Gene Expression Profile of the Synovium and Cartilage in a Chronic Arthritis Rat Model

Zhu, Weimin; Wang, Daping; Lü, Wei; Han, Yisheng; Yu-xiang, OU; Zhou, Ke; Peng, Liangquan; Feng, Wenzhe; Li, Hao; Chen, Qi; Zhang, Kai; Zeng, Yanjun; Zhang, Xiaojun

doi:10.3109/10731199.2011.592493

Cited by 2 publications

(2 citation statements)

References 17 publications

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“…Interestingly, while human FN1 gene has three alternatively spliced regions, with the potential to produce 20 different transcript variants, most of these variants have the same 5’UTR which as we demonstrated is important for Fn1 efficient translation. Our data are in line with an early work that suggested the regulation of Fn1 expression in OA cartilage through protein synthesis (2) as well as with data demonstrated an increase in Fn1 protein (but not mRNA) level in OA cartilage (10, 11, 13). It is important to notice that while we used IL-1β, other pro-inflammatory cytokines stimulating mTORC1 activity would ultimately lead to 4E-BP inactivation and have similar effect on translationally regulated genes and on protein synthesis in general.…”

Section: Discussionsupporting

confidence: 93%

Control of cartilage homeostasis and osteoarthritis progression by mTORC1/4E-BP/eIF4E axis

Katsara

Attur²,

Kolupaeva³

2019

Preprint

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As world population growing older, burden of age-related conditions soars. One of them is osteoarthritis (OA), a debilitating joint disease with no effective treatment. Articular cartilage degeneration is a central event in OA, and changes in expression of many genes in OA cartilage are well-documented. Still, the specific mechanisms are rarely known. We showed that in OA cartilage the increased abundance of many proteins, including extracellular matrix protein Fibronectin (Fn1) and an orphan nuclear receptor Nr4a1 is translationally controlled and requires inactivation of 4EBP, an inhibitor of cap-dependent translation. Importantly, intra-articular injection of the translation inhibitor 4E1RCat reduces Fn1 and Nr4a upregulation in a rodent OA model and delays cartilage degeneration. Our results support the hypothesis that maintaining proper translational control is an important homeostatic mechanism, the loss of which contributes to OA development.Recent publications from two independent groups have highlighted the importance of IL-1 signaling in various small and larger animal models of posttraumatic OA (22)(23)(24)(25). For example, IL-1 receptor antagonist therapy significantly improved cartilage, synovial membrane parameters, and disease-modifying effects in the equine OA model (26). The role of translation control in the inflammatory response was examined in macrophages (27), but never in chondrocytes. We therefore used polysome profiling to assess the translational landscape of IL-1β treated primary articular chondrocytes. In polysomal profiling, actively translated mRNAs bound by several ribosomes (polysomes) are separated from "free" mRNA and the 80S monosomes by sucrose gradient centrifugation. This allows determining the translational status of a specific mRNA. Potential clinical relevance of several identified translationally controlled targets, such as Fn and an orphan receptor Nr4a1, was tested in diseased cartilage and in a rodent model of post-traumatic OA. To demonstrate the importance of translational control for cartilage homeostasis, we injected intra-articularly an inhibitor of cap-dependent translation. This treatment significantly delays OA progression. Our findings therefore reveal that translational control, acting at Fn and Nr4a1 among other targets, is essential for maintaining cartilage homeostasis.Moreover, targeting translational apparatus represents a new strategy to treat/prevent OA, particularly as it opens up the possibility to target simultaneously a pool of functionally distinct proteins. MATERIALS AND METHODSIsolation and characterization of translationally active pool of mRNAs by polysome fraction analysis, library preparation, and sequencing. RAC was isolated and treated at the first passage as described previously (18). For 10 final minutes, cells were incubated with Cyclohexamide (100ug/ml) at 37 o C.Cells were collected, washed twice with ice-cold PBS supplemented with Cyclohexamide (100ug/ml) and lysed on ice for 10min in buffer "A" (SI). 2OD units of extract (3 independ...

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Section: Discussionsupporting

confidence: 93%

Control of cartilage homeostasis and osteoarthritis progression by mTORC1/4E-BP/eIF4E axis

Katsara

Attur²,

Kolupaeva³

2019

Preprint

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“…To further explore whether leptin is involved in the pathogenesis of OA, our leptin-mediated gene expression profile was compared with those of two previous microarray studies performed by Zhu et al [26] and Meng et al [27]. In the study by Zhu et al, a total of 82 differentially expressed genes were reported, many of which are known to play an important role in the pathogenesis of osteoarthritis, including inflammatory factors and matrix metalloproteinase (MMP), growth factors, apoptosis, energy and other related genes.…”

Section: Resultsmentioning

confidence: 99%

Microarray study of gene expression profile to identify new candidate genes involved in the molecular mechanism of leptin-induced knee joint osteoarthritis in rat

Fan

Shen

et al. 2017

Hereditas

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BackgroundOsteoarthritis (OA) is one of the most prevalent chronic joint diseases while the precise genetic mechanism remains elusive. In this study, we investigated the gene expression profile in OA by microarray analysis.ResultsHistopathological characteristics of OA cartilage were examined using a rat model of leptin-induced OA. Gene expression profile of leptin-induced articular cartilage and healthy rat cartilage were compared using genome-wide microarray hybridization. A total of 1857 genes differentially expressed genes (1197 upregulated and 660 downregulated) were identified, some of which are known to be associated with leptin-induced OA phenotype. These included genes related to MMPs, inflammatory factors, growth factors, apoptotic genes and osteogenic genes. In addition, upregulated expressions of some new candidate genes, which have hitherto fore not been linked to OA (such as BCL2L11) were detected in leptin-induced OA cartilage, which suggests that these genes might be important for OA molecular mechanism.ConclusionOur findings suggest that pathogenesis of leptin-induced OA involves modulation of expression of multiple genes, although the underlying molecular mechanisms need to be studied further. Further investigation of leptin-induced gene expression changes is needed to gain new insights into the molecular mechanism of OA pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s41065-017-0039-z) contains supplementary material, which is available to authorized users.

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Gene Expression Profile of the Synovium and Cartilage in a Chronic Arthritis Rat Model

Cited by 2 publications

References 17 publications

Control of cartilage homeostasis and osteoarthritis progression by mTORC1/4E-BP/eIF4E axis

Control of cartilage homeostasis and osteoarthritis progression by mTORC1/4E-BP/eIF4E axis

Microarray study of gene expression profile to identify new candidate genes involved in the molecular mechanism of leptin-induced knee joint osteoarthritis in rat

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