Wnt and Rho GTPase signaling in osteoarthritis development and intervention: implications for diagnosis and therapy

Zhu, Shouan; Liu, Huanhuan; Wu, Yan; Heng, Boon Chin; Chen, Pengfei; Liu, Hua; Ouyang, Hong

doi:10.1186/ar4240

Cited by 20 publications

(11 citation statements)

References 92 publications

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“…While uncultured bacterium (77133) was observed to be involved in the upregulation of most of the ECM signaling and collagen pathways, the other microbes were significantly correlated to the downregulation of other signaling pathways crucial to joint and immune function. Wnt and Rho GTPase signaling pathways have a synergistic role in transducing signals from the ECM to govern numerous aspects of cell physiology and were both found to be downregulated [ 33 ]. In addition, the neutrophil degranulation pathway was also downregulated.…”

Section: Resultsmentioning

confidence: 99%

Identification and Characterization of the Intra-Articular Microbiome in the Osteoarthritic Knee

Tsai

Casteneda

Lee

et al. 2020

IJMS

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Osteoarthritis (OA) is the most common joint disorder in the United States, and the gut microbiome has recently emerged as a potential etiologic factor in OA development. Recent studies have shown that a microbiome is present at joint synovia. Therefore, we aimed to characterize the intra-articular microbiome within osteoarthritic synovia and to illustrate its role in OA disease progression. RNA-sequencing data from OA patient synovial tissue was aligned to a library of microbial reference genomes to identify microbial reads indicative of microbial abundance. Microbial abundance data of OA and normal samples was compared to identify differentially abundant microbes. We computationally explored the correlation of differentially abundant microbes to immunological gene signatures, immune signaling pathways, and immune cell infiltration. We found that microbes correlated to OA are related to dysregulation of two main functional pathways: increased inflammation-induced extracellular matrix remodeling and decreased cell signaling pathways crucial for joint and immune function. We also confirmed that the differentially abundant and biologically relevant microbes we had identified were not contaminants. Collectively, our findings contribute to the understanding of the human microbiome, well-known OA risk factors, and the role microbes play in OA pathogenesis. In conclusion, we present previously undiscovered microbes implicated in the OA disease progression that may be useful for future treatment purposes.

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Section: Resultsmentioning

confidence: 99%

Identification and Characterization of the Intra-Articular Microbiome in the Osteoarthritic Knee

Tsai

Casteneda

Lee

et al. 2020

IJMS

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“…PI3K/AKT-, MAPK-, WNT-, NTRK-, ERBB2-, and EGFR- signaling pathways were also overrepresented with key miR-375 target genes. However, PI3K/AKT-, MAPK- pathways are known to be significantly intermingled with Rho-GTPase signaling [ 7 , 8 ], whereas WNT-, NTRK-, ERBB2-, and EGFR-pathways may function via Rho-GTPase dependent transducers [ 9 , 10 , 11 , 12 , 13 ]. Thus, we may assume that miR-375 action in the heart muscle is primarily directed to the regulation of Rho-GTPase genes’ expression.…”

Section: Discussionmentioning

confidence: 99%

From miRNA Target Gene Network to miRNA Function: miR-375 Might Regulate Apoptosis and Actin Dynamics in the Heart Muscle via Rho-GTPases-Dependent Pathways

Osmak

Kiselev

Baulina

et al. 2020

IJMS

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MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, which are involved in the regulation of main biological processes, such as apoptosis or cell proliferation and differentiation, through sequence-specific interaction with target mRNAs. In this study, we propose a workflow for predicting miRNAs function by analyzing the structure of the network of their target genes. This workflow was applied to study the functional role of miR-375 in the heart muscle (myocardium), since this miRNA was previously shown to be associated with heart diseases, and data on its function in the myocardium are mostly unclear. We identified PIK3CA, RHOA, MAPK3, PAFAH1B1, CTNNB1, MYC, PRKCA, ERBB2, and CDC42 as key genes in the miR-375 regulated network and predicted the possible function of miR-375 in the heart muscle, consisting mainly in the regulation of the Rho-GTPases-dependent signaling pathways. We implemented our algorithm for miRNA function prediction into a Python module, which is available at GitHub.

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“…Rac1, a member of the Rho GTPase family, plays divergent roles in controlling cell cycle, cell–cell adhesion, motility (through controlling the actin network), and epithelial differentiation . Recent studies by our group and others have identified a key role of aberrant Rac1 activation in promoting chondrocyte hypertrophy and mineralization during OA development .…”

mentioning

confidence: 93%

Down‐Regulation of Rac GTPase‐Activating Protein OCRL1 Causes Aberrant Activation of Rac1 in Osteoarthritis Development

Zhu

Dai

Liu

et al. 2015

Arthritis & Rheumatology

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Objective. Chondrocyte hypertrophy and mineralization are considered to be important pathologic factors in osteoarthritis (OA). We previously reported that Rac1 was aberrantly activated to promote chondrocyte hypertrophy, mineralization, and expression of matrix metalloproteinase 13 and ADAMTS in OA. However, the underlying mechanism of aberrant Rac1 activation in OA is unclear. The present study was undertaken to identify the specific molecular regulator controlling Rac1 activity in OA, as well as to investigate its function in chondrocyte hypertrophy, mineralization, and OA development.Methods. Expression levels of 28 upstream regulators of Rac1 activity, including 8 GTPase-activating proteins (GAPs) and 20 guanine nucleotide exchange factors, in OA and normal cartilage were assessed by quantitative polymerase chain reaction. Chondrocytes were transduced with lentiviral vectors encoding OCRL1, GAP, non-GAP, CA-Rac1, and DN-Rac1, either alone or in combination. Alkaline phosphatase staining was used as a marker of chondrocyte hypertrophy. Rac1 activity was analyzed by pulldown assay. Finally, OA was established in mice by surgical transection of the anterior cruciate ligament and cutting of the medial meniscus. The mice were injected intraarticularly with OCRL1-encoding lentivirus, and whole joints were assessed histologically 6 weeks after surgery.Results. OCRL1 was abundantly expressed in normal cartilage and was the only significantly downregulated RacGAP in OA cartilage. Overexpression of OCRL1 inhibited interleukin-1b-induced Rac1 activity, chondrocyte hypertrophy, and expression of hypertrophyrelated genes. Conversely, knockdown of OCRL1 elevated Rac1 activity and promoted chondrocyte hypertrophy and mineralization. Further, OCRL1 modulated Rac1 activity via its GAP domain. Finally, intraarticular injection of OCRL1-encoding lentivirus protected against destruction and degeneration of cartilage in the mouse OA model.Conclusion. OCRL1 acts as a RacGAP in cartilage to impede chondrocyte hypertrophy and OA development through modulating Rac1 activity. This regulatory pathway might provide potential targets for the development of new therapies for OA.Osteoarthritis (OA), characterized by cartilage degradation, synovial inflammation, and subchondral bone remodeling, is the most common form of degenerative joint disease (1). There is now a general consensus that chondrocytes in OA undergo hypertrophy and mineralization (characterized by expression of matrix metalloproteinase 13 [2], type X collagen [3],

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Wnt and Rho GTPase signaling in osteoarthritis development and intervention: implications for diagnosis and therapy

Cited by 20 publications

References 92 publications

Identification and Characterization of the Intra-Articular Microbiome in the Osteoarthritic Knee

Identification and Characterization of the Intra-Articular Microbiome in the Osteoarthritic Knee

From miRNA Target Gene Network to miRNA Function: miR-375 Might Regulate Apoptosis and Actin Dynamics in the Heart Muscle via Rho-GTPases-Dependent Pathways

Down‐Regulation of Rac GTPase‐Activating Protein OCRL1 Causes Aberrant Activation of Rac1 in Osteoarthritis Development

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