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.
Highlights
In vitro studies have shown that Rela/p65, a key subunit mediating nuclear factor kappa B (NF-kB) signalling, is involved in chondrogenic differentiation, cell survival and catabolic enzyme production
Homozygous knockout of Rela led to marked acceleration of OA through enhanced chondrocyte apoptosis, whereas heterozygous knockout of Rela resulted in suppression of OA development through inhibition of catabolic gene expression
The expression of Hif2a and Adamts[5] was suppressed in Col2a1-CreERT; Relafl/fl knee joints of both models (Fig. 4b). These findings indicate that Rela is a critical regulator of articular cartilage homeostasis, and its deficiency results in enhanced cartilage degradation caused by increased chondrocyte apoptosis, despite suppression of Adamts[5]
Summary
In vitro studies have shown that Rela/p65, a key subunit mediating NF-kB signalling, is involved in chondrogenic differentiation, cell survival and catabolic enzyme production. 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. The NF-kB family of transcription factors has essential roles in a wide range of biological processes such as immune responses, inflammation, proliferation, differentiation, cell survival and apoptosis[8,9,10] This family includes v-rel reticuloendotheliosis viral oncogene homologue A (Rela, known as p65), Relb, Rel, p105/p50 and p100/p52, each of which includes a Rel homology domain that mediates DNA binding and dimerization. Homozygous knockout of Rela led to marked acceleration of OA through enhanced chondrocyte apoptosis, whereas heterozygous knockout of Rela resulted in suppression of OA development through inhibition of catabolic gene expression. Our findings provide new insights into the regulation of articular cartilage homeostasis and OA development
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