Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes.
In vitro studies have shown that Rela/p65, a key subunit mediating NF-κB signalling, is involved in chondrogenic differentiation, cell survival and catabolic enzyme production. Here, we analyse in vivo functions of Rela in embryonic limbs and adult articular cartilage, and find that Rela protects chondrocytes from apoptosis through induction of anti-apoptotic genes including Pik3r1. During skeletal development, homozygous knockout of Rela leads to impaired growth through enhanced chondrocyte apoptosis, whereas heterozygous knockout of Rela does not alter growth. In articular cartilage, homozygous knockout of Rela at 7 weeks leads to marked acceleration of osteoarthritis through enhanced chondrocyte apoptosis, whereas heterozygous knockout of Rela results in suppression of osteoarthritis development through inhibition of catabolic gene expression. Haploinsufficiency or a low dose of an IKK inhibitor suppresses catabolic gene expression, but does not alter anti-apoptotic gene expression. The biphasic regulation of chondrocytes by Rela contributes to understanding the pathophysiology of osteoarthritis.
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Hiroshi
H
Kobayashi
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Song Ho
SH
Chang
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.|Department of Bone and Cartilage Regenerative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Daisuke
D
Mori
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Shozo
S
Itoh
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Makoto
M
Hirata
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.|Department of Bone and Cartilage Regenerative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Yoko
Y
Hosaka
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Yuki
Y
Taniguchi
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Keita
K
Okada
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Yoshifumi
Y
Mori
Department of Bone and Cartilage Regenerative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.|Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Fumiko
F
Yano
Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Ung-Il
UI
Chung
Department of Orthopaedic Surgery, Gifu University, 1-1 Yanagito, Gifu 501-1193, Japan.
Haruhiko
H
Akiyama
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.|Department of Spine Center, Tokyo Shinjuku Medical Center, Japan Community Health Care Organization, 5-1 Tsukudotyo, Shinjuku-ku, Tokyo 162-8543, Japan.
Hiroshi
H
Kawaguchi
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Sakae
S
Tanaka
Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.|Department of Bone and Cartilage Regenerative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Taku
T
Saito
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D020219:Chondrogenesis / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism
D051996:Transcription Factor RelA