Dataset Information

Characterisation of peripheral and central components of the rat monoiodoacetate model of Osteoarthritis.

ABSTRACT:

Objective

Pain is the main reason patients report Osteoarthritis (OA), yet current analgesics remain relatively ineffective. This study investigated both peripheral and central mechanisms that lead to the development of OA associated chronic pain.

Design

The monoiodoacetate (MIA) model of OA was investigated at early (2-6 days post injection) and late (>14 days post injection) time points. Pain-like behaviour and knee histology were assessed to understand the extent of pain due to cartilage degradation. Electrophysiological single-unit recordings were taken from spinal wide dynamic range (WDR) neurons to investigate Diffuse Noxious Inhibitory Controls (DNIC) as a marker of potential changes in descending controls. Immunohistochemistry was performed on dorsal root ganglion (DRG) neurons to assess any MIA induced neuronal damage. Furthermore, qPCR was used to measure levels of glia cells and cytokines in the dorsal horn.

Results

Both MIA groups develop pain-like behaviour but only late phase (LP) animals display extensive cartilage degradation. Early phase animals have a normally functioning DNIC system but there is a loss of DNIC in LP animals. We found no evidence for neuronal damage caused by MIA in either group, yet an increase in IL-1? mRNA in the dorsal horn of LP animals.

Conclusion

The loss of DNIC in LP MIA animals suggests an imbalance in inhibitory and facilitatory descending controls, and a rise in the mRNA expression of IL-1? mRNA suggest the development of central sensitisation. Therefore, the pain associated with OA in LP animals may not be attributed to purely peripheral mechanisms.

SUBMITTER: Lockwood SM

PROVIDER: S-EPMC6444078 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Characterisation of peripheral and central components of the rat monoiodoacetate model of Osteoarthritis.

Lockwood S M SM Lopes D M DM McMahon S B SB Dickenson A H AH

Osteoarthritis and cartilage 20190103 4

<h4>Objective</h4>Pain is the main reason patients report Osteoarthritis (OA), yet current analgesics remain relatively ineffective. This study investigated both peripheral and central mechanisms that lead to the development of OA associated chronic pain.<h4>Design</h4>The monoiodoacetate (MIA) model of OA was investigated at early (2-6 days post injection) and late (>14 days post injection) time points. Pain-like behaviour and knee histology were assessed to understand the extent of pain due to ...[more]

PMID: 30611904

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Project description:ObjectiveThis study aimed to quantify the cartilage- and subchondral bone-related effects of low-dose and high-dose meloxicam treatment in the late phase of mono-iodoacetate-induced osteoarthritis of the stifle.MethodsThirty-four male Wistar rats received intra-articular injection of mono-iodoacetate to trigger osteoarthritis; 10 control animals (Grp Co) received saline. The mono-iodoacetate-injected rats were assigned to three groups and treated from week 4 to the end of week 7 with placebo (Grp P, n = 11), low-dose (GrpM Lo, 0.2 mg/kg, n = 12) or high-dose (GrpM Hi, 1 mg/kg, n = 11) meloxicam. After a period of 4 additional weeks (end of week 11) the animals were sacrificed, and the stifle joints were examined histologically and immunohistochemically for cyclooxygenase 2, in conformity with recommendations of the Osteoarthritis Research Society International. Serum cytokines IL-6, TNF? and IL-10 were measured at the end of weeks 3, 7, and 11.ResultsCompared with saline-treated controls, animals treated with mono-iodoacetate developed various degrees of osteoarthritis. The cartilage degeneration score and the total cartilage degeneration width were significantly lower in both the low-dose (p = 0.012 and p = 0.014) and high-dose (p = 0.003 and p = 0.006) meloxicam-treated groups than in the placebo group. In the subchondral bone, only high-dose meloxicam exerted a significant protective effect (p = 0.011). Low-grade Cox-2 expression observed in placebo-treated animals was abolished in both meloxicam groups. Increase with borderline significance of TNF? in GrpP from week 3 to week 7 (p = 0.049) and reduction of IL-6 in GrpM Lo from week 3 to week 11 (p = 0.044) were observed.ConclusionIn this rat model of osteoarthritis, both low-dose and high-dose meloxicam had a chondroprotective effect, and the high dose also protected against subchondral bone lesions. The results suggest a superior protection of the high-dose meloxicam arresting the low-grade inflammatory pathway accompanied by chronic cartilage deterioration.

Project description:Osteoarthritis (OA) is a degenerative joint disease that primarily affects people over 65 years old. During OA progression irreversible cartilage, synovial membrane and subchondral bone degradation is observed, which results in the development of difficult-to-treat chronic pain. One of the most important factors in OA progression is joint inflammation. Both proinflammatory and anti-inflammatory factors, as well as extracellular matrix degradation enzymes (matrix metalloproteinases (MMPs), play an important role in disease development. One of the most widely used animal OA models involves an intra-articular injection of sodium monoiodoacetate (MIA) directly into the joint capsule, which results in glycolysis inhibition in chondrocytes and cartilage degeneration. This model mimics the degenerative changes observed in OA patients. However, the dose of MIA varies in the literature, ranging from 0.5 to 4.8 mg. The aim of our study was to characterize grading changes after injection of 1, 2 or 3 mg of MIA at the behavioral and molecular levels over a 28-day period. In the behavioral studies, MIA injection at all doses resulted in a gradual increase in tactile allodynia and resulted in abnormal weight bearing during free walking sequences. At several days post-OA induction, cartilage, synovial membrane and synovial fluid samples were collected, and qPCR and Western blot analyses were performed. We observed significant dose- and time-dependent changes in both gene expression and protein secretion levels. Inflammatory factors (CCL2, CXCL1, IL-1β, COMP) increased at the beginning of the experiment, indicating a transient inflammatory state connected to the MIA injection and, in more severe OA, also in the advanced stages of the disease. Overall, the results in the 1 mg MIA group were not consistently clear, indicating that the lowest tested dose may not be sufficient to induce long-lasting OA-like changes at the molecular level. In the 2 mg MIA group, significant alterations in the measured factors were observed. In the 3 mg MIA group, MMP-2, MMP-3, MMP-9, and MMP-13 levels showed very strong upregulation, which may cause overly strong reactions in animals. Therefore, a dose of 2 mg appears optimal, as it induces significant but not excessive OA-like changes in a rat model.

Dataset Information

Characterisation of peripheral and central components of the rat monoiodoacetate model of Osteoarthritis.

Objective

Design

Results

Conclusion

Publications

Characterisation of peripheral and central components of the rat monoiodoacetate model of Osteoarthritis.

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