Human genome-wide expression analysis reorients the study of inflammatory mediators and biomechanics in osteoarthritis

Sandy, John D.; Chan, Deva D.; Trevino, Robert L.; Wimmer, Markus A.; Plaas, Anna

doi:10.1016/j.joca.2015.03.027

Cited by 44 publications

(37 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[79][80][81] In contrast, the two cytokines for which we observed differences between the OAC-AM and NC-AM group -namely IL-6 and IL-8 -have been demonstrated to increase in late versus early shoulder OA. 82 Combined, these points of comparison of NC-AM to OAC-AM to human disease suggest that our OAC-AM system may be serving as a disease mimic for later stage OA than the NC-AM system.…”

Section: Discussioncontrasting

confidence: 60%

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

Samavedi

Díaz‐Rodríguez

Erndt-Marino

et al. 2017

Tissue Engineering Part A

View full text Add to dashboard Cite

The goal of the present study was to develop a fully three-dimensional (3D) coculture system that would allow for systematic evaluation of the interplay between activated macrophages (AMs) and chondrocytes in osteoarthritic disease progression and treatment. Toward this end, our coculture system was first validated against existing in vitro osteoarthritis models, which have generally cultured healthy normal chondrocytes (NCs)-in two-dimensional (2D) or 3D-with proinflammatory AMs in 2D. In this work, NCs and AMs were both encapsulated within poly(ethylene glycol) diacrylate hydrogels to mimic the native 3D environments of both cell types within the osteoarthritic joint. As with previous studies, increases in matrix metalloproteinases (MMPs) and proinflammatory cytokines associated with the early stages of osteoarthritis were observed during NC-AM coculture, as were decreases in protein-level Aggrecan and collagen II. Thereafter, the coculture system was extended to osteoarthritic chondrocytes (OACs) and AMs to evaluate the potential effects of AMs on pre-existing osteoarthritic phenotypes. OACs in coculture with AMs expressed significantly higher levels of MMP-1, MMP-3, MMP-9, MMP-13, IL-1b, TNF-a, IL-6, IL-8, and IFN-g compared to OACs in mono-culture, indicating that proinflammatory macrophages may intensify the abnormal matrix degradation and cytokine secretion already associated with OACs. Likewise, AMs cocultured with OACs expressed significantly more IL-1b and VEGF-A compared to AM mono-culture controls, suggesting that OACs may intensify abnormal macrophage activation. Finally, OACs cultured in the presence of nonactivated macrophages produced lower levels of MMP-9 and proinflammatory cytokines IL-1b, TNF-a, and IFN-g compared to OACs in the OAC-AM system, results that are consistent with anti-inflammatory agents temporarily reducing certain OA symptoms. In summary, the 3D coculture system developed herein captures several key features of inflammatory OA and may prove useful in future screening of therapeutic agents and/or assessment of disease progression mechanisms.

show abstract

Section: Discussioncontrasting

confidence: 60%

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

Samavedi

Díaz‐Rodríguez

Erndt-Marino

et al. 2017

Tissue Engineering Part A

View full text Add to dashboard Cite

show abstract

“…Although both IL-1b and Fn-fs have been described as mediators of cartilage degradation in OA, our findings indicate that despite the contribution of both mediators, they are Fn-fs rather than IL-1b, which plays the major pathological role, in agreement with recent studies. 12 We showed that constitutive levels of ADAMTS-4, one of the main aggrecanases in cartilage destruction, were higher in OA than in HD. Interestingly, the higher levels of ADAMTS-7 in OA compared to HD, as well as the regulation of ADAMTS-12 by IL-1b and Fn-fs exclusively in SF from OA patients, suggest their potential as new therapeutic targets for the treatment of the disease.…”

Section: Q18mentioning

confidence: 80%

“…33 At the functional level, our results are in agreement with previous findings showing that ADAMTS 4 and 5 are not regulated by this cytokine in SF. 9,12,31 The role of IL-1b in OA is controversial, and the implication of other mediators, as cartilage ECM degradation products, seems to be more relevant in the pathology. 12 Despite that, the study of IL-1b, as a pleiotropic proinflammatory cytokine, also contributes to the knowledge of the mechanism involved in the disease.…”

Section: Synovial Fibroblasts In Osteoarthritismentioning

confidence: 99%

“…9,12,31 The role of IL-1b in OA is controversial, and the implication of other mediators, as cartilage ECM degradation products, seems to be more relevant in the pathology. 12 Despite that, the study of IL-1b, as a pleiotropic proinflammatory cytokine, also contributes to the knowledge of the mechanism involved in the disease. In addition, because synovial inflammation intensity is greater in OA initial stages, 4 the lack of effects observed in the aggrecanase activity after IL-1b stimulation could be explained by the advanced disease state of our patients.…”

Section: Synovial Fibroblasts In Osteoarthritismentioning

confidence: 99%

See 1 more Smart Citation

Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

Pérez‐García

Gutiérrez‐Cañas

Seoane

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

Current description of osteoarthritis includes the involvement of synovial inflammation. Studies contributing to understanding the mechanisms of cross-talk and feedback among the joint tissues could be relevant to the development of therapies that block disease progression. During osteoarthritis, synovial fibroblasts exposed to anomalous mechanical forces and an inflammatory microenvironment release factors such as a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) metalloproteinases that mediate tissue damage and perpetuate inflammation. We therefore studied the production of ADAMTS by synovial fibroblasts and their contribution to cartilage degradation. Moreover, we analyzed the implication of two mediators present in the osteoarthritis joint, IL-1b as proinflammatory cytokine, and 45-kDa fibronectin fragments as products of matrix degradation. We reported that synovial fibroblasts constitutively express and release ADAMTS 4, 5, 7, and 12. Despite the contribution of both mediators to the stimulation of Runx2 and Wnt/b-catenin signaling pathways, as well as to ADAMTS expression, promoting the degradation of aggrecan and cartilage oligomeric matrix protein from cartilage, fibronectin fragments rather than IL-1b played the major pathological role in osteoarthritis, contributing to the maintenance of the disease. Moreover, higher levels of ADAMTS 4 and 7 and a specific regulation of ADAMTS-12 were observed in osteoarthritis, suggesting them as new potential therapeutic targets. Therefore, synovial fibroblasts provide the biochemical tools to the chronicity and destruction of the osteoarthritic joints. (Am J Pathol 2016, -: 1e13; http:// dx

show abstract

“…4,23-25 However, the available results are inconsistent and controversial. For example, Sandy et al 26 confirmed that the activation of matrix genes, but not IL-1β-responsive genes, played a critical role in the pathology of human OA. However, many results suggested that IL-1β was a significant modulator in cartilage degradation and IL-1β-induced cartilage degradation was involved in the regulation of miRNAs.…”

Section: Discussionmentioning

confidence: 99%

Silencing of microRNA-138-5p promotes IL-1β-induced cartilage degradation in human chondrocytes by targeting FOXC1

Yuan

Zhang

Chai

et al. 2016

Bone & Joint Research

View full text Add to dashboard Cite

ObjectivesOsteoarthritis (OA) is characterised by articular cartilage degradation. MicroRNAs (miRNAs) have been identified in the development of OA. The purpose of our study was to explore the functional role and underlying mechanism of miR-138-5p in interleukin-1 beta (IL-1β)-induced extracellular matrix (ECM) degradation of OA cartilage.Materials and MethodsHuman articular cartilage was obtained from patients with and without OA, and chondrocytes were isolated and stimulated by IL-1β. The expression levels of miR-138-5p in cartilage and chondrocytes were both determined. After transfection with miR-138-5p mimics, allele-specific oligonucleotide (ASO)-miR-138-5p, or their negative controls, the messenger RNA (mRNA) levels of aggrecan (ACAN), collagen type II and alpha 1 (COL2A1), the protein levels of glycosaminoglycans (GAGs), and both the mRNA and protein levels of matrix metalloproteinase (MMP)-13 were evaluated. Luciferase reporter assay, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot were performed to explore whether Forkhead Box C1 (FOCX1) was a target of miR-138-5p. Further, we co-transfected OA chondrocytes with miR-138-5p mimics and pcDNA3.1 (+)-FOXC1 and then stimulated with IL-1β to determine whether miR-138-5p-mediated IL-1β-induced cartilage matrix degradation resulted from targeting FOXC1.ResultsMiR-138-5p was significantly increased in OA cartilage and in chondrocytes in response to IL-1β-stimulation. Overexpression of miR-138-5p significantly increased the IL-1β-induced downregulation of COL2A1, ACAN, and GAGs, and increased the IL-1β-induced over expression of MMP-13.We found that FOXC1 is directly regulated by miR-138-5p. Additionally, co-transfection with miR-138-5p mimics and pcDNA3.1 (+)-FOXC1 resulted in higher levels of COL2A1, ACAN, and GAGs, but lower levels of MMP-13.ConclusionmiR-138-5p promotes IL-1β-induced cartilage degradation in human chondrocytes, possibly by targeting FOXC1.Cite this article: Y. Yuan, G. Q. Zhang, W. Chai,M. Ni, C. Xu, J. Y. Chen. Silencing of microRNA-138-5p promotes IL-1β-induced cartilage degradation in human chondrocytes by targeting FOXC1: miR-138 promotes cartilage degradation. Bone Joint Res 2016;5:523–530. DOI: 10.1302/2046-3758.510.BJR-2016-0074.R2.

show abstract

Human genome-wide expression analysis reorients the study of inflammatory mediators and biomechanics in osteoarthritis

Cited by 44 publications

References 83 publications

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

Silencing of microRNA-138-5p promotes IL-1β-induced cartilage degradation in human chondrocytes by targeting FOXC1

Contact Info

Product

Resources

About