Great Debate: Joint tissue impacts nerves, or vice versa, in OA
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This year’s iteration of the Great Debate at the OARSI 2021 World Congress centered on the role of nerves in pain, functionality and pathogenesis of osteoarthritis.
Stefan Lohmander, MD, PhD, senior professor of orthopedics at Lund University in Sweden, and Anne-Marie Malfait, MD, PhD, The George W. Stuppy, MD, Chair of Arthritis at Rush Medical College in Chicago, debated whether nerves impact joint tissue or whether joint tissue impacts nerves as patients experience the pain and functionality outcomes associated with OA.
“Pain is a driver of functional limitation of OA burden,” Lohmander said. “Understanding of how OA drives pain and neural responses is very incomplete.”
One reason for that incomplete understanding is that the tools used to measure pain are also incomplete, if not imperfect. This is largely because pain is a “personal experience” based on biological, psychological and social factors, according to Lohmander.
Another reason pertains to actually defining osteoarthritis itself. “Joint pain is the primary symptom,” Lohmander said. “Structural damage is the ‘disease.’”
He then raised the key question: “When speaking about joint pain in OA, are we speaking of symptoms or the disease or both?”
Understanding the “wheres” and the “whys” of joint pain in OA may shed light on the issues at hand, according to Lohmander. Pain can originate in the muscles, bone, synovial tissue or meniscus, among other places.
Looking deeper, Lohmander noted that where inflammatory mediator NGF channels can be found, there are also nerve endings. “We can find nerve endings in the cartilage, even the non-calcified cartilage,” he said.
That begins to answer the question of where, but Lohmander offered several explanations as to why OA causes pain. “Mechanical injury of cartilage and other tissue leads to inflammatory responses and downstream activation of chondrocytes,” he said.
In addition, nociceptor neurons may activate toll-like receptors. Another explanation is that aging tissue activates senescent cells and interleukin-1. “There is no shortage of alternative pathways in which pain could be elicited in the joint,” Lohmander said.
He added that there is a “wide array” of signals that could eventually result in pain signaling and sensitization of these nerve endings.
“But the complexity doesn’t end there,” he said, noting complexity in the dorsal root ganglion, the spinal cord and “further onward and upward into the brain where we experience the pain response.”
In short, the signaling is going from the joint to the brain, Lohmander concluded. He suggested that the nervous system is reacting to damage that has already been incurred in the joint and signaling the brain to feel pain.
For her argument, Malfait opened with the hypothesis that it is impossible to have pain without the nerves in the joint. She noted that both sensory and sympathetic nerves can be found in any joint.
To the question of how these nerves affect OA, she quoted from the rheumatologist Jason McDougal, who noted that an “elaborate nervous system meanders” through the joint, allowing for response to injuries or overloading. With this response, the body is alerted and then responds by altering the gate to “minimize catastrophic loading.”
It is for this reason Malfait offered her central argument: “The nervous system is key to prevent breakdown of the osteoarthritic knee.”
A large body of animal data has shown that denervation has promoted age-associated osteoarthritis, including in rats, mice and rabbits. “Denervation that has occurred here has contributed to the vulnerability of joints to OA,” she said.
For Malfait, the issue of joint pain in OA is “not just about nociceptors.” As humans age, there is “marked decline in proprioception and vibratory perception,” even when OA is not present.
“We have been talking about joint pain and neurons,” Malfait said. “What the joint is after here is to maintain homeostasis in the face of aging and loading.”
Malfait argued that while the innate and adaptive immune systems neutralize harmful stimuli and oversee repairs, the nervous system should not be left out of the equation. “Neurons are really in that same business,” she said. “They actually do that much faster, and at a magnitude faster than immune system because they use an electric signal as a mode of transduction.
“Healthy nerves are really important to preserve healthy joints,” Malfait concluded.
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Lohmander S, Malfait AM. Debate: Nerve Impacting Joint tissues or Joint Tissues Impacting on Nerves. Presented at: OARSI 2021 World Congress on Osteoarthritis; April 29-May 1 (virtual meeting).
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