A tool for evaluating novel osteoarthritis therapies using multivariate analyses of human cartilage-synovium explant co-culture
| Autor: | Rajiv Gandhi, M. Chan, Alejandro Gómez-Aristizábal, Sowmya Viswanathan, Nizar N. Mahomed |
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| Rok vydání: | 2022 |
| Předmět: |
Cartilage
Articular Male musculoskeletal diseases MMP3 MMP1 medicine.medical_treatment Biomedical Engineering Osteoarthritis Matrix metalloproteinase Rheumatology Downregulation and upregulation medicine Humans Orthopedics and Sports Medicine Aged Aged 80 and over business.industry Cartilage Synovial Membrane Middle Aged medicine.disease Coculture Techniques Cytokine medicine.anatomical_structure Multivariate Analysis Cancer research Female business Explant culture |
| Zdroj: | Osteoarthritis and Cartilage. 30:147-159 |
| ISSN: | 1063-4584 |
| Popis: | Summary Objective There is a need to incorporate multiple tissues into in vitro OA models to evaluate novel therapeutics. This approach is limited by inherent donor variability. We present an optimized research tool: a human OA cartilage-synovium explant co-culture model (OA-EXM) that employs donor-matched lower and upper limit response controls combined with statistical approaches to address variability. Multiple rapid read-outs allow for evaluation of therapeutics while cataloguing cartilage-synovium interactions. Design 48-h human explant cultures were sourced from OA knee arthroplasties. An OA-like cartilage-synovium co-culture baseline was established relative to donor-matched upper limit supraphysiological pro-inflammatory cytokine and lower limit OA cartilage or synovium alone controls. 100 nM dexamethasone treatment validated possible “rescue effects” within the OA-EXM dual tissue environment. Gene expression, proteoglycan loss, MMP activity, and soluble protein concentrations were analyzed using blocking and clustering methods. Results The OA-EXM demonstrates the value of the co-culture approach as the addition of OA synovium increases OA cartilage proteoglycan loss and expression of MMP1, MMP3, MMP13, CXCL8, CCL2, IL6, and PTGS2, but not to the extent of supraphysiological stimulation. Conversely, OA cartilage does not affect gene expression or MMP activity of OA synovium. Dexamethasone shows dual treatment effects on synovium (pro-resolving macrophage upregulation, protease downregulation) and cartilage (pro-inflammatory, catabolic, and anabolic downregulation), and decreases soluble CCL2 levels in co-culture, thereby validating OA-EXM utility. Conclusions The OA-EXM is representative of late-stage OA pathology, captures dual interactions between cartilage and synovium, and combined with statistical strategies provides a rapid, sensitive research tool for evaluating OA therapeutics. |
| Databáze: | OpenAIRE |
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