Mannosylated bioreducible nanoparticle-mediated macrophage-specific TNF-α RNA interference for IBD therapy

Psoriatic arthritis (PsA) results from joint destruction by osteoclasts. The promising efficacy of TNF-α blockage indicates its important role in osteoclastogenesis of PsA. WNT ligands actively regulate osteoclastogenesis. We investigated how WNT ligands activate osteoclasts amid the TNF-α milieu in PsA. We first profiled the expression of WNT ligands in CD14+ monocyte-derived osteoclasts (MDOC) from five PsA patients and five healthy controls (HC) and then validated the candidate WNT ligands in 32 PsA patients and 16 HC. Through RNA interference against WNT ligands in MDOC, we determined the mechanisms by which TNF-α exerts its effects on osteclastogenesis or chemotaxis. WNT5A was selectively upregulated by TNF-α in MDOC from PsA patients. The number of CD68+WNT5A+ osteoclasts increased in PsA joints. CXCL1, CXCL16, and MCP-1 was selectively increased in supernatants of MDOC from PsA patients. RNA interference against WNT5A abolished the increased MCP-1 from MDOC and THP-1-cell-derived osteoclasts. The increased migration of osteoclast precursors (OCP) induced by supernatant from PsA MDOC was abolished by the MCP-1 neutralizing antibody. WNT5A and MCP-1 expressions were decreased in MDOC from PsA patients treated by biologics against TNF-α but not IL-17. We conclude that TNF-α recruits OCP by increased MCP-1 production but does not directly activate osteoclastogenesis in PsA.

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The time-course and RNA interference of TNF-α, IL-6, and IL-1β expression on neuropathic pain induced by L5 spinal nerve transection in rats

Korean Journal of Anesthesiology ◽

10.4097/kjae.2015.68.2.159 ◽

2015 ◽

Vol 68 (2) ◽

pp. 159 ◽

Cited By ~ 9

Author(s):

Byung Moon Choi ◽

Soo Han Lee ◽

Sang Mee An ◽

Do Yang Park ◽

Gwan Woo Lee ◽

...

Keyword(s):

Neuropathic Pain ◽

Rna Interference ◽

Time Course ◽

Spinal Nerve ◽

Nerve Transection ◽

Tnf Α

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TNF-α activates WNT5A, which recruits osteoclast precursors by MCP-1 production, but not directly activates osteoclastogenesis, in psoriatic arthritis

10.21203/rs.3.rs-1016394/v1 ◽

2021 ◽

Author(s):

Shang-Hung Lin ◽

Ji-Chen Ho ◽

Chung-Yuan Hsu ◽

Sung-Chou Li ◽

Wen-Yi Chou ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Rna Interference ◽

Joint Destruction ◽

Neutralizing Antibody ◽

Healthy Controls ◽

Osteoclast Precursors ◽

Tnf Α ◽

Wnt Ligands

Abstract Background: Psoriatic arthritis (PsA) results from joint destruction by osteoclasts. Promising efficacy of TNF-α blockage indicates its important role in osteoclastogenesis of PsA. WNT ligands actively regulate osteoclastogenesis. We investigated how WNT ligands activate osteoclasts amid the TNF-α milieu in PsA. Methods: We first profiled the expression of WNT ligands in CD14+ monocyte-derived osteoclasts (MDOC) from 3 PsA patients and 3 healthy controls (HC) and then validated the candidate WNT ligands in 32 PsA patients and 16 HC. Through RNA interference against WNT ligands in MDOC, we determined the mechanisms by which TNF-α exerts its effects on osteclastogenesis or chemotaxis. Results: The results showed numbers of CD68+WNT5A+ osteoclasts are increased in PsA joints. WNT5A was selectively upregulated by TNF-α in MDOC from PsA patients. However, direct osteoclastogenesis effect (RANK expression) by TNF-αwas not inhibited by WNT5A siRNA. Instead, CXCL1, CXCL16, and MCP-1 was selectively increased in supernatants of MDOC from PsA patients. RNA interference against WNT5A abolished the increased MCP-1 from MDOC and THP-1-cell-derived osteoclasts. The increased migration of osteoclast precursors (OCP) induced by supernatant from PsA MDOC was abolished by MCP-1 neutralizing antibody. WNT5A and MCP-1 expressions were decreased in MDOC from PsA patients treated by biologics against TNF-a but not IL-17. Conclusion: We conclude TNF-α recruits OCP by WNT5A-mediated MCP-1 production but not directly activates osteoclastogenesis in PsA.

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Branched RNA: A New Architecture for RNA Interference

Journal of Nucleic Acids ◽

10.4061/2011/586935 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Anna Aviñó ◽

Sandra M. Ocampo ◽

José Carlos Perales ◽

Ramon Eritja

Keyword(s):

Rna Interference ◽

Gene Silencing ◽

Delivery Systems ◽

Specific Gene ◽

Rna Modifications ◽

Tnf Α ◽

Innovative Tool ◽

Branched Rna ◽

Gene Inhibition ◽

Novel Structures

Branched RNAs with two and four strands were synthesized. These structures were used to obtain branched siRNA. The branched siRNA duplexes had similar inhibitory capacity as those of unmodified siRNA duplexes, as deduced from gene silencing experiments of the TNF-α protein. Branched RNAs are considered novel structures for siRNA technology, and they provide an innovative tool for specific gene inhibition. As the method described here is compatible with most RNA modifications described to date, these compounds may be further functionalized to obtain more potent siRNA derivatives and can be attached to suitable delivery systems.

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MiR-146a-5p Expression in Peripheral CD14+ Monocytes from Patients with Psoriatic Arthritis Induces Osteoclast Activation, Bone Resorption, and Correlates with Clinical Response

Journal of Clinical Medicine ◽

10.3390/jcm8010110 ◽

2019 ◽

Vol 8 (1) ◽

pp. 110 ◽

Cited By ~ 11

Author(s):

Shang-Hung Lin ◽

Ji-Chen Ho ◽

Sung-Chou Li ◽

Jia-Feng Chen ◽

Chang-Chun Hsiao ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Rna Interference ◽

Bone Resorption ◽

Clinical Response ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Monocyte Activation ◽

Tnf Α ◽

Osteoclast Activation ◽

Normal Controls

In psoriatic arthritis (PsA), progressive bone destruction is mediated by monocyte-derived osteoclasts. MicroRNAs (miRNAs) regulate many pathophysiological processes; however, their function in PsA patient monocytes has not been examined. This study aims to address whether specific miRNAs in CD14+ monocytes and monocyte-derived osteoclasts cause active osteoclastogenesis in PsA patients. Candidate miRNAs related to monocyte activation (miR-146a-5p, miR-146b-5p and miR-155-5p) were measured in circulatory CD14+ monocytes collected from 34 PsA patients, 17 psoriasis without arthritis (PsO) patients, and 34 normal controls (NCs). CD14+ monocytes were cultured with media containing TNF-α and RANKL to differentiate into osteoclasts. Osteoclast differentiation and bone resorption were measured by TRAP immunostaining and dentin slice resorption, respectively. The results showed that the miR-146a-5p expression was higher in PsA patient-derived CD14+ monocytes compared to PsO and NCs. Activation and bone resorption were selectively enhanced in osteoclasts from PsA patients, but both were abrogated by RNA interference against miR-146a-5p. More importantly, after clinical improvement using biologics, the increased miR-146a-5p expression in CD14+ monocytes from PsA patients was selectively abolished, and associated with blood CRP level. Our findings indicate that miR-146a-5p expression in CD14+ monocytes derived from PsA patients correlates with clinical efficacy, and induction of osteoclast activation and bone resorption.

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c-Jun N-terminal kinase – c-Jun pathway transactivates Bim to promote osteoarthritis

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2013-0228 ◽

2014 ◽

Vol 92 (2) ◽

pp. 132-139 ◽

Cited By ~ 18

Author(s):

Zhiqiang Ye ◽

Yuxian Chen ◽

Rongkai Zhang ◽

Haitao Dai ◽

Chun Zeng ◽

...

Keyword(s):

Nitric Oxide ◽

Articular Cartilage ◽

Rna Interference ◽

Animal Models ◽

Chondrocyte Apoptosis ◽

Kinase C ◽

Tnf Α ◽

Chemical Inhibitors ◽

Joint Disorder

Osteoarthritis (OA) is a chronic degenerative joint disorder. Previous studies have shown abnormally increased apoptosis of chondrocytes in patients and animal models of OA. TNF-α and nitric oxide have been reported to induce chondrocyte ageing; however, the mechanism of chondrocyte apoptosis induced by IL-1β has remained unclear. The aim of this study is to identify the role of the c-Jun N-terminal kinase (JNK) – c-Jun pathway in regulating induction of Bim, and its implication in chondrocyte apoptosis. This study showed that Bim is upregulated in chondrocytes obtained from the articular cartilage of OA patients and in cultured mouse chondrocytes treated with IL-1β. Upregulation of Bim was found to be critical for chondrocyte apoptosis induced by IL-1β, as revealed by the genetic knockdown of Bim, wherein apoptosis was greatly reduced in the chondrocytes. Moreover, activation of the JNK–c-Jun pathway was observed under IL-1β treatment, as indicated by the increased expression levels of c-Jun protein. Suppression of the JNK–c-Jun pathway, using chemical inhibitors and RNA interference, inhibited the Bim upregulation induced by IL-1β. These findings suggest that the JNK–c-Jun pathway is involved in the upregulation of Bim during OA and that the JNK–c-Jun–Bim pathway is vital for chondrocyte apoptosis.

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