Novel model for age-related OA: ER stress in articular cartilage induces joint degeneration in mice

Abstract

Purpose: The lifetime risk of osteoarthritis (OA) to an individual is 45% and arthritis is the most common form of disability in the United States, making burden to the individual and society extensive. Age is the most important risk factor for adult-onset OA and ER stress response declines with age. Multiple lines of evidence indicates that pathological ER stress contributes to OA progression. In this work, tested the hypothesis that ER stress in articular chondrocytes alone is sufficient to drive joint degeneration in adult mice. In addition to ER stress, one group of mice was subjected to intense exercise to determine if mechanical stress would hasten joint degeneration. Methods: In the inducible-ER-stress mouse (I-ERS), ER stress was induced by expressing a mis-folded protein, mutant cartilage oligomeric matrix protein, in adult articular chondrocytes (from 16 to 20 weeks). There were three treatment groups: 1) control, 2) ER stress and 3) ER stress with treadmill exercise. Results: Four weeks of ER stress in healthy articular cartilage stimulated joint degeneration including increases matrix metalloproteinase (MMP) activity, inflammation, chondrocyte death, decreases in articular cartilage thickness and proteoglycan content and gait dysfunction, all of which are outcomes associated with OA. Intense exercise increased OARSI score, loss of proteoglycans, articular cartilage thinning and gait dysfunction suggesting that some aspects of OA are exacerbated by mechanical stress. Conclusions: OA is a multifactorial disease involving many risk factors including genetic factors, age, BMI, sex, joint injury and repetitive mechanical stress. Many models recapitulate post-traumatic OA and fewer models address age-related cellular stress. In these studies, physiology relevant ER chondrocyte stress was used to induce joint degeneration in previously healthy joints. This unique model of non-trauma adult-onset OA is useful for 1) defining the role of ER stress in the molecular pathology of OA, 2) for studying age-related OA and 3) testing prevention/treatment strategies and complements other OA models. Defining the role that ER stress plays in OA will lead to a better understand of this complex pathology and may offer new therapeutic strategies.