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 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.
Published In/Presented At
Catheline, S. E., Bell, R. D., Oluoch, L. S., James, M. N., Escalera-Rivera, K., Maynard, R. D., Chang, M. E., Dean, C., Botto, E., Ketz, J. P., Boyce, B. F., Zuscik, M. J., & Jonason, J. H. (2021). IKKβ-NF-κB signaling in adult chondrocytes promotes the onset of age-related osteoarthritis in mice. Science signaling, 14(701), eabf3535. https://doi.org/10.1126/scisignal.abf3535
Medical Education | Medicine and Health Sciences
USF-LVHN SELECT Program, USF-LVHN SELECT Program Students