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

Autor:	Catheline SE; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA., Bell RD; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA., Oluoch LS; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA., James MN; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA., Escalera-Rivera K; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA., Maynard RD; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA., Chang ME; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA., Dean C; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA., Botto E; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA., Ketz JP; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA., Boyce BF; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA., Zuscik MJ; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA.; Colorado Program for Musculoskeletal Research, Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Jonason JH; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.; Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, NY, USA.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2021 Sep 21; Vol. 14 (701), pp. eabf3535. Date of Electronic Publication: 2021 Sep 21.
DOI:	10.1126/scisignal.abf3535
Abstrakt:	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.
Databáze:	MEDLINE
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