Related Experiment Video
Updated: Aug 3, 2025
The Monoiodoacetate Model of Osteoarthritis Pain in the Mouse
Published on: May 16, 2016
Re-thinking osteoarthritis pathogenesis: what can we learn (and what do we need to unlearn) from mouse models about
Raewyn C Poulsen1, Lekha Jain2, Nicola Dalbeth3
1Department of Pharmacology & Clinical Pharmacology, Faculty of Medical & Health Sciences, University of Auckland, 85 Park Rd, Grafton, Auckland, 1023, New Zealand. r.poulsen@auckland.ac.nz.
Abstract:
Efforts to develop effective disease-modifying drugs to treat osteoarthritis have so far proved unsuccessful with a number of promising drug candidates from pre-clinical studies failing to show efficacy in clinical trials. It is therefore timely to re-evaluate our current understanding of osteoarthritis pathogenesis and the similarities and differences in disease development between commonly used pre-clinical mouse models and human patients. There is substantial heterogeneity between patients presenting with osteoarthritis and mounting evidence that the pathways involved in osteoarthritis (e.g. Wnt signalling) differ between patient sub-groups. There is also emerging evidence that the pathways involved in osteoarthritis differ between the STR/ort mouse model (the most extensively studied mouse model of spontaneously occurring osteoarthritis) and injury-induced osteoarthritis mouse models. For instance, while canonical Wnt signalling is upregulated in the synovium and cartilage at an early stage of disease in injury-induced osteoarthritis mouse models, this does not appear to be the case in the STR/ort mouse. Such findings may prove insightful for understanding the heterogeneity in mechanisms involved in osteoarthritis pathogenesis in human disease. However, it is important to recognise that there are differences between mice and humans in osteoarthritis pathogenesis. A much more extensive array of pathological changes are evident in osteoarthritic joints in individual mice with osteoarthritis compared to individual patients. There are also specified differences in the pathways involved in disease development. For instance, although increased TGF-β signalling is implicated in osteoarthritis development in both mouse models of osteoarthritis and human disease, in mice, this is mainly mediated through TGF-β3 whereas in humans, it is through TGF-β1. Studies in other tissues have shown TGF-β1 is more potent than TGF-β3 in inducing the switch to SMAD1/5 signalling that occurs in osteoarthritic cartilage and that TGF-β1 and TGF-β3 have opposing effects on fibrosis. It is therefore possible that the relative contribution of TGF-β signalling to joint pathology in osteoarthritis differs between murine models and humans. Understanding the similarities and differences in osteoarthritis pathogenesis between mouse models and humans is critical for understanding the translational potential of findings from pre-clinical studies.
Insights
Osteoarthritis drug development faces challenges due to differences between mouse models and human disease. Re-evaluating osteoarthritis pathogenesis in preclinical models is crucial for translating findings to human patients.
Area of Science:
- * Biomedical research
- * Translational medicine
- * Osteoarthritis pathogenesis
Background:
- * Current osteoarthritis (OA) drug development efforts have largely failed in clinical trials, despite promising preclinical data.
- * Significant heterogeneity exists in human OA, with distinct molecular pathways implicated in disease development across patient subgroups.
- * Preclinical mouse models of OA exhibit variations in disease mechanisms, complicating direct translation to human OA.
Purpose of the Study:
- * To re-evaluate the understanding of osteoarthritis pathogenesis.
- * To compare disease development pathways between preclinical mouse models and human OA patients.
- * To identify critical similarities and differences for improving translational research.
Main Methods:
- * Comparative analysis of molecular pathways involved in OA pathogenesis.
- * Review of existing literature on OA mechanisms in human patients and mouse models (STR/ort and injury-induced).
- * Examination of signaling pathways such as Wnt and TGF-β in different OA contexts.
Main Results:
- * Evidence suggests differing pathway involvement in OA between human patient subgroups and between distinct mouse models.
- * Canonical Wnt signaling upregulation observed in injury-induced OA models, but not consistently in STR/ort mice.
- * Transforming Growth Factor-beta (TGF-β) signaling differences noted, with TGF-β3 predominant in mice and TGF-β1 in humans, potentially impacting disease progression.
Conclusions:
- * Understanding the nuances of OA pathogenesis in both mouse models and humans is essential for successful drug development.
- * Recognizing species-specific differences in signaling pathways (e.g., TGF-β1 vs. TGF-β3) is critical for interpreting preclinical findings.
- * The heterogeneity in OA pathogenesis necessitates a refined approach to preclinical model selection and translational research strategies.
