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.
Highlights
Osteoarthritis (OA) is the most prevalent joint disease worldwide, causing pain, decreased quality of life, and reduced productivity in those affected by this condition.[1,2,3] current OA treatment regimens do not contain any disease-modifying therapeutics but instead rely upon symptom-reducing compounds, though promising advancements have been made in the field
We show that macrophage-chondrocyte co-cultures treated with IL-1β had increased tartrate-resistant acid phosphatase (TRAP) positive cells compared to those without IL-1β in the presence of permissive levels of exogenous Rankl, which was added to prime commitment of monocyte/macrophage into OC precursors (Fig. 2a, b)
We identified in vivo that meniscal ligamentous injury (MLI) joints had higher expression levels of cleaved caspase-3, which is an apoptosis marker, as well as increased staining for γ-H2AX, which is a marker of DNA damage that can be associated with oxidative stress, suggesting that these in vitro findings likely extend in vivo
Summary
Osteoarthritis (OA) is the most prevalent joint disease worldwide, causing pain, decreased quality of life, and reduced productivity in those affected by this condition.[1,2,3] current OA treatment regimens do not contain any disease-modifying therapeutics but instead rely upon symptom-reducing compounds, though promising advancements have been made in the field. The response of articular chondrocytes to these inflammatory stimuli contributes to the development and progression of OA by promoting the expression of catabolic factors that break down ECM that normally gives cartilage its joint protective properties. The role of senescent chondrocytes in articular cartilage as a source of pro-inflammatory factors has been highlighted in recent years,[10,11,12,13] primarily due to the production of senescence-associated secretory phenotype (SASP) factors that are pathogenic. This can lead to a positive feedback cycle of chronic inflammation through autocrine and paracrine effects. It is predicted that prevention of senescence or reduction of SASP expression from senescent chondrocytes, which overlaps with the inflammatory response, may be important for reducing the chronic inflammatory state of OA joints and prevent OA progression.[18]
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