Models of Osteoarthritis: Relevance and New Insights

Abstract

Osteoarthritis (OA) is a progressive and disabling musculoskeletal disease affecting millions of people and resulting in major healthcare costs worldwide. It is the most common form of arthritis, characterised by degradation of the articular cartilage, formation of osteophytes, subchondral sclerosis, synovial inflammation and ultimate loss of joint function. Understanding the pathogenesis of OA and its multifactorial aetiology will lead to the development of effective treatments, which are currently lacking. Two-dimensional (2D) in vitro tissue models of OA allow affordable, high-throughput analysis and stringent control over specific variables. However, they are linear in fashion and are not representative of physiological conditions. Recent in vitro studies have adopted three-dimensional (3D) tissue models of OA, which retain the advantages of 2D models and are able to mimic physiological conditions, thereby allowing investigation of additional variables including interactions between the cells and their surrounding extracellular matrix. Numerous spontaneous and induced animal models are used to reproduce the onset and monitor the progression of OA based on the aetiology under investigation. This therefore allows elucidation of the pathogenesis of OA and will ultimately enable the development of novel and specific therapeutic interventions. This review summarises the current understanding of in vitro and in vivo OA models in the context of disease pathophysiology, classification and relevance, thus providing new insights and directions for OA research.

Characterisation of growth plate dynamics in murine models of osteoarthritis

“…Taken together, our studies indicate that accelerated GP chondrocyte dynamics and bridging events may contribute to OA pathology in both surgical and loading C57BL/6 mouse OA models and that similar osteoarthritic pathological changes happen in different in vivo models of secondary (post-traumatic) OA 18 through inducing direct (DMM) or indirect (mechanical loading) injuries to the joints. The GP bony bridging analysis may signify accelerated cartilage-bone transition and growth cessation in these affected bones advancing our understanding of GP closure mechanisms and how these contribute to the health of the joint.…”

EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis

“…MMX, which is one of the most commonly used surgical model in mice 20 , offer also a good tool to understand why in humans, 50% of people who undergo a meniscectomy develop OA within 20 years of the date of the surgery 16 , 20 . Other experimental OA models exist, such as chemically induced model (monoiodoacetate or collagenase intraarticular injection), loading model, or naturally occurring (STR/ort mice) 21 . It will be pertinent in the future to test the efficiency of targeting EZH2 in these other models to evaluate whether this strategy may be useful for all OA patients whatever their clinical phenotypes (post-traumatic, metabolic, ageing, genetic and pain phenotypes), or only for patients having post-traumatic OA.…”

Peripheral mechanisms of arthritic pain: A proposal to leverage large animals for in vitro studies

“…Experimentally, OA can be induced by numerous methods, including: injection of chemical substances like monosodium iodoacetate (MIA), surgical damage to the joint, joint destabilization, and by impact trauma on the joint surface. Among chemically induced OA models, MIA injection into the joint is most commonly used and acts by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH, an enzyme involved in glycolysis), which leads to the death of chondrocytes and has proven useful for understanding OA pain mechanisms ( Combe et al, 2004 , Samvelyan et al, 2020 ). The MIA model of OA has been successfully induced in pigs and dogs, as evidenced by both lameness and structural changes in the joints being observed in these animals following MIA administration ( Budsberg et al, 2019 , Uilenreef et al, 2019 ).…”

“…Currently, these experimental models are largely conducted in rodents, due to them being amenable to genetic manipulation, having a short reproduction time and ease/cost of housing. These in vivo rodent models of arthritis and the behavioral outcomes measured in such models have been extensively reviewed ( Gregory et al, 2013 , Krock et al, 2018 , Kuyinu et al, 2016 , Samvelyan et al, 2020 ) and hence this review will focus on in vivo models of arthritis in large animals. However, a review of in vitro models and assays for dissecting arthritic pain in the periphery is lacking, a gap this review will address in rodents and in large animals, and conclude that leveraging large animals for in vitro studies could potentially accelerate the field of arthritic pain research.…”