Novel Insights into Osteoarthritis Joint Pathology from Studies in Mice

Moon, Paxton M.; Beier, Frank

doi:10.1007/s11926-015-0524-1

Cited by 30 publications

(25 citation statements)

References 91 publications

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“…Thus, chondrocyte proliferation and/or survival may be compromised. Several of the genes that are modulated in joints with different OA grades have been examined in mouse models of OA (39, 40). For example, mutations in ECM genes (e.g., COL2 , MMP13 ) cause mice to develop OA (41).…”

Section: Discussionmentioning

confidence: 99%

The synovial microenvironment of osteoarthritic joints alters RNA-seq expression profiles of human primary articular chondrocytes

Lewallen

Bonin

et al. 2016

Gene

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Osteoarthritis (OA) is a disabling degenerative joint disease that prompts pain with limited treatment options. To permit early diagnosis and treatment of OA, a high resolution mechanistic understanding of human chondrocytes in normal and diseased states is necessary. In this study, we assessed the biological effects of OA-related changes in the synovial microenvironment on chondrocytes embedded within anatomically intact cartilage from joints with different pathological grades by next generation RNA-sequencing (RNA-seq). We determined the transcriptome of primary articular chondrocytes derived from pristine knees and ankles, as well as from joints affected by OA. The GALAXY bioinformatics platform was used to facilitate biological interpretations. Comparisons of patient samples by k-means, hierarchical clustering and principal component analysis reveal that primary chondrocytes exhibit OA grade-related differences in gene expression, including genes involved in cell-adhesion, ECM production and immune response. We conclude that diseased synovial microenvironments in joints with different histopathological OA grades directly alter gene expression in chondrocytes. One ramification of this finding is that sampling anatomically intact cartilage from OA joints is not an ideal source of healthy chondrocytes, nor should they be used to generate a normal baseline for the molecular characterization of diseased joints.

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Section: Discussionmentioning

confidence: 99%

The synovial microenvironment of osteoarthritic joints alters RNA-seq expression profiles of human primary articular chondrocytes

Lewallen

Bonin

et al. 2016

Gene

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“…This argues strongly for more precise reporting, interpretation, and extrapolation of findings from preclinical models to the human condition, and not only a prefix to define the OA phenotype (e.g., post‐traumatic‐, age‐associated‐, inflammatory‐) as previously suggested, but perhaps even subdivisions within a given phenotype (e.g., meniscal‐destabilization‐PTOA, meniscotomy‐PTOA, meniscectomy‐PTOA). Much of our understanding about the distinct cellular and molecular pathophysiology of OA phenotypes and now PTOA sub‐types has come from and indeed until recently was only possible through using genetically modified mice . Recent advances in gene editing technologies such as CRISPR/Cas9, may allow for similar studies in larger animal species .…”

Section: What Is Post‐traumatic Osteoarthritis (Ptoa)?mentioning

confidence: 99%

“…Environmental and subject variables can be well controlled and standardized across experiments and laboratories, minimizing experimental variability, and allowing effects of risk factors such as diet, obesity, exercise, sex, age, etc., on PTOA risk/onset/progression to be explored Not withstanding the absolute specificity of available promoters, genetically modified mice enable the temporal and tissue specific molecular regulation of PTOA pathology and pain to be determined Systemic (oral, injected) and local (intra‐articular) interventions can be used, and together with low body weight and rapid PTOA progression this makes mice ideal for high throughput screening and DMOAD development. …”

Section: What Is Post‐traumatic Osteoarthritis (Ptoa)?mentioning

confidence: 99%

Using mouse models to investigate the pathophysiology, treatment, and prevention of post‐traumatic osteoarthritis

Blaker

Clarke

Little

2016

Journal Orthopaedic Research

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Post-traumatic osteoarthritis (PTOA) is defined by its development after joint injury. Factors contributing to the risk of PTOA occurring, the rate of progression, and degree of associated disability in any individual, remain incompletely understood. What constitutes an "OA-inducing injury" is not defined. In line with advances in the traumatic brain injury field, we propose the scope of PTOA-inducing injuries be expanded to include not only those causing immediate structural damage and instability (Type I), but also those without initial instability/damage from moderate (Type II) or minor (Type III) loading severity. A review of the literature revealed this full spectrum of potential PTOA subtypes can be modeled in mice, with 27 Type I, 6 Type II, and 4 Type III models identified. Despite limitations due to cartilage anatomy, joint size, and bio-fluid availability, mice offer advantages as preclinical models to study PTOA, particularly genetically modified strains. Histopathology was the most common disease outcome, cartilage more frequently studied than bone or synovium, and meniscus and ligaments rarely evaluated. Other methods used to examine PTOA included gene expression, protein analysis, and imaging. Despite the major issues reported by patients being pain and biomechanical dysfunction, these were the least commonly measured outcomes in mouse models. Informative correlations of simultaneously measured disease outcomes in individual animals, was rarely done in any mouse PTOA model. This review has identified knowledge gaps that need to be addressed to increase understanding and improve prevention and management of PTOA. Preclinical mouse models play a critical role in these endeavors. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:424-439, 2017.

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“…Given that Panx1 phosphorylation by Src has recently been reported to induce channel opening, this particular peptide may also be a useful Panx1 channel inhibitor [122][123][124]. In another study, Panx3 ablation inhibited the onset of surgically induced osteoarthritis, raising the possibility that a peptide therapeutic specifically inhibiting Panx3 channels may provide treatment for a poorly controlled disease [125,126]. While these studies are encouraging, new and more specific inhibitors of pannexin channels are necessary.…”

Section: Connexin and Pannexin Therapeuticsmentioning

confidence: 98%