IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology

Abstract

Osteoarthritis is a joint disease characterized by a poorly-defined inflammatory response that does not encompass a massive immune cell infiltration yet contributes to cartilage degradation and loss of joint mobility, suggesting a chondrocyte intrinsic inflammatory response. Using primary chondrocytes from joints of osteoarthritic mice and patients, we first show that these cells express ample pro-inflammatory markers and RANKL in an NF-κB dependent manner. The inflammatory phenotype of chondrocytes was recapitulated by exposure of chondrocytes to IL-1β and bone particles, which were used to model bone matrix breakdown products revealed to be present in synovial fluid of OA patients, albeit their role was not defined. We further show that bone particles and IL-1β can promote senescent and apoptotic changes in primary chondrocytes due to oxidative stress from various cellular sources such as the mitochondria. Finally, we provide evidence that inflammation, oxidative stress and senescence converge upon IκB-ζ, the principal mediator downstream of NF-κB, which regulates expression of RANKL, inflammatory, catabolic, and SASP genes. Overall, this work highlights the capacity and mechanisms by which inflammatory cues, primarily joint degradation products, i.e., bone matrix particles in concert with IL-1β in the joint microenvironment, program chondrocytes into an “inflammatory phenotype” which inflects local tissue damage.

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Funding

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)(AR049192)

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Shriners Hospitals for Children(85160)

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)