CXCL12/CXCR4 Axis Regulates Aggrecanase Activation and Cartilage Degradation in a Post-Traumatic Osteoarthritis Rat Model

Lu, Weiwei; Shi, Jia; Zhang, Jinming; Lv, Zheng‐tao; Guo, Fengjing; Huang, Hui; Zhu, Wentao; Chen, Anmin

doi:10.3390/ijms17101522

Cited by 40 publications

(30 citation statements)

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“…16) It was reported that CXCL12/CXCR4 axis regulated activation of aggrecanase and degradation of cartilage in a rat model with post-traumatic osteoarthritis. 17) Osteoarthritis could be attenuated via blocking of the SDF-1/CXCR4 signaling pathway 18) . CXCR4 was confirmed to be regulated by microRNAs.…”

Section: Discussionmentioning

confidence: 99%

MiR-140-3p Ameliorates the Progression of Osteoarthritis <i>via</i> Targeting CXCR4

Ren

Wei

Song

et al. 2020

Biological & Pharmaceutical Bulletin

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Osteoarthritis is a common disease character with progressive destruction of cartilage. MiR-140-3p was validated as a biomarker for osteoarthritis. However, the mechanism by which miRNA-140-3p regulates osteoarthritis remains unclear. Thus, this study aims to evaluate the potential function of miRNA-140-3p during the pathogenesis of osteoarthritis. MiRNA-140-3p expression in tissue and CHON-001 chondrocyte cells was determined with qRT-PCR. In vitro osteoarthritis model was established by treatment of the chondrocyte cells CHON-001 with IL-1β. Cell proliferation and apoptosis were measured with CCK8 and Annexin V/PI apoptosis assay, respectively. Protein expressions were evaluated using western blot. The target gene of miR-140-3p was predicted using Targetscan and miRDB. MiR-140-3p was downregulated in knee tissue from patients with osteoarthritis. IL-1β inhibited the proliferation of CHON-001 cells via inducing apoptosis. In addition, IL-1β significantly inhibited the expressions of collagen II and aggrecan and increased the level of MMP13. However, the effects of IL-1β could be ameliorated by the addition of miR-140-3p mimics. Moreover, luciferase reporter assay demonstrated CXCR4 as a target gene of miR-140-3p. IL-1β-induced upregulation of CXCR4 could be blocked by miR-140-3p mimics. Our study indicated that miR-140-3p could suppress the progression of osteoarthritis by directly targeting CXCR4. Therefore, miR-140-3p might serve as a potential therapeutic target for the treatment of osteoarthritis.

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Section: Discussionmentioning

confidence: 99%

MiR-140-3p Ameliorates the Progression of Osteoarthritis <i>via</i> Targeting CXCR4

Ren

Wei

Song

et al. 2020

Biological & Pharmaceutical Bulletin

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“…Antibodies against GFAP (ab10062), CXCL12 (ab25117), CXCR4 (ab197203), NeuN (ab104224), and OX42 (ab1211) were purchased from Abcam. Antibodies against CXCR4 (11073‐2‐AP) were purchased from Proteintech (San Ying biotechnology, Wuhan, China).…”

Section: Methodsmentioning

confidence: 99%

CXCL12/CXCR4 signaling contributes to neuropathic pain via central sensitization mechanisms in a rat spinal nerve ligation model

et al. 2019

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Summary Background Previous studies have demonstrated that the CXCL12/CXCR4 signaling axis is involved in the regulation of neuropathic pain (NP). Here, we performed experiments to test whether the CXCL12/CXCR4 signaling pathway contributes to the pathogenesis of neuropathic pain after spinal nerve ligation (SNL) via central sensitization mechanisms. Methods Neuropathic pain was induced and assessed in a SNL rat model. The expression and distribution of CXCL12 or CXCR4 were examined by immunofluorescence staining and western blot. The effects of CXCL12 rat peptide, CXCL12 neutralizing antibody, CXCR4 antagonist, and astrocyte metabolic inhibitor on pain hypersensitivity were explored by behavioral tests in naive or SNL rats. We measured the expression level of c‐Fos and CGRP to evaluate the sensitization of neurons by RT‐PCR. The activation of astrocyte and microglia was analyzed by measuring the level of GFAP and iba‐1. The mRNA levels of the pro‐inflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6 and Connexin 30, Connexin 43, EAAT 1, EAAT 2 were also detected by RT‐PCR. Results First, we found that the expression of CXCL12 and CXCR4 was upregulated after SNL. CXCL12 was mainly expressed in the neurons while CXCR4 was expressed both in astrocytes and neurons in the spinal dorsal horn after SNL. Moreover, intrathecal administration of rat peptide, CXCL12, induced hypersensitivity in naive rats, which was partly reversed by fluorocitrate. In addition, the CXCL12 rat peptide increased mRNA levels of c‐Fos, GFAP, and iba‐1. A single intrathecal injection of CXCL12 neutralizing antibody transiently reversed neuropathic pain in the SNL rat model. Consecutive use of CXCL12 neutralizing antibody led to significant delay in the induction of neuropathic pain, and reduced the expression of GFAP and iba‐1 in the spinal dorsal horn. Finally, repeated intrathecal administration of the CXCR4 antagonist, AMD3100, significantly suppressed the initiation and duration of neuropathic pain. The mRNA levels of c‐Fos, CGRP, GFAP, iba‐1, and pro‐inflammatory cytokines, also including Connexin 30 and Connexin 43 were decreased after injection of AMD3100, while EAAT 1 and EAAT 2 mRNAs were increased. Conclusion We demonstrate that the CXCL12/CXCR4 signaling pathway contributes to the development and maintenance of neuropathic pain via central sensitization mechanisms. Importantly, intervening with CXCL12/CXCR4 presents an effective therapeutic approach to treat the neuropathic pain.

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“…Cartilage regeneration process that involves recruitment of reparative cells can be negatively affected by antichondrogenic or proinflammatory cells chemoattracted concomitantly to the damaged area. The SDF-1/CXCR4 pathway is known to recruit and activate MSCs in chondrogenic differentiation 47,98 ; however, blocking this pathway to some extent attenuates cartilage pathogenesis by reducing MMP and aggrecanase production stimulated from chondrocytes 99,100 . A recent study shows that engineering chondrocytes to overexpress HMGB1 A-box significantly decreases the IL-1b-stimulated production of MMPs and ADAMTs and suppression of HMGB1/TLR4/NF-kB pathway improves chondrogenesis 101 .…”

Section: Future Prospects For the Regenerative Treatment Of Oamentioning

confidence: 99%

Regenerative approaches for cartilage repair in the treatment of osteoarthritis

Xiao

et al. 2017

Osteoarthritis and Cartilage

105

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Osteoarthritis (OA) as a debilitating affliction of joints currently affects millions of people and remains an unsolved problem. The disease involves multiple cellular and molecular pathways that converge on the progressive destruction of cartilage. Activation of cartilage regenerative potential and specific targeting pathogenic mediators have been the major focus of research efforts aimed at slowing the progression of cartilage degeneration and preserve joint function. This review will summarize recent key discoveries toward better understanding of the complex mechanisms behind OA development and highlight the latest advances in basic and clinical research in the approach for cartilage regeneration. Prospectively, more potent therapeutic strategies against progressive cartilage deterioration may use a combination of cytotherapy, pharmacotherapy, and bioscaffoldings for improved chondrogenic differentiation and stem/progenitor cell homing as well as the concomitant reduced enzymatic matrix degradation and inflammation. Further, treatments need to be provided with increased preciseness of targeted therapy. One might expect that the regenerative therapies could potentially control or even possibly cure OA if performed at early stages of the disease.

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CXCL12/CXCR4 Axis Regulates Aggrecanase Activation and Cartilage Degradation in a Post-Traumatic Osteoarthritis Rat Model

Cited by 40 publications

References 50 publications

MiR-140-3p Ameliorates the Progression of Osteoarthritis <i>via</i> Targeting CXCR4

MiR-140-3p Ameliorates the Progression of Osteoarthritis <i>via</i> Targeting CXCR4

CXCL12/CXCR4 signaling contributes to neuropathic pain via central sensitization mechanisms in a rat spinal nerve ligation model

Regenerative approaches for cartilage repair in the treatment of osteoarthritis

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