Publications by Eccles ǀ UKD
In recent years a number of animal models have been developed which share similarities with the human disease process. These include naturally occurring OA models in guinea pig and instability-induced OA in mice with a natural predisposition to spontaneous OA. Most studies have used either:. In addition, there is also a markedly increased sensitivity to any further noxious mechanical stimulation hyperalgesia.
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In the case of OA this is largely due to the destruction of cartilage and bone remodelling osteophytes or bony spurs that is a response of bone to local damage. Prostaglandins are formed when membrane phospholipids are broken down by the enzyme PLA2 to form arachidonic acid. This evidence combined with ample evidence that COX inhibitors are clinically usefully treatments for arthritis in man shows that the joint tissues are a major target for this class of drugs.
COX-1 Funk et al is a constitutive enzyme that is present in a large number of cell types and is seen as the housekeeping isoform. Joint pressure is normally subatmospheric and lowest when the joint is in resting or in the midrange position. The way forward with this type of research is not entirely clear. On the negative side, there is clearly a gap in the present knowledge regarding the location and responsiveness of joint mechanonociceptors in osteoarthritic joints.
Only by combining electrophysiological measurements from single cells, molecular biology, protein biochemistry, and modern neuroanatomical and imaging techniques can we hope to start to understand the molecular mechanisms of articular mechanonociception in OA. References Bendele AM Animal models of osteoarthritis in an era of molecular biology. Pressure changes during passive joint distension.
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In OA, the CO2 concentration in blood from the medullary space is elevated, lactate concentration is increased and O2 tension is decreased. Grubb: In the models that we have used to study nociceptors, there is little damage to the bone. Kuettner: In clinical terms, we are studying OA in older individuals. In your animal models, have you taken age as a component?
Most animal work is done on young animals. Grubb: It is almost all done on young animals. Kuettner: The question is, can we interpret data from young animals and apply them to the adult population either in humans or animals? Henry: This raises another issue: when does OA start? Does it start with the clinical signs, or before? Dieppe: Good question. Is it possible from what you are saying that the increased sensitization of mechanoreceptors is such that they can respond to these miniscule changes in barometric pressure?
The patients can certainly detect them. If it is not this, then what on earth is going on? It is interesting that this only happens when pressure is falling, because this would be when any change in the capsule stretching would be occurring. I have no evidence for this, though, and I stress that this is pure speculation. Koltzenburg: It may be that the source of pain in OA is much more the bone than the joint itself.
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How do you think this is implicated in mechanosensation? Grubb: All I can say is that many neurons respond to both mechanical and thermal stimuli. Whether this occurs in addition to the changes in mechanosensitivity is not clear. But if they respond to capsaicin they must contain the TRPV1 heat sensitive ion channel. This is an interesting idea.
I am not sure whether this Peter Reid model applies to the joint. Pisetsky: How are gravity, weight bearing and compression perceived? Pisetsky: What about just weight bearing? Grubb: I am not sure. Evans: I was interested in the suggested pathogenesis of OA that you showed. If so, how? Grubb: These articular nociceptors have become extremely mechanically sensitive.
If the subchondral bone has become damaged and the nociceptors are very close to the surface, and you have particular matter in there, this could be contributing. I just had them in there to suggest that they contribute to the nociceptor activation. What about the rate at which a joint is moved? Grubb: I presented a lot of work from Hans-Georg Schaible, and he has done most of the work on joint movement, so I think he should answer that question. Schaible: Whenever we move our joints in the normal range there is not much torque.
But when we twist the joint against the resistance of the tissue this is what we call noxious movement. A nociceptor is usually not even activated during the ramp of a stimulation, but when the stimulus is there, it is activated one or two seconds after the joint has reached an extreme position. Pisetsky: Does duration of joint use matter? Hunter: In an abnormal joint which is mechanically unstable, would you expect that this would produce a nociceptive stimulus in a lower range of movement than is needed for a normal joint?
From our experience so far we believe that if you apply just mechanical stimuli, the response properties will not change a lot. You need something additional. Felson: Can you give us a sense of the mechanical stimuli you have applied? The local stresses within osteoarthritic joints are often very high. Is there some way that you can characterize the magnitude of the twisting beyond the normal range of motion that you apply?
Fernihough: What is seen as a noxious twisting movement by ligaments may not be seen at all by the synovium, which is a fully deformable tissue. Herzog: One of the interesting questions is raised when you have unstable joints, such as in some forms of OA where the anterior cruciate ligament ACL is absent and twisting movements like medial rotation become much easier.
The ACL is one of the primary structures to prevent excessive anterior translation and medial rotation of the tibia relative to the femur. Therefore, if the ACL is absent torn , anterior tibial translation and medial rotation encounter much less resistance than in the intact knee e. Maitland et al When you apply this noxious torque, and then take one of the structures out that primarily resist the torque e. Schaible: The anterior cruciate ligament seems to be quite important.
We have studied the response properties of mechanoreceptors supplying the ACL Krauspe et al On each movement they exactly indicate the torque and the stress which is applied to the joint. This proprioception is quite necessary.
We need proprioceptive control all the time, and the ACL with its mechanoreceptors seems to be particularly important for this reason. Koltzenburg: Charcot joints are often a sequel of severe neuropathy. This protects us from rupturing the joint. In the presence of symptoms joint pain, swelling of the joint, loss of joint stability caused by ligament damage etc. Qualitatively, similar results have been obtained for humans, where swelling was associated with a decrease in knee extensor activation compared to normal e.
Such muscle inhibition is normal i. What may also be interesting is that if the nociceptors are truly in the bone, do you get remodelling of the terminals within the bone as a result of the ongoing damage in OA? They may be sprouting or changing, constantly having to re-grow and sprout. Brandt: They may also be present in the walls of the blood vessels.
This could be very true.
Who knows? There may be a neuropathic component of OA. Brandt: With regard to the issue of innervation or not of articular cartilage, with advanced disease when there is capillary invasion these capillaries do contain nerve endings. Grubb: That is an interesting question. Pisetsky: Have people done these kinds of experiments in either transgenic or knockout mice with relevant cytokines?
There are enough mouse models around for this to be approached. Lohmander: What is the degree of biological variability in the sensitization response in these standardized animal models? Do you have any understanding at this time of the biological basis for this variability, if it exists? And is there anything in these models that could teach us about the basis of the variability that appears to be present in the response of patients to what seems to be a standardized structural change in the joint? This is hugely simplistic. There are many subgroups depending on their sensitivity to thermal or mechanical stimuli and so on.
Lohmander: Is there a genotype for pain response? Are we in these studies looking for the pain genotype instead of the OA genotype? Koltzenburg: There is one caveat.