Studies of mechanisms of OA-pain on a rat osteoarthritis model of the ankle joint
Bibliographic record
Abstract
Osteoarthritis (OA), the degenerative and most common form of arthritis, is a complex disease of the whole joint and affects over 3 million Canadian adults. To this day, there is no satisfactory method of relieving osteoarthritic pain and, although chronic pain is the most reported complaint of the disease, our understanding of its driving mechanisms remains limited. Studies in this thesis were devised with the objective of contributing to understanding of the mechanism of pain in OA.Studies investigating changes of innervation of bone have been few and sparse in the literature, mostly due to the complexity and poor success of performing histological labellings on decalcified bone tissue. As a result, there has been a lack of understanding of mechanisms contributing to pain in diseases such as arthritis, osteoporosis, and low back pain. In this thesis, we developed a robust methodology for labelling nerve fibers in bone in various animal models of OA, osteoporosis, and bone fracture.In this thesis, we provide a multi-facetted time-course study of relevant changes in a mono-iodoacetate (MIA) model of OA in the rat ankle joint. We showed a correlation between pain-related behavior and pathological changes, including cartilage and bone degeneration, sprouting of sensory and sympathetic nerves in the bone and synovium, and increased density and activation of glial cells in the dorsal horn. There are many clinical and pre-clinical lines of evidence suggesting a neuropathic component to OA pain, including the occurrence of microgliosis in the spinal cord and modulation of nociceptors by sympathetic afferents. However, putative for a neuropathic pain-like component to OA is the possible contribution of primary afferent damage following joint degeneration. We have shown expression of Activating Transcription Factor 3 (ATF3), a marker of neuronal stress, principally in large-diameter cell bodies that also colocalize with parvalbumin (PV), a marker of proprioceptors. This suggests that Aβ mechanoreceptors innervating the articular joint in OA pain are mostly affected following joint degeneration, which drives interest in understanding the contribution of lamina III-V that receives input from these fibers, in the persistence of OA pain. The internalization of the receptor for substance P, the neurokinin-1 receptor (NK1-r) on lamina I projection neurons of the spinal dorsal horn has been used as a marker of nociceptive responses. Lamina I is an important centre for the modulation and forwarding to the brain of pain-related information. Therefore, changes in the properties of lamina I projection neurons may be important for pain. Previous work from our lab has shown increased expression of NK1-r on lamina I pyramidal neurons in both neuropathic pain and inflammatory arthritis models. In this thesis, we showed similar morphological changes and internalization of the receptor on NK1-r positive neurons, in a rat ankle joint model of osteoarthritis (OA) following movement of the affected joint in lamina I. This work combines many studies of important changes occurring in OA in the peripheral and central nervous systems, identifying various contributing mechanisms to chronic and irreversible pain in the disease, including a neuropathic pain-like component. Such studies have important implications in the development of more suitable therapeutic strategies by identifying potential targets
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".