NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1.
Postmenopausal osteoporosis and rheumatoid joint destruction result from increased osteoclast formation and bone resorption induced by receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor (TNF). Osteoclast formation induced by these cytokines requires NF-kappaB p50 and p52, c-Fos, and NFATc1 expression in osteoclast precursors. c-Fos induces NFATc1, but the relationship between NF-kappaB and these other transcription factors in osteoclastogenesis remains poorly understood. We report that RANKL and TNF can induce osteoclast formation directly from NF-kappaB p50/p52 double knockout (dKO) osteoclast precursors when either c-Fos or NFATc1 is expressed. RANKL- or TNF-induced c-Fos up-regulation and activation are abolished in dKO cells and in wild-type cells treated with an NF-kappaB inhibitor. c-Fos expression requires concomitant RANKL or TNF treatment to induce NFATc1 activation in the dKO cells. Furthermore, c-Fos expression increases the number and resorptive capacity of wild-type osteoclasts induced by TNF in vitro. We conclude that NF-kappaB controls early osteoclast differentiation from precursors induced directly by RANKL and TNF, leading to activation of c-Fos followed by NFATc1. Inhibition of NF-kappaB should prevent RANKL- and TNF-induced bone resorption.
Yamashita
Teruhito
T
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642.
Yao
Zhenqiang
Z
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642.
Li
Fang
F
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642.
Zhang
Qian
Q
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642.
Badell
I Raul
IR
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642.
Schwarz
Edward M
EM
Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York 14642.
Takeshita
Sunao
S
Department of Bone and Joint Disease, Research Institute, National Center for Geriatrics and Gerontology, Obu 474-8522, Japan.
Wagner
Erwin F
EF
Research Institute of Molecular Pathology, A-1030 Vienna, Austria.
Noda
Masaki
M
Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
Matsuo
Koichi
K
Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Xing
Lianping
L
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York 14642.
Boyce
Brendan F
BF
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York 14642. Electronic address: Brendan_Boyce@urmc.rochester.edu.
D000818:Animals; D002454:Cell Differentiation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000502:physiology*; D052003:NF-kappa B p52 Subunit / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology*; D010010:Osteoclasts / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D050778:NFATC Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha