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

Abstract

Pain arising from musculoskeletal disorders such as arthritis is one of the leading causes of disability. Whereas the past 20-years has seen an increase in targeted therapies for rheumatoid arthritis (RA), other arthritis conditions, especially osteoarthritis, remain poorly treated. Although modulation of central pain pathways occurs in chronic arthritis, multiple lines of evidence indicate that peripherally driven pain is important in arthritic pain. To understand the peripheral mechanisms of arthritic pain, various in vitro and in vivo models have been developed, largely in rodents. Although rodent models provide numerous advantages for studying arthritis pathogenesis and treatment, the anatomy and biomechanics of rodent joints differ considerably to those of humans. By contrast, the anatomy and biomechanics of joints in larger animals, such as dogs, show greater similarity to human joints and thus studying them can provide novel insight for arthritis research. The purpose of this article is firstly to review models of arthritis and behavioral outcomes commonly used in large animals. Secondly, we review the existing in vitro models and assays used to study arthritic pain, primarily in rodents, and discuss the potential for adopting these strategies, as well as likely limitations, in large animals. We believe that exploring peripheral mechanisms of arthritic pain in vitro in large animals has the potential to reduce the veterinary burden of arthritis in commonly afflicted species like dogs, as well as to improve translatability of pain research into the clinic.

Keywords: Arthritis; In vitro; Large animals; Pain models; Sensory neurons.

Fig. 1

Schematic diagram emphasizing the potential for large animals in translational arthritic pain research. Large animals have similar sized knee and cartilage thickness compared to humans (McCoy, 2015, Proffen et al., 2012), longer lifespan (Carey and Judge, 2000), and larger DRG neurons compared to rodents (brighter neurons indicate CGRP immunoreactivity, Scale bar = 50 um). Unlike rodents which are prey species (Rice et al., 2008), large animals are less likely to hide pain behavior and are susceptible to naturally-occurring arthritis (mostly OA) similar to humans (K. L. Anderson et al., 2018; Centers for Disease Control and Prevention, 2015, Slater, 2016).

Fig. 2

Pictorial representation of existing in vitro models to study and assess mechanisms of arthritic pain.