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Osteoarthritis Pain Model Induced by Intra-Articular Injection of Mono-Iodoacetate in Rats
Published on: May 20, 2020
Sequential alterations in catabolic and anabolic gene expression parallel pathological changes during progression of
Jin Nam1, Priyangi Perera, Jie Liu
1The Biomechanics and Tissue Engineering Laboratory, College of Dentistry, The Ohio State University, Columbus, Ohio, United States of America.
Abstract:
Chronic inflammation is one of the major causes of cartilage destruction in osteoarthritis. Here, we systematically analyzed the changes in gene expression associated with the progression of cartilage destruction in monoiodoacetate-induced arthritis (MIA) of the rat knee. Sprague Dawley female rats were given intra-articular injection of monoiodoacetate in the knee. The progression of MIA was monitored macroscopically, microscopically and by micro-computed tomography. Grade 1 damage was observed by day 5 post-monoiodoacetate injection, progressively increasing to Grade 2 by day 9, and to Grade 3-3.5 by day 21. Affymetrix GeneChip was utilized to analyze the transcriptome-wide changes in gene expression, and the expression of salient genes was confirmed by real-time-PCR. Functional networks generated by Ingenuity Pathways Analysis (IPA) from the microarray data correlated the macroscopic/histologic findings with molecular interactions of genes/gene products. Temporal changes in gene expression during the progression of MIA were categorized into five major gene clusters. IPA revealed that Grade 1 damage was associated with upregulation of acute/innate inflammatory responsive genes (Cluster I) and suppression of genes associated with musculoskeletal development and function (Cluster IV). Grade 2 damage was associated with upregulation of chronic inflammatory and immune trafficking genes (Cluster II) and downregulation of genes associated with musculoskeletal disorders (Cluster IV). The Grade 3 to 3.5 cartilage damage was associated with chronic inflammatory and immune adaptation genes (Cluster III). These findings suggest that temporal regulation of discrete gene clusters involving inflammatory mediators, receptors, and proteases may control the progression of cartilage destruction. In this process, IL-1β, TNF-α, IL-15, IL-12, chemokines, and NF-κB act as central nodes of the inflammatory networks, regulating catabolic processes. Simultaneously, upregulation of asporin, and downregulation of TGF-β complex, SOX-9, IGF and CTGF may be central to suppress matrix synthesis and chondrocytic anabolic activities, collectively contributing to the progression of cartilage destruction in MIA.
Insights
Chronic inflammation drives osteoarthritis cartilage destruction. This study reveals distinct gene expression patterns, including inflammatory mediators and suppressed matrix synthesis genes, that correlate with osteoarthritis progression in rats.
Area of Science:
- Biomedical Science
- Molecular Biology
- Immunology
Background:
- Osteoarthritis (OA) is characterized by cartilage destruction, significantly driven by chronic inflammation.
- Understanding the molecular mechanisms underlying OA progression is crucial for developing effective treatments.
Purpose of the Study:
- To systematically analyze gene expression changes during the progression of cartilage destruction in a rat model of monoiodoacetate-induced arthritis (MIA).
- To correlate these molecular changes with macroscopic, microscopic, and micro-computed tomography findings of OA progression.
Main Methods:
- Intra-articular injection of monoiodoacetate in Sprague Dawley female rats to induce MIA.
- Monitoring disease progression macroscopically, microscopically, and via micro-computed tomography.
- Transcriptome-wide gene expression analysis using Affymetrix GeneChip, with validation by real-time PCR.
- Functional network analysis using Ingenuity Pathways Analysis (IPA) to identify key molecular interactions.
Main Results:
- Cartilage damage progressed from Grade 1 at day 5 to Grade 3-3.5 by day 21.
- Early damage (Grade 1) showed upregulation of acute inflammatory genes and suppression of musculoskeletal development genes.
- Moderate damage (Grade 2) involved upregulation of chronic inflammatory and immune trafficking genes.
- Severe damage (Grade 3-3.5) was associated with chronic inflammatory and immune adaptation genes.
- Key inflammatory mediators (IL-1β, TNF-α, NF-κB) and suppressed anabolic factors (SOX-9, TGF-β) were identified as central nodes.
Conclusions:
- Temporal regulation of specific gene clusters, including inflammatory mediators and proteases, controls OA cartilage destruction.
- Inflammatory networks involving IL-1β, TNF-α, and NF-κB drive catabolic processes.
- Suppression of matrix synthesis and chondrocytic activity, mediated by factors like asporin and downregulated TGF-β, contributes to disease progression.
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