Understanding osteoarthritis pathogenesis: a multiomics system-based approach

Ratneswaran, A.; Rockel, Jason S.; Kapoor, Mohit

doi:10.1097/bor.0000000000000680

Cited by 37 publications

(22 citation statements)

References 91 publications

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“…Osteoarthritis (OA) poses an enormous burden on the individual patient that adds up to a profound socioeconomic impact on health care sectors worldwide [1]. This justifies vigorous efforts to systematically study the molecular basis of disease onset and progression with the aim to develop innovative therapeutic strategies that interfere with the complex OA pathogenesis [2,3], currently culminating in multiomics approaches to identify relevant molecular signatures [4]. Obviously, the strategic combination of work on clinical material with tailored in vitro models would be helpful to generate meaningful pathobiological results and improve translatability of new knowledge into clinical practice [5].…”

Section: Introductionmentioning

confidence: 99%

The Dysregulated Galectin Network Activates NF-κB to Induce Disease Markers and Matrix Degeneration in 3D Pellet Cultures of Osteoarthritic Chondrocytes

et al. 2020

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This work aimed to study the dysregulated network of galectins in OA chondrocyte pellets, and to assess whether their recently discovered activity as molecular switches of functional biomarkers results in degradation of extracellular matrix in vitro. Scaffold-free 3D pellet cultures were established of human OA chondrocytes. Expression and secretion of galectin(Gal)-1, -3, and -8 were monitored relative to 2D cultures or clinical tissue sections by RT-qPCR, immunohistochemistry and ELISAs. Exposure of 2D and 3D cultures to an in vivo-like galectin mixture (Gal-1 and Gal-8: 5 µg/ml, Gal-3: 1 µg/ml) was followed by the assessment of pellet size, immunohistochemical matrix staining, and/or quantification of MMP-1, -3, and -13. Application of inhibitors of NF-κB activation probed into the potential of intervening with galectin-induced matrix degradation. Galectin profiling revealed maintained dysregulation of Gal-1, -3, and -8 in pellet cultures, resembling the OA situation in situ. The presence of the galectin mixture promoted marked reduction of pellet size and loss of collagen type II-rich extracellular matrix, accompanied by the upregulation of MMP-1, -3, and -13. Inhibition of p65-phosphorylation by caffeic acid phenethyl ester effectively alleviated the detrimental effects of galectins, resulting in downregulated MMP secretion, reduced matrix breakdown and augmented pellet size. This study suggests that the dysregulated galectin network in OA cartilage leads to extracellular matrix breakdown, and provides encouraging evidence of the feasible inhibition of galectin-triggered activities. OA chondrocyte pellets have the potential to serve as in vitro disease model for further studies on galectins in OA onset and progression.

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Section: Introductionmentioning

confidence: 99%

The Dysregulated Galectin Network Activates NF-κB to Induce Disease Markers and Matrix Degeneration in 3D Pellet Cultures of Osteoarthritic Chondrocytes

et al. 2020

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“…To obtain a more complete understanding of the specific molecular mediators and networks regulating OA, studies are now using integrative‐omics approaches (genomics, transcriptomics, proteomics, metabolomics, lipidomics, and epigenomics) 70 . However, few studies have investigated the miRNA interactome by correlating miRNA expression levels to protein or mRNA changes in human OA tissues 29,32 .…”

Section: Discussionmentioning

confidence: 99%

The miRNA‐mRNA interactome of murine induced pluripotent stem cell‐derived chondrocytes in response to inflammatory cytokines

et al. 2020

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Osteoarthritis (OA) is a degenerative joint disease, and inflammation within an arthritic joint plays a critical role in disease progression. Pro‐inflammatory cytokines, specifically IL‐1 and TNF‐α, induce aberrant expression of catabolic and degradative enzymes and inflammatory cytokines in OA and result in a challenging environment for cartilage repair and regeneration. MicroRNAs (miRNAS) are small noncoding RNAs and are important regulatory molecules that act by binding to target messenger RNAs (mRNAs) to reduce protein synthesis and have been implicated in many diseases, including OA. The goal of this study was to understand the mechanisms of miRNA regulation of the transcriptome of tissue‐engineered cartilage in response to IL‐1β and TNF‐α using an in vitro murine induced pluripotent stem cell (miPSC) model system. We performed miRNA and mRNA sequencing to determine the temporal and dynamic responses of genes to specific inflammatory cytokines as well as miRNAs that are differentially expressed (DE) in response to both cytokines or exclusively to IL‐1β or TNF‐α. Through integration of mRNA and miRNA sequencing data, we created networks of miRNA‐mRNA interactions which may be controlling the response to inflammatory cytokines. Within the networks, hub miRNAs, miR‐29b‐3p, miR‐17‐5p, and miR‐20a‐5p, were identified. As validation of these findings, we found that delivery of miR‐17‐5p and miR‐20a‐5p mimics significantly decreased degradative enzyme activity levels while also decreasing expression of inflammation‐related genes in cytokine‐treated cells. This study utilized an integrative approach to determine the miRNA interactome controlling the response to inflammatory cytokines and novel mediators of inflammation‐driven degradation in tissue‐engineered cartilage.

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“…As the most common form of arthritis and one of the leading causes of disability in the elderly population, OA is characterized by chronic inflammation, articular cartilage degeneration and structural changes of whole joints. There is currently an unmet need for disease-modifying drugs (DMOADs) that slow or even revert disease progression [3][4][5]. Pharmacological treatment options focus on symptom management.…”

Section: Introductionmentioning

confidence: 99%

Osteoarthritis In Vitro Models: Applications and Implications in Development of Intra-Articular Drug Delivery Systems

2021

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Osteoarthritis (OA) is a complex multi-target disease with an unmet medical need for the development of therapies that slow and potentially revert disease progression. Intra-articular (IA) delivery has seen a surge in osteoarthritis research in recent years. As local administration of molecules, this represents a way to circumvent systemic drug delivery struggles. When developing intra-articular formulations, the main goals are a sustained and controlled release of therapeutic drug doses, taking into account carrier choice, drug molecule, and articular joint tissue target. Therefore, the selection of models is critical when developing local administration formulation in terms of accurate outcome assessment, target and off-target effects and relevant translation to in vivo. The current review highlights the applications of OA in vitro models in the development of IA formulation by means of exploring their advantages and disadvantages. In vitro models are essential in studies of OA molecular pathways, understanding drug and target interactions, assessing cytotoxicity of carriers and drug molecules, and predicting in vivo behaviors. However, further understanding of molecular and tissue-specific intricacies of cellular models for 2D and 3D needs improvement to accurately portray in vivo conditions.

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Understanding osteoarthritis pathogenesis: a multiomics system-based approach

Cited by 37 publications

References 91 publications

The Dysregulated Galectin Network Activates NF-κB to Induce Disease Markers and Matrix Degeneration in 3D Pellet Cultures of Osteoarthritic Chondrocytes

The Dysregulated Galectin Network Activates NF-κB to Induce Disease Markers and Matrix Degeneration in 3D Pellet Cultures of Osteoarthritic Chondrocytes

The miRNA‐mRNA interactome of murine induced pluripotent stem cell‐derived chondrocytes in response to inflammatory cytokines

Osteoarthritis In Vitro Models: Applications and Implications in Development of Intra-Articular Drug Delivery Systems

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