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

The genesis of age-related osteoarthritis: Proinflammatory signaling mediated by the transcription factor NF-κB is implicated in osteoarthritis (OA) induced by joint injury. However, aging is the most common cause of OA. In a mouse model of spontaneous, age-related OA of the knee, Catheline et al. found that NF-κB signaling in articular chondrocytes increased with age and correlated with the onset of joint degeneration. Activating NF-κB signaling in chondrocytes accelerated the onset of joint degeneration and promoted the expression of proinflammatory senescence-associated secretory phenotype (SASP) factors, which was further enhanced by the NF-κB subunit p65. In contrast, the p50 subunit inhibited the expression of SASP factors and cartilage degeneration. These findings implicate NF-κB signaling in the onset of age-related OA and demonstrate that p65 and p50 play distinct roles in this context. 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. [ABSTRACT FROM AUTHOR]

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