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Science Daily are reporting: Pain Is Not A Symptom Of Arthritis, Pain Causes Arthritis, Study Shows
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Pain is more than a symptom of osteoarthritis, it is an inherent and damaging part of the disease itself, according to a new study. (Credit: iStockphoto/Sebastian Meckelmann)ScienceDaily (Sep. 29, 2008) — Pain is more than a symptom of osteoarthritis, it is an inherent and damaging part of the disease itself, according to a study just published in journal Arthritis and Rheumatism. More specifically, the study revealed that pain signals originating in arthritic joints, and the biochemical processing of those signals as they reach the spinal cord, worsen and expand arthritis.
In addition, researchers found that nerve pathways carrying pain signals transfer inflammation from arthritic joints to the spine and back again, causing disease at both ends.
Technically, pain is a patient's conscious realization of discomfort. Before that can happen, however, information must be carried along nerve cell pathways from say an injured knee to the pain processing centers in dorsal horns of the spinal cord, a process called nociception. The current study provides strong evidence that two-way, nociceptive "crosstalk" may first enable joint arthritis to transmit inflammation into the spinal cord and brain, and then to spread through the central nervous system (CNS) from one joint to another.
Furthermore, if joint arthritis can cause neuro-inflammation, it could have a role in conditions like Alzheimer's disease, dementia and multiple sclerosis. Armed with the results, researchers have identified likely drug targets that could interfere with key inflammatory receptors on sensory nerve cells as a new way to treat osteoarthritis (OA), which destroys joint cartilage in 21 million Americans. The most common form of arthritis, OA eventually brings deformity and severe pain as patients loose the protective cushion between bones in weight-bearing joints like knees and hips.
"Until relatively recently, osteoarthritis was believed to be due solely to wear and tear, and inevitable part of aging," said Stephanos Kyrkanides, D.D.S., Ph.D., associate professor of Dentistry at the University of Rochester Medical Center. "Recent studies have revealed, however, that specific biochemical changes contribute to the disease, changes that might be reversed by precision-designed drugs. Our study provides the first solid proof that some of those changes are related to pain processing, and suggests the mechanisms behind the effect," said Kyrkanides, whose work on genetics in dentistry led to broader applications. The common ground between arthritis and dentistry: the jaw joint is a common site of arthritic pain.
Study Details:
Past studies have shown that specific nerve pathways along which pain signals travel repeatedly become more sensitive to pain signals with each use. This may be a part of ancient survival skill (if that hurt once, don't do it again). Secondly, pain has long been associated with inflammation (swelling and fever).
In fact, past research has shown that the same chemicals that cause inflammation also cause the sensation of pain and hyper-sensitivity to pain if injected. Kyrkanides' work centers around one such pro-inflammatory, signaling chemical called Interleukin 1-beta (IL-1β), which helps to ramp up the bodies attack on an infection.
Specifically, Kyrkanides' team genetically engineered a mouse where they could turn up on command the production of IL-1β in the jaw joint, a common site of arthritis. Experiments showed for the first time that turning up IL-1β in a peripheral joint caused higher levels of IL-1β to be produced in the dorsal horns of the spinal cord as well.
Using a second, even more elaborately engineered mouse model, the team also demonstrated for the first time that creating higher levels of IL-1β in cells called astrocytes in the spinal cord caused more osteoarthritic symptoms in joints. Past studies had shown astrocytes, non-nerve cells (glia) in the central nervous system that provide support for the spinal cord and brain, also serve as the immune cells of CNS organs. Among other things, they release cytokines like IL-1β to fight disease when triggered. The same cytokines released from CNS glia may also be released from neurons in joints, possibly explaining how crosstalk carries pain, inflammation and hyper-sensitivity back and forth.
In both mouse models, experimental techniques that shut down IL-1β signaling reversed the crosstalk effects. Specifically, researchers used a molecule, IL-1RA, known to inhibit the ability of IL-1β to link up with its receptors on nerve cells. Existing drugs (e.g. Kineret® (anakinra), made by Amgen and indicated for rheumatoid arthritis) act like IL-1RA to block the ability IL-1β to send a pain signal through its specific nerve cell receptor, and Kyrkanides' group is exploring a new use for them as osteoarthritis treatment.
The implications of this process go further, however, because the cells surrounding sensory nerve cell pathways too can be affected by crosstalk. If 10 astrocytes secrete IL-1β in response to a pain impulse, Kyrkanides said, perhaps 1,000 adjacent cells will be affected, greatly expanding the field of inflammation. Spinal cord astrocytes are surrounded by sensory nerve cells that connect to other areas of the periphery, further expanding the effect. According to Kyrkanides' model, increased inflammation by in the central nervous system can then send signals back down the nerve pathways to the joints, causing the release of inflammatory factors there.
Among the proposed, inflammatory factors is calcitonin gene related peptide (CGRP). The team observed higher levels calcitonin-gene related peptide (CGRP) production in primary sensory fibers in the same regions where IL-1β levels rose, and the release of IL-1β by sensory neurons may cause the release of CGRP in joints. Past studies in Kyrkanides reveal that CGRP can also cause cartilage-producing cells (chondrocytes) to mature too quickly and die, a hallmark of osteoarthritis.
Joining Kyrkanides in the publication from the University of Rochester School of Medicine and Dentistry were co-authors M. Kerry O'Banion, M.D., Ph.D., Ross Tallents, D.D.S., J. Edward Puzas, Ph.D. and Sabine M. Brouxhon, M.D. Paolo Fiorentino was a student contributor and Jennie Miller was involved as Kyrkanides' technical associate. Maria Piancino, led a collaborative effort at the University of Torino, Italy. This work was supported in part by grants from the National Institutes of Health.
"Our study results confirm that joints can export inflammation in the form of higher IL-1β along sensory nerve pathways to the spinal cord, and that higher IL-1β inflammation in the spinal cord is sufficient in itself to create osteoarthritis in peripheral joints," Kyrkanides said. "We believe this to be a vitally important process contributing to orthopaedic and neurological diseases in which inflammation is a factor."
Objective
Pain from arthritis has been associated with peripheral sensitization of primary sensory afferents and the development of inflammation at the dorsal horns. This study was undertaken to determine whether the role of spinal interleukin-1 (IL-1) in central processing of pain is important in the development of arthritis.
Methods
Col1-IL-1XAT mice and GFAP-IL-1XAT mice were injected with the feline immunodeficiency virus (FIV) (Cre) vector in the right and left temporomandibular joints (TMJs), or in the cisterna magna, respectively, to induce IL-1 expression in the dorsal horns of the spinal horn. To inhibit intrathecal IL-1 receptor type I (IL-1RI) signaling, FIV(IL-1Ra) vector was injected into the cisterna magna of Col1-IL-1XAT mice. The effects of IL-1RI receptor inhibition in GFAP-IL-1XAT mice were studied in the GFAP-IL-1XAT-IL-1RI-/- compound mouse model. Neuroinflammatory, sensory, and behavioral changes were evaluated in conjunction with arthritic changes in the TMJ, assessed by histopathologic and immunohistochemical analyses.
Results
Induction of an osteoarthritis-like condition in the TMJ in the Col1-IL-1XAT mouse model resulted in up-regulation of murine IL-1 at the dorsal horns. Moreover, intrathecal inhibition of IL-1RI in Col1-IL-1XAT mice with arthritis led to amelioration of joint pathology and attenuation of the attendant joint pain. Overexpression of spinal IL-1 in the recently developed GFAP-IL-1XAT somatic mosaic model of neuroinflammation led to development of arthritis-like pathology accompanied by increased pain-like behavior.
Conclusion
Our results indicate that joint pathology and pain are dependent on spinal IL-1, and suggest the presence of a bidirectional central nervous system-peripheral joints crosstalk that may contribute to the development, expansion, and exacerbation of arthritis.
Re: Pain Is Not A Symptom Of Osteoarthritis, Pain Causes Osteoarthritis
Not surprising really, even my very superficial 12 months dabbling in the field showed that our current understanding of OA is not very comprehensive. I am sure that 100 yrs down the track what we call OA will be a number of different conditions triggered and mediated in a variety of ways.
regards Phill
Re: Pain Is Not A Symptom Of Osteoarthritis, Pain Causes Osteoarthritis
"Our study results confirm that joints can export inflammation in the form of higher IL-1β along sensory nerve pathways to the spinal cord, and that higher IL-1β inflammation in the spinal cord is sufficient in itself to create osteoarthritis in peripheral joints," Kyrkanides said. "We believe this to be a vitally important process contributing to orthopaedic and neurological diseases in which inflammation is a factor."
Maybe I"m not getting this right, but I think their conclusion is crap.
We are supposed to belive that inflammation travels along the spinal cord to then "infect" perfipheral joints with inflammation / arthritis?
Lack of motion in a joint, or improper motion of a joint causes arthritis / arthrosis and pain / inflammation. I find it hard to reason it any other way.
I have no problem with the notion " you don't limp because you hurt, you hurt becase you limp."
i just feel they are missing a step or two in why these findings are important.
Re: Pain Is Not A Symptom Of Osteoarthritis, Pain Causes Osteoarthritis
I feel that they are being indiscriminant and imprecise in their terminology of this study.
OA is not classified as an inflammatory arthritide as is RA, therefore it is not a truly rheumatic cause of the bony changes associated with the inflammatory arthritides. I also feel that terms such as degenerative 'arthritis' also need to be updated. There are often degenerative changes in OA without inflammation and symptoms whereas in the inflammatory arthritic conditons this is a hallmark feature of an acute complaint.
I may be wrong but I think that what they were trying to prove is that in OA that through the inflammatory cascade, PGE, archadonic acid, cytokines that bony changes can be initiated in in the glia in response to this tissue level inflammatory component?
I see this frequently in sprain acceleration/deceleration patients from motor vehicle accident trauma. Local inflammation as described above initiates a cellular 'glue' that limits ROM and function to protect the injured spinal joints. This matrix is much like a scab on the dermis from a deep cut; less tensile strength, less flexibility, more prone to re-injury and more highly innervated = sensitive and often painful.
I have reviewed numerous films of patients who either had no physical medicine treatment following such an even or events or have had multiple traumatic events (rugby players come to mind) and many have long-term bony changes but no inflammation. Hmm.
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"If we all worked on the assumption that what is accepted as true is really true, there would be little hope of advance." - Orville Wright
Re: Pain Is Not A Symptom Of Osteoarthritis, Pain Causes Osteoarthritis
David;
does this not still potentially come back to the thought that if you start limping due to arthritis, or arthrosis of a foot joint, that over time you can alter your gait adn thereby cause back or hip or knee pain???
Re: Pain Is Not A Symptom Of Osteoarthritis, Pain Causes Osteoarthritis
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Originally Posted by Bruce Williams
David;
does this not still potentially come back to the thought that if you start limping due to arthritis, or arthrosis of a foot joint, that over time you can alter your gait adn thereby cause back or hip or knee pain???
Bruce
I absolutely agree Bruce, we've all witnessed this in practice. I think we would also agree that via the current theory of DJD that altered joint function causes bony changes.
It appears that what these authors are saying is that pain is the catalyst that precludes degenerative changes, although we believe currently that those changes produce the pain of OA and not the other way around?
Does nociception have a role in initiating degenerative changes via the inflammatory cascade?
Very chicken vs. egg
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"If we all worked on the assumption that what is accepted as true is really true, there would be little hope of advance." - Orville Wright
Pain Is Not A Symptom Of Osteoarthritis, Pain Causes Osteoarthritis
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