inflammatory bone loss.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Jules
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Jason W
authors.initials: JW
authors.lastname: Ashley
authors.forename: Shi
authors.initials: S
authors.lastname: Wei
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Shi
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Liu
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Michalek
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism / Q000494:pharmacology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007375:Interleukin-1; D053594:Myeloid Differentiation Factor 88; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D049452:Green Fluorescent Proteins