A selective c-Fos/AP-1 inhibitor prevents cartilage destruction and subsequent osteophyte formation

Motomura, Hiroyuki; Seki, Shoji; Shiozawa, Shunichi; Aikawa, Yukihiko; Nogami, Makiko; Kimura, Takeshi

doi:10.1016/j.bbrc.2018.02.147

Cited by 42 publications

(33 citation statements)

References 30 publications

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“…For instance, mice with a knockout gene that encodes a protease specific to the knee joint might be less likely to develop OA than wild type mice. Genetically modifying mice to find protective factors is a promising avenue in developing future treatments for OA [22]. For example, Motomura et al found that c-Fos/activator protein (AP)-1 inhibitor, T-5224, which inhibits matrix metalloproteinases (MMPs) prevents cartilage destruction and reduces rates of OA in mice [22].…”

Section: Genetically Modified Modelsmentioning

confidence: 99%

“…Genetically modifying mice to find protective factors is a promising avenue in developing future treatments for OA [22]. For example, Motomura et al found that c-Fos/activator protein (AP)-1 inhibitor, T-5224, which inhibits matrix metalloproteinases (MMPs) prevents cartilage destruction and reduces rates of OA in mice [22]. The advantage of using mice which are likely to develop OA is that it saves researchers time and money compared to using wild type mice which have a lower incidence of OA [5,6,8].…”

Section: Genetically Modified Modelsmentioning

confidence: 99%

“…Naturally occurring X X X X [9][10][11] Genetically modified X X X X [12][13][14][15][16][17][18][19][20][21][22][23][24] Surgically induced (all) X X X X X [25][26][27][28][29][30] Chemically induced (all) X [31][32][33][34][35][36][37][38][39] Non-invasive induction X X X X X [40][41][42][43][44][45][46][47][48][49][50][51][52] [5,8,63,64]…”

Section: Referencesmentioning

confidence: 99%

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Pros and cons of mouse models for studying osteoarthritis

Bapat¹,

Hubbard²,

Munjal³

et al. 2018

Clinical & Translational Med

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Osteoarthritis (OA) is one of the most common chronic conditions in the world today. It results in breakdown of cartilage in joints and causes the patient to experience intense pain and even disability. The pathophysiology of OA is not fully understood; therefore, there is currently no cure for OA. Many researchers are investigating the pathophysiology of the disease and attempting to develop methods to alleviate the symptoms or cure the OA entirely using animal models. Most studies on OA use animal models; this is necessary as the disease develops very slowly in humans and presents differently in each patient. This makes it difficult to effectively study the progression of osteoarthritis. Animal models can be spontaneous, in which OA naturally occurs in the animal. Genetic modifications can be used to make the mice more susceptible to developing OA. Osteoarthritis can also be induced via surgery, chemical injections, or non-invasive trauma. This review aims to describe animal models of inducing osteoarthritis with a focus on the models used on mice and their advantages and disadvantages that each model presents.

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Section: Genetically Modified Modelsmentioning

confidence: 99%

Section: Genetically Modified Modelsmentioning

confidence: 99%

See 1 more Smart Citation

Pros and cons of mouse models for studying osteoarthritis

Bapat¹,

Hubbard²,

Munjal³

et al. 2018

Clinical & Translational Med

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show abstract

“…Indeed, MMP-3 has been identi ed in OA synovium and synovia, and its expression levels are regarded to be relative to OA severity and SDF-1 release [12,19,24]. Following the release of MMPs, collagens, and matrix proteins such as ACAN degrade, the OA pathological process accelerates [25]. Our previous studies have determined that levels of col II and ACAN are notably reduced in a spontaneous OA guinea pig model, and they reversibly increased as a consequence of T140 treatment [19].…”

Section: Discussionmentioning

confidence: 99%

Comparative effectiveness of two methods for inducing osteoarthritis in a novel animal model, the Diannan small-ear pig1

Jia

Cai

et al. 2020

Preprint

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Abstract Background: Varieties of animals were used to study osteoarthritis pathogenesis. The Diannan small-ear pig, which is native to Yunnan, China, is thought to have an articular anatomy similar to that of humans and is more likely to be a source of pathological tissues than other animals. The aim of this study was determine whether this animal can serve as a more effective osteoarthritis model.[A1] Methods: Twenty-seven adult pigs were randomly divided into three groups and underwent the Hulth procedure, papain articular injection [A2] , and conventional breeding. After 4, 8, and 12 weeks, cartilage tissues from knee joint were extracted for general and histological observation, immunofluorescence, and biochemical analysis. [A3] Synovium was taken out for stromal cell-derived factor-1 analysis. Results: Histopathological observation showed obvious cartilage loss in two experimental groups, this cartilage loss was more severe in the chemical groups. Synovial stromal cell-derived factor1 levels increased over time in all groups. mRNA and protein levels of matrix metalloproteinase-3 were much higher in the chemical groups than in the other groups, whereas levels of collagen type II[A4] and aggrecan were significantly lower in the chemical groups than in the other groups. Immunofluorescence assays of collagen type II[A5] revealed an apparent reduction in this marker in the chemical groups compared with the other groups. Conclusions: These results indicated that the Diannan small-ear pig can be used as an effective osteoarthritis model. In addition, it is much more convenient and much faster to induce osteoarthritis by intra-articular injection of papain, which is a method worthy of being promoted.

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“…Early-response genes (both up-and downregulated) exhibited changes in expression as early as 3 hours but generally peaked at 6 hours of FN-f treatment. These early-response genes include many upregulated genes that have been previously implicated in OA, including AP-1 components FOS and JUN 24,37 , NOD2 38 , RIPK2 38 , the aggrecanase ADAMTS4 24,39 , CXCL1, CXCL2, and CXCL3 16 , LIF, TNF [40][41][42] , TNFAIP6 and TNFRSF11B 19 , PTGES 19 , IL6 and IL8 39,41,43,44 . Among genes that decreased early was the transcription factor SP7, which is downregulated by TNF 45 .…”

Section: Fn-f Triggers Both Early-and Late-response Genesmentioning

confidence: 99%

Transcriptional response of human articular chondrocytes treated with fibronectin fragments: anin vitromodel of the osteoarthritis phenotype

Reed¹,

Ulici²,

Kim³

et al. 2020

Preprint

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Objective: Fibronectin is a matrix protein that is fragmented during cartilage degradation in osteoarthritis (OA). Treatment of chondrocytes with fibronectin fragments (FN-f) has been used to model OA in vitro, but the system has not been fully characterized. This study sought to define the transcriptional response of chondrocytes to FN-f, and directly compare it to responses traditionally observed in OA.Design: Normal human femoral chondrocytes isolated from tissue donors were treated with either FN-f or PBS (control) for 3, 6, or 18 hours. RNA-seq libraries were compared between time-matched FN-f and control samples in order to identify changes in gene expression over time. Differentially expressed genes were compared to a published OA gene set and used for pathway, transcription factor motif, and kinome analysis.Results: FN-f treatment resulted in 1,224 differentially expressed genes over the time course. Genes that are up-or downregulated in OA were significantly up-(p < 0.00001) or downregulated (p < 0.0004) in response to FN-f. Early response genes were involved in proinflammatory pathways and their promoters were enriched for NF-κB-related motifs, whereas many late response genes were involved in ferroptosis, and their promoters were enriched for Jun-related motifs. Highly upregulated kinases included CAMK1G, IRAK2, and the uncharacterized kinase DYRK3, while growth factor receptors TGFBR2 and FGFR2 were downregulated.Conclusions: FN-f treatment of normal human articular chondrocytes recapitulated many key aspects of the OA chondrocyte phenotype. This in vitro model is promising for future OA studies, especially considering its compatibility with genomics and genome-editing techniques.

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A selective c-Fos/AP-1 inhibitor prevents cartilage destruction and subsequent osteophyte formation

Cited by 42 publications

References 30 publications

Pros and cons of mouse models for studying osteoarthritis

Pros and cons of mouse models for studying osteoarthritis

Comparative effectiveness of two methods for inducing osteoarthritis in a novel animal model, the Diannan small-ear pig1

Transcriptional response of human articular chondrocytes treated with fibronectin fragments: anin vitromodel of the osteoarthritis phenotype

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