Dataset Information

Multi-tissue network analysis for drug prioritization in knee osteoarthritis.

ABSTRACT: Knee osteoarthritis (OA) is a joint disease that affects several tissues: cartilage, synovium, meniscus and subchondral bone. The pathophysiology of this complex disease is still not completely understood and existing pharmaceutical strategies are limited to pain relief treatments. Therefore, a computational method was developed considering the diverse mechanisms and the multi-tissue nature of OA in order to suggest pharmaceutical compounds. Specifically, weighted gene co-expression network analysis (WGCNA) was utilized to identify gene modules that were preserved across four joint tissues. The driver genes of these modules were selected as an input for a network-based drug discovery approach. WGCNA identified two preserved modules that described functions related to extracellular matrix physiology and immune system responses. Compounds that affected various anti-inflammatory pathways and drugs targeted at coagulation pathways were suggested. 9 out of the top 10 compounds had a proven association with OA and significantly outperformed randomized approaches not including WGCNA. The method presented herein is a viable strategy to identify overlapping molecular mechanisms in multi-tissue diseases such as OA and employ this information for drug discovery and compound prioritization.

SUBMITTER: Neidlin M

PROVIDER: S-EPMC6811565 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Multi-tissue network analysis for drug prioritization in knee osteoarthritis.

Neidlin Michael M Dimitrakopoulou Smaragda S Alexopoulos Leonidas G LG

Scientific reports 20191023 1

Knee osteoarthritis (OA) is a joint disease that affects several tissues: cartilage, synovium, meniscus and subchondral bone. The pathophysiology of this complex disease is still not completely understood and existing pharmaceutical strategies are limited to pain relief treatments. Therefore, a computational method was developed considering the diverse mechanisms and the multi-tissue nature of OA in order to suggest pharmaceutical compounds. Specifically, weighted gene co-expression network anal ...[more]

PMID: 31645614

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Project description:BackgroundMultiple surgical interventions exist for the treatment of symptomatic knee osteoarthritis, but the surgeon and patient may often have difficulty deciding which interventions are the best option.MethodsWe conducted a systematic review to identify randomized clinical trials (RCTs) that compared complications, revisions, reoperations, and functional outcomes among TKA (total knee arthroplasty), UKA (unicompartmental knee arthroplasty), HTO (high tibial osteotomy), BCA (bicompartmental knee arthroplasty), BIU (bi-unicompartmental knee arthroplasty), and KJD (knee joint distraction). The PubMed, Embase, and Cochrane databases were reviewed for all studies comparing two or more surgical interventions. Direct-comparison meta-analysis and network meta-analysis (NMA) were performed to combine direct and indirect evidence. The risk of bias was assessed using the revised Cochrane risk of bias tool for RCTs.ResultsThis NMA and systematic review included 21 studies (17 RCTs), with a total of 1749 patients. The overall risk-of-bias assessment of the RCTs revealed that 7 studies had low risk, 5 had some concerns, and 9 had high risk. SUCRA (the surface under the cumulative ranking curve) rankings revealed that KJD had the greatest risk of appearing postoperative complications, revisions, and reoperations, and UKA or TKA had the lowest risk. The majority of comparisons among various treatments showed no difference for functional outcomes.ConclusionEach surgical intervention is noninferior to other treatments in functional outcomes, but UKA and TKA are better options to treat OA according to SUCRA rankings by comparing complications, revisions, and reoperations. KJD is an imperfect option for treating OA. Other treatments should be carefully considered for each patient in accordance with their actual conditions. However, this conclusion is limited by the selection of reviewed publications and individual variation of surgical indications for patients.Trial registrationThis study was registered with Research Registry (reviewregistry1395).

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Project description:Arthrofibrosis is characterized by excessive extracellular matrix (ECM) deposition that results in restricted joint motion after total knee arthroplasty (TKA). Current surgical and pharmacologic treatment options are limited. Therefore, an in vitro model for joint myofibroblastogenesis is valuable to investigate the arthrofibrotic process and identify diagnostic biomarkers and treatment options. In this study, we obtained intraoperative posterior capsule (PC), quadriceps tendon (QT), and suprapatellar pouch (SP) tissue from knees of four patients undergoing primary TKA for osteoarthritis and characterized primary outgrowth cells from these tissues in the absence and presence of transforming growth factor beta 1 (TGFβ1), a pro-myofibroblastic cytokine. Light microscopy of knee outgrowth cells revealed spindle-shaped cells while immunofluorescence (IF) established staining for the fibroblast-specific antigen TE-7 and Vimentin, which are characteristics of fibroblasts. These fibroblasts differentiate readily into myofibroblasts as highlighted by enhanced alpha smooth muscle actin (ACTA2) mRNA and protein expression and increased collagen mRNA (i.e., collagen type 1 (COL1A1) and collagen type 3 (COL3A1)) expression and collagenous matrix deposition in the presence of TGFβ1. Of note, these studies also revealed that knee-derived fibroblasts are more sensitive to TGFβ1-mediated myofibroblastogenesis than adipose-derived mesenchymal stem cells. Importantly, while outgrowth fibroblasts isolated from four patients and three anatomical regions exhibit similar gene expression profiles, these knee fibroblasts form a unique gene expression cluster within the fibroblast niche as revealed by RNA-sequencing analysis. In conclusion, our study provides a fibroblast/myofibroblast model of outgrowth knee cells derived from patients undergoing primary TKA that can be employed to assess myofibroblast-related processes and test novel pharmacological strategies in vitro for arthrofibrosis.

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Dataset Information

Multi-tissue network analysis for drug prioritization in knee osteoarthritis.

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Multi-tissue network analysis for drug prioritization in knee osteoarthritis.

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