Inhibition of smoothened decreases proliferation of synoviocytes in rheumatoid arthritis

Zhu, Shang Ling; Huang, Jian; Peng, Wei; Wu, Dan; Luo, Min; Li, Qiu Xia; Li, Zhao Xia; Feng, Xiao; Liu, Fang; Wang, Ming Xia; Chen, Wei Qian; Olsen, Nancy J.; Zheng, Song Guo

doi:10.1038/cmi.2015.67

Cited by 27 publications

(19 citation statements)

References 29 publications

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“…Moreover, the level of activation and aberrant expression of Ihh protein correlates with disease severity (Lin et al, ; Shuang et al, ). Targeting Hedgehog signaling in disease models has shown some efficacy in the prevention of articular cartilage degeneration (Li, Cai, & Ding, ; Lin et al, ), osteophyte formation (Ruiz‐Heiland et al, ) and synovitis, and synovial hyperplasia (Zhu et al, ). Given the dependence of Hedgehog signaling upon primary cilia integrity and the disruptions to cilia structure reported in this study, the concept of “ciliotherapy” (targeting disease pathways through the cilium) is one that could be readily applied to the treatment of cartilage degeneration not only in OA, but in the arthropathy associated with AKU.…”

Section: Discussionmentioning

confidence: 99%

Reduced primary cilia length and altered Arl13b expression are associated with deregulated chondrocyte Hedgehog signaling in alkaptonuria

Thorpe

Gambassi

Thompson

et al. 2017

Journal Cellular Physiology

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Alkaptonuria (AKU) is a rare inherited disease resulting from a deficiency of the enzyme homogentisate 1,2‐dioxygenase which leads to the accumulation of homogentisic acid (HGA). AKU is characterized by severe cartilage degeneration, similar to that observed in osteoarthritis. Previous studies suggest that AKU is associated with alterations in cytoskeletal organization which could modulate primary cilia structure/function. This study investigated whether AKU is associated with changes in chondrocyte primary cilia and associated Hedgehog signaling which mediates cartilage degradation in osteoarthritis. Human articular chondrocytes were obtained from healthy and AKU donors. Additionally, healthy chondrocytes were treated with HGA to replicate AKU pathology (+HGA). Diseased cells exhibited shorter cilia with length reductions of 36% and 16% in AKU and +HGA chondrocytes respectively, when compared to healthy controls. Both AKU and +HGA chondrocytes demonstrated disruption of the usual cilia length regulation by actin contractility. Furthermore, the proportion of cilia with axoneme breaks and bulbous tips was increased in AKU chondrocytes consistent with defective regulation of ciliary trafficking. Distribution of the Hedgehog‐related protein Arl13b along the ciliary axoneme was altered such that its localization was increased at the distal tip in AKU and +HGA chondrocytes. These changes in cilia structure/trafficking in AKU and +HGA chondrocytes were associated with a complete inability to activate Hedgehog signaling in response to exogenous ligand. Thus, we suggest that altered responsiveness to Hedgehog, as a consequence of cilia dysfunction, may be a contributing factor in the development of arthropathy highlighting the cilium as a novel target in AKU.

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Section: Discussionmentioning

confidence: 99%

Reduced primary cilia length and altered Arl13b expression are associated with deregulated chondrocyte Hedgehog signaling in alkaptonuria

Thorpe

Gambassi

Thompson

et al. 2017

Journal Cellular Physiology

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“…Several cell types, including T cells, B cells, macrophages, fibroblast-like synoviocytes (FLSs), and the complex interaction of many pro-inflammatory cytokines play a major role in the pathogenesis of this disease ( 3 ). Among these, the FLSs are the main effector cells responsible for initiating and driving both the inflammatory process as well as the invasive nature of rheumatoid synovium ( 4 – 7 ). A congeries of evidence now suggests that the RA-FLSs, when activated in a chronic inflammatory environment, display many features of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Long Non-Coding RNA GAPLINC Promotes Tumor-Like Biologic Behaviors of Fibroblast-Like Synoviocytes as MicroRNA Sponging in Rheumatoid Arthritis Patients

Guo

Yang

et al. 2018

Front. Immunol.

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Rapidly accumulating evidence has now suggested that the long non-coding RNAs (LncRNAs), a large and diverse class of non-coding transcribed RNA molecules with diverse functional roles and mechanisms, play a major role in the pathogenesis of many human inflammatory diseases. Although some LncRNAs are overexpressed in plasma, T cell, and synovial tissues of patients with rheumatoid arthritis (RA), there is a dearth of knowledge in what role these transcripts play in fibroblast-like synoviocytes (FLSs) of these patients. Here, our studies showed that GAPLINC, a newly identified functional LncRNA in oncology, displayed a greater degree of expression in FLSs from RA than in patients with traumatic injury. GAPLINC suppression in RA-FLS cells revealed significant alterations in cell proliferation, invasion, migration, and proinflammatory cytokines production. Additionally, we performed a preliminary bioinformatics analysis of GAPLINC gene sequence in order to find its target molecules, using miRanda, PITA, RNAhybrid algorithms, Kyoto encyclopedia of genes and genomes, and gene ontology analysis. Since the results predicted that some of microRNAs and mRNA may interact with GAPLINC, we simulated a gene co-action network model based on a competitive endogenous RNA theory. Further verification of this model demonstrated that silencing of GAPLINC increased miR-382-5p and miR-575 expression. The results of this study suggest that GAPLINC may function as a novel microRNAs sponging agent affecting the biological characteristics of RA-FLSs. Additionally, GAPLINC may also promote RA-FLS tumor-like behaviors in a miR-382-5p-dependent and miR-575-dependent manner. Based upon these findings, LncRNA GAPLINC may provide a novel valuable therapeutic target for RA patients.

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“…Sonic hedgehog (SHH) signaling pathway plays a pivotal role in FLSs proliferation in a SMO-dependent manner. Upregulation of SMO promotes proliferation of FLSs [17][18]. Targeting SHH signaling pathway may help control joint damage in patients with RA [19].…”

Section: Discussionmentioning

confidence: 99%

New perspective: the multi-targets mechanism of hydroxychloroquine in the treatment of rheumatoid arthritis based on network pharmacology

Xie

et al. 2020

Preprint

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Background Network pharmacology is a new method of bioinformatics in exploring drug targets in recent 3 years. Hydroxychloroquine (HCQ) is a multi-targets drug that are clinically effective in rheumatoid arthritis (RA) but whose mechanism is not well understood. Methods The predicted targets of HCQ and the proteins related to RA were returned from databases. Followed by protein-protein interaction (PPI) network, the intersection of the two group of proteins was conducted. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment was used to analyse these proteins in a macro perspective. Finally, the candidate targets were verified by molecular docking. Results The results suggest that the efficacy of HCQ against RA is mainly associated with 4 targets of smoothened homolog (SMO), sphingosine kinase (SPHK) 1, SPHK2 and gatty-acid amide hydrolase (FAAH), with their related 3316 proteins’ network which regulate ErbB, HIF-1, NF-κB, FoxO, Chemokine, MAPK, PI3K/Akt pathways and so forth. Biological process are mainly concentrated in the regulation of cell activation, myeloid leukocyte activation, regulated exocytosis and so forth. Molecular docking analysis shows that hydrogen bonding and π-π stacking are the main forms of chemical force. Conclusions Our research provides protein targets affected by HCQ in the treatment of RA. SMO, SPHK1, SPHK2 and FAAH involving 3316 proteins become the multi-targets mechanism of HCQ in the treatment of RA. As well, the research also provides a new idea for introducing network pharmacology into the evaluation of the multi-target drugs in internal medicine.

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Inhibition of smoothened decreases proliferation of synoviocytes in rheumatoid arthritis

Cited by 27 publications

References 29 publications

Reduced primary cilia length and altered Arl13b expression are associated with deregulated chondrocyte Hedgehog signaling in alkaptonuria

Reduced primary cilia length and altered Arl13b expression are associated with deregulated chondrocyte Hedgehog signaling in alkaptonuria

Long Non-Coding RNA GAPLINC Promotes Tumor-Like Biologic Behaviors of Fibroblast-Like Synoviocytes as MicroRNA Sponging in Rheumatoid Arthritis Patients

New perspective: the multi-targets mechanism of hydroxychloroquine in the treatment of rheumatoid arthritis based on network pharmacology

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