Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes

Hiroshi Kobayashi, Song Ho Chang, Daisuke Mori, Shozo Itoh, Makoto Hirata, Yoko Hosaka, Yuki Taniguchi, Keita Okada, Yoshifumi Mori, Fumiko Yano, Ung-il Chung, Haruhiko Akiyama, Hiroshi Kawaguchi, Sakae Tanaka and Taku Saito ()
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Hiroshi Kobayashi: Faculty of Medicine, The University of Tokyo
Song Ho Chang: Faculty of Medicine, The University of Tokyo
Daisuke Mori: Faculty of Medicine, The University of Tokyo
Shozo Itoh: Faculty of Medicine, The University of Tokyo
Makoto Hirata: Faculty of Medicine, The University of Tokyo
Yoko Hosaka: Faculty of Medicine, The University of Tokyo
Yuki Taniguchi: Faculty of Medicine, The University of Tokyo
Keita Okada: Faculty of Medicine, The University of Tokyo
Yoshifumi Mori: Faculty of Medicine, The University of Tokyo
Fumiko Yano: Faculty of Medicine, The University of Tokyo
Ung-il Chung: Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo
Haruhiko Akiyama: Gifu University
Hiroshi Kawaguchi: Faculty of Medicine, The University of Tokyo
Sakae Tanaka: Faculty of Medicine, The University of Tokyo
Taku Saito: Faculty of Medicine, The University of Tokyo

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13336

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