IKKβ-NF-κB signaling in adult chondrocytes promotes the onset of age-related osteoarthritis in mice

Canonical nuclear factor κB (NF-κB) signaling mediated by homo- and heterodimers of the NF-κB subunits p65 (RELA) and p50 (NFKB1) is associated with age-related pathologies and with disease progression in posttraumatic models of osteoarthritis (OA). Here, we established that NF-κB signaling in artic...

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Bibliographic Details
Published in:	Science signaling Vol. 14; no. 701; p. eabf3535
Main Authors:	Catheline, Sarah E, Bell, Richard D, Oluoch, Luke S, James, M Nick, Escalera-Rivera, Katherine, Maynard, Robert D, Chang, Martin E, Dean, Christopher, Botto, Elizabeth, Ketz, John P, Boyce, Brendan F, Zuscik, Michael J, Jonason, Jennifer H
Format:	Journal Article
Language:	English
Published:	United States 21-09-2021
Subjects:	Animals Chondrocytes - metabolism I-kappa B Kinase - genetics I-kappa B Kinase - metabolism Mice NF-kappa B - genetics NF-kappa B - metabolism Osteoarthritis - genetics Signal Transduction
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Summary:	Canonical nuclear factor κB (NF-κB) signaling mediated by homo- and heterodimers of the NF-κB subunits p65 (RELA) and p50 (NFKB1) is associated with age-related pathologies and with disease progression in posttraumatic models of osteoarthritis (OA). Here, we established that NF-κB signaling in articular chondrocytes increased with age, concomitant with the onset of spontaneous OA in wild-type mice. Chondrocyte-specific expression of a constitutively active form of inhibitor of κB kinase β (IKKβ) in young adult mice accelerated the onset of the OA-like phenotype observed in aging wild-type mice, including degenerative changes in the articular cartilage, synovium, and menisci. Both in vitro and in vivo, chondrocytes expressing activated IKKβ had a proinflammatory secretory phenotype characterized by markers typically associated with the senescence-associated secretory phenotype (SASP). Expression of these factors was differentially regulated by p65, which contains a transactivation domain, and p50, which does not. Whereas the loss of p65 blocked the induction of genes encoding SASP factors in chondrogenic cells treated with interleukin-1β (IL-1β) in vitro, the loss of p50 enhanced the IL-1β–induced expression of some SASP factors. The loss of p50 further exacerbated cartilage degeneration in mice with chondrocyte-specific IKKβ activation. Overall, our data reveal that IKKβ-mediated activation of p65 can promote OA onset and that p50 may limit cartilage degeneration in settings of joint inflammation including advanced age.
ISSN:	1937-9145
DOI:	10.1126/scisignal.abf3535