Abstract
IntroductionAlthough the prevalence of arthritis dramatically increases with age, the great majority of preclinical studies concerning the mechanisms that drive arthritic joint pain have been performed in young animals. One mechanism hypothesized to contribute to arthritic pain is ectopic nerve sprouting; however, neuroplasticity is generally thought to be greater in young versus old nerves. Here we explore whether sensory and sympathetic nerve fibers can undergo a significant ectopic nerve remodeling in the painful arthritic knee joint of geriatric mice.MethodsVehicle (saline) or complete Freund's adjuvant (CFA) was injected into the knee joint of 27- to 29-month-old female mice. Pain behaviors, macrophage infiltration, neovascularization, and the sprouting of sensory and sympathetic nerve fibers were then assessed 28 days later, when significant knee-joint pain was present. Knee joints were processed for immunohistochemistry by using antibodies raised against CD68 (monocytes/macrophages), PECAM (endothelial cells), calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kDa (NF200; sensory nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), and growth-associated protein 43 (GAP43; nerve fibers undergoing sprouting).ResultsAt 4 weeks after initial injection, CFA-injected mice displayed robust pain-related behaviors (which included flinching, guarding, impaired limb use, and reduced weight bearing), whereas animals injected with vehicle alone displayed no significant pain-related behaviors. Similarly, in the CFA-injected knee joint, but not in the vehicle-injected knee joint, a remarkable increase was noted in the number of CD68+ macrophages, density of PECAM+ blood vessels, and density and formation of neuroma-like structures by CGRP+, NF200+, and TH+ nerve fibers in the synovium and periosteum.ConclusionsSensory and sympathetic nerve fibers that innervate the aged knee joint clearly maintain the capacity for robust nerve sprouting and formation of neuroma-like structures after inflammation/injury. Understanding the factors that drive this neuroplasticity, whether this pathologic reorganization of nerve fibers contributes to chronic joint pain, and how the phenotype of sensory and sympathetic nerves changes with age may provide pharmacologic insight and targets for better controlling aging-related joint pain.
Highlights
The prevalence of arthritis dramatically increases with age, the great majority of preclinical studies concerning the mechanisms that drive arthritic joint pain have been performed in young animals
Assessment of arthritic joint pain-related behaviors, including spontaneous guarding and flinching, and limbuse analysis of the hindlimb was performed on day 28 after initial intraarticular complete Freund’s adjuvant (CFA) injection, and dynamic weight-bearing analysis was performed on day 23 after initial intraarticular CFA injection (Figure 1)
In this study, CFA-induced inflammation of the geriatric knee joint resulted in significant pain, robust nerve sprouting, and formation of neuroma-like structures in the synovium and periosteum by both sensory (CGRP+ and neurofilament 200 kDa (NF200)+) and sympathetic (TH+) nerve fibers
Summary
The prevalence of arthritis dramatically increases with age, the great majority of preclinical studies concerning the mechanisms that drive arthritic joint pain have been performed in young animals. It is believed that spontaneous arthritic pain (joint pain at rest) and movementevoked pain are largely driven by joint injury and/or inflammation, which induces both a peripheral sensitization (an increase of sensitivity of nociceptive primary afferent neurons) and central sensitization (hyperexcitability of neurons conveying nociceptive information in the central nervous system (CNS)) (see [1,18,19,20] for review) It remains largely unknown why a relatively poor correlation exists in OA between the radiologic signs of arthritis (for example, joint-space narrowing, erosive changes) and the severity of arthritic pain [1,2,21] as well as the specific mechanisms that drive spontaneous versus movement-evoked arthritic joint pain in OA. This dissociation between pain and disease progression is observed in RA, as even therapies such as tumor necrosis factor-a inhibitors that can be quite effective at decreasing the severity of joint inflammation/swelling in RA are generally much less efficacious at attenuating RA pain [22]
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