New molecular targets for the treatment of osteoarthritis

Alcaraz, Marı́a José; Megías, Javier; García-Arnandis, Isabel; Clérigues, Victoria; Guillén, Marı́a Isabel

doi:10.1016/j.bcp.2010.02.017

Cited by 123 publications

(96 citation statements)

References 96 publications

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“…Because Runx2 transcription factor and Wnt/b-catenin signaling are involved in aggrecanase gene expression, 16e18 and also seem to be implicated in the OA pathology, 23,24 we decided to examine whether IL-1b or Fn-fs could alter the ADAMTS 4 and 5 expressions by the modulation of these factors.…”

Section: Runx2 and B-catenin Activation In Sfmentioning

confidence: 99%

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

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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

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Section: Runx2 and B-catenin Activation In Sfmentioning

confidence: 99%

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

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“…Novel targets in OA include genes that are involved in OA pathophysiology, which have been discovered using gene network, epigenetic and miRNAs approaches. Studies on different miRNAs have revealed that they have pro-inflammatory and catabolic/anabolic roles in the pathophysiology of OA [11]. MiRNAs have…”

Section: Introductionmentioning

confidence: 99%

Next-generation Sequencing Identifies Articular Cartilage and Subchondral Bone Mirnas after ESWT on Early Osteoarthritis Knee

Wang

Cheng

et al. 2017

Osteoarthritis and Cartilage

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Extracorporeal shockwave therapy (ESWT) has shown chondroprotective effects on the initiation of the osteoarthritis (OA) changes of the rat knee. This study evaluated 69 significant expressed profiles of microRNA (miRNA) in the articular cartilage and subchondral bone after ESWT. There were 118 target genes identified for miRNAs of interest in articular cartilage and 214 target genes in subchondral bone by next generation sequencing (NGS). In principal component analysis (PCA), the relationships of miRNA expression in bone and cartilage were improved after ESWT. Global functional annotation showed that predicted targets were involved in cartilage development, inflammatory and immune response, ion binding, angiogenesis, cell adhesion, cell cycle, transcription and translation, gene expression, NTP binding, signal transduction, collagen fibril organization, apoptotic process, chondrocyte differentiation, cell differentiation, bone development as well as cell proliferation. The miRNAs profile and the target genes were comprehensively surveyed and compared in articular cartilage and subchondral bone of early OA knee before and after ESWT. Our study represents the direct assessment to date of miRNA expression profiling in early OA articular cartilage and subchondral bone. The results provide insights that could contribute to the development of new biomarkers and therapeutic strategies for OA changes and the treatment with ESWT.

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“…Nevertheless, and despite Osteoarthritis Research Society International recommendations, 3 both pharmacological (nonsteroidal anti-inflammatory medicines, analgesics, and anti-arthritic medicines) and nonpharmacological treatments (exercise, weight reduction) are unable to restore a hyaline functional cartilage, even if some of them improve the patient's life. Although there are now new molecular targets, 4 since 1956, in patients suffering from severe OA, the affected joint is commonly removed and replaced with an orthopedic prosthesis. 5 Currently, there are some methods that can repair the affected joint, such as osteochondral allograft transplantation, 6 but most of them do not restore functional hyaline cartilage and generally result in a fibrocartilage, which is more rapidly degraded.…”

Section: Introductionmentioning

confidence: 99%

BMP-2, Hypoxia, and COL1A1/HtrA1 siRNAs Favor Neo-Cartilage Hyaline Matrix Formation in Chondrocytes

Ollitrault

Legendre

Drougard

et al. 2015

Tissue Engineering Part C: Methods

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Osteoarthritis (OA) is an irreversible pathology that causes a decrease in articular cartilage thickness, leading finally to the complete degradation of the affected joint. The low spontaneous repair capacity of cartilage prevents any restoration of the joint surface, making OA a major public health issue. Here, we developed an innovative combination of treatment conditions to improve the human chondrocyte phenotype before autologous chondrocyte implantation. First, we seeded human dedifferentiated chondrocytes into a collagen sponge as a scaffold, cultured them in hypoxia in the presence of a bone morphogenetic protein (BMP), BMP-2, and transfected them with small interfering RNAs targeting two markers overexpressed in OA dedifferentiated chondrocytes, that is, type I collagen and/or HtrA1 serine protease. This strategy significantly decreased mRNA and protein expression of type I collagen and HtrA1, and led to an improvement in the chondrocyte phenotype index of differentiation. The effectiveness of our in vitro culture process was also demonstrated in the nude mouse model in vivo after subcutaneous implantation. We, thus, provide here a new protocol able to favor human hyaline chondrocyte phenotype in primarily dedifferentiated cells, both in vitro and in vivo. Our study also offers an innovative strategy for chondrocyte redifferentiation and opens new opportunities for developing therapeutic targets.

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New molecular targets for the treatment of osteoarthritis

Cited by 123 publications

References 96 publications

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

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

Next-generation Sequencing Identifies Articular Cartilage and Subchondral Bone Mirnas after ESWT on Early Osteoarthritis Knee

BMP-2, Hypoxia, and COL1A1/HtrA1 siRNAs Favor Neo-Cartilage Hyaline Matrix Formation in Chondrocytes

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