The Genesis of Pain in Osteoarthritis: Inflammation as a Mediator of Osteoarthritis Pain

Abstract

Chronic pain is a substantial personal and societal burden worldwide. Osteoarthritis (OA) is one of the leading causes of chronic pain and is increasing in prevalence in accordance with a global aging population. In addition to affecting patients' physical lives, chronic pain also adversely affects patients' mental wellbeing. However, there remain no pharmacologic interventions to slow down the progression of OA and pain-alleviating therapies are largely unsuccessful. The presence of low-level inflammation in OA has been recognized for many years as a major pathogenic driver of joint damage. Inflammatory mechanisms can occur locally in joint tissues, such as the synovium, within the sensory nervous system, as well as systemically, caused by modifiable and unmodifiable factors. Understanding how inflammation may contribute to, and modify pain in OA will be instrumental in identifying new druggable targets for analgesic therapies. In this narrative review, we discuss recent insights into inflammatory mechanisms in OA pain. We discuss how local inflammation in the joint can contribute to mechanical sensitization and to the structural neuroplasticity of joint nociceptors, through pro-inflammatory factors such as nerve growth factor, cytokines, and chemokines. We consider the role of synovitis, and the amplifying mechanisms of neuroimmune interactions. We then explore emerging evidence around the role of neuroinflammation in the dorsal root ganglia and dorsal horn. Finally, we discuss how systemic inflammation associated with obesity may modify OA pain and suggest future research directions.

Keywords: Inflammation; Neuroinflammation; Nociceptors; Obesity; Osteoarthritis; Pain; Sensitization; Synovitis.

Figure 1:. Pain pathway and sites of inflammation and neuroplasticity in osteoarthritis.

Nociceptors (Aδ or C- fibers) detect stimuli in joint tissues, generating action potentials that are transmitted to the dorsal horn via the dorsal root ganglia (DRG), and to the brain via the central nervous system. Inflammatory states and neuroimmune interactions can occur at multiple points along this pathway. Structural neuroplasticity occurs in the OA joint, with free nerve endings sprouting in the subchondral bone and synovium. Joint nociceptors become sensitized by mediators released in OA pathology, including nerve growth factor (NGF), inflammatory cytokines and chemokines, and damage-associated molecular patterns (DAMPs). Immune cell infiltration in synovium and DRG can include macrophages, T- and B- lymphocytes, and mast cells, which can further amplify pain mechanisms. Neuroimmune interactions also occur in the DRG and the dorsal horn. Finally, factors such as obesity, age, and sex may alter systemic inflammatory inputs and modify OA pain.