Not long ago, said David Walsh MD, it was open to question whether pain sensitization was a significant factor in osteoarthritis (OA), or whether nociception—direct nerve stimulation—was the only important driver of pain.
"Now a line has been drawn," he added, speaking in a review presentation at the Seattle meeting of the Osteoarthritis Research Society International.
"You automatically think of inflammation in OA models that describe pain," said E. N. Blaney Davidson PhD, later in the same session. "Yet if you block nerve growth factor, you relieve the pain. Where does that come from?"
These speakers could now draw a fairly clear picture of how damaged synovium can send signals that drive pain well beyond the joint, how this can be identified, and its potential for new treatments.
During OA, the osteochondral junction is disrupted, new blood vessels form, accompanied by sensory nerve growth directly into cartilage and meniscus alongside the blood vessels, said Walsh, who is director of the Arthritis Pain Research UK Centre in Nottingham. Nerve growth factor (NGF) is released, which can alter neurotransmitter expression and augment peripheral sensory nerve function, leading to sensitization.
Two chief drivers of this process, NGF and calcitonin gene-related peptide (CGRP), may have potential for new kinds of pain relieving treatments in OA, he added. Already NGF blockers have shown some promise for OA pain in animal models and clinical trials.1
Sensitization, Caught in the Act
Functional MRI (fMRI) studies have now documented changes in the way that the brain works in OA patients with sensitization, and they distinguish it from the pain that fibromyalgia patients experience. Rheumatologist Jordi Monfort MD of the Hospital del Mar in Barcelona described an fMRI study that compared responses to pressure and heat stimuli between 30 healthy controls and 60 OA patients, half of whom showed sensitization of pain according to clinical criteria.2
"This is not a black and white, but a gray and white, situation," Monfort remarked. Only 19 of the 60 patients fulfilled all criteria for sensitization.
Patients with clinically defined sensitization showed responses in anterior regions of the brain in response to pressure on the tibia remote from the affected knee that were clearly different from those in either normal controls or OA patients without sensitization. But their responses to a heat stimulus on the arm were not notably different at the knee joint.
Areas of the brain that lighted up during the pressure tests were also different from the regions of the frontal cortex triggered in fibromyalgia patients during recent fMRI studies by another member of the team, Jesus Pujol MD.3
Applying pressure to a nonpainful area of the tibia quite far from the affected knee is a good test to discriminate sensitized patients, Monfort said.
Exactly What Damaged Cartilage is Doing
At Radboud University in the Netherlands, where Davidson is a postdoctoral researcher, she and her coworkers have been defining the biochemical pathways that trigger damaged chondrocytes to release NGF, setting off the sensitization process.
"Cartilage is usually packed with TGF [transforming growth factor]-ß," she said. In immortalized cell lines, in isolated bovine cartilage explants, and in cultured chondrocytes from OA patients, she reported, TGF-ß triggers the release of NGF. But how does it do so?
The process is entirely dependent on two particular subtypes of the SMAD family of proteins, she said. (The acronym combines the names of two proteins originally found in Drosophila and C. elegans.) It is blocked completely by inhibiting phosphorylation of these proteins.
Why should there be nerve growth factor, asked someone in the audience, in cartilage that's normally aneural? That's only our name for the protein, Davidson replied. It probably has unrecognized effects beyond the nerves.
"So many people are working on this," she added, "that we'll probably have answers in the near future."
1.Ishikawa G, Koya Y, Tanaka H, Nagakura Y. Long-term analgesic effect of a single dose of anti-NGF antibody on pain during motion without notable suppression of joint edema and lesion in a rat model of osteoarthritis. Osteoarthritis Cartilage. 2015 Feb 9. doi: 10.1016/j.joca.2015.02.002. [Epub ahead of print]
2. Arendt-Nielsen L, Nie H, Laursen MB, et al. Sensitization in patients with painful knee osteoarthritis. Pain. 2010; 149:573-81. doi: 10.1016/j.pain.2010.04.003. Epub 2010 Apr 24.
3. Pujol J, Macià D, Garcia-Fontanals A, et al. The contribution of sensory system functional connectivity reduction to clinical pain in fibromyalgia. Pain. 2014;155:1492-503. doi: 10.1016/j.pain.2014.04.028. Epub 2014 May 2.