Osteoarthritis Pain

Abstract

Joint pain is the hallmark symptom of osteoarthritis (OA) and the main reason for patients to seek medical assistance. OA pain greatly contributes to functional limitations of joints and reduced quality of life. Although several pain-relieving medications are available for OA treatment, the current intervention strategy for OA pain cannot provide satisfactory pain relief, and the chronic use of the drugs for pain management is often associated with significant side effects and toxicities. These observations suggest that the mechanisms of OA-related pain remain undefined. The current review mainly focuses on the characteristics and mechanisms of OA pain. We evaluate pathways associated with OA pain, such as nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA), calcitonin gene-related peptide (CGRP), C-C motif chemokine ligands 2 (CCL2)/chemokine receptor 2 (CCR2) and tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, and the Wnt/β-catenin signaling pathway. In addition, animal models currently used for OA pain studies and emerging preclinical studies are discussed. Understanding the multifactorial components contributing to OA pain could provide novel insights into the development of more specific and effective drugs for OA pain management.

Keywords: CCL2/CCR2; CGRP; IL-1β; NGF/TrkA; NLRP3; TNF-α; osteoarthritis; pain; β-catenin.

Figure 1

Overview of OA pain transmission and associated signaling pathways. (A). Peripheral terminals of nociceptors contain a variety of transducing channels that convert harmful stimuli into electrical activity, and thus action potentials in nociceptors that travel back to the central nervous system. In the event of painful stimulatory factors such as NGF, TNFα, and IL-1β acting on their receptors, ion channels such as TRPV1 and Nav1.7 are activated to transmit a pain signal and CCL2 expression, and are upregulated to recruit macrophage. (B). Cell bodies of nociceptors are located in the dorsal root ganglion. Increased expression of NLRP3, Wnt/β-catenin, CCL2, Wnt5a in DRG in chronic pain states. (C). Nociceptive signals are transmitted at a central synapse in the spinal cord through the release of a variety of excitatory neurotransmitters, such as glutamate, CGRP, or substance P, which could excite second-order nociceptive projection neurons. NLRP3, Wnt/β-catenin, CCL2, and Wnt5a expression is upregulated in presynaptic neurons.