Effect and mechanism of the CACNA2D1-CGRP pathway in osteoarthritis-induced ongoing pain

Sun, Liang; Wang, Guodong; He, Mingbo; Mei, Zhigang; Zhang, Fazhou; Liu, Ping

doi:10.1016/j.biopha.2020.110374

Cited by 15 publications

(11 citation statements)

References 41 publications

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“…Elsewhere, Xu et al [69] reported that the mechanosensitive ion channel transient receptor potential channel 4 (TRPV4) of chondrocytes could detect mechanical stress and induce extracellular Ca2+ influx thereby upregulating levels of fas-related proteins and caspase-3, caspase-6, caspase-7, and caspase-8 triggering chondrocyte apoptosis. Some studies reported that voltage-dependent calcium channels are involved in the perception of persistent OA pain by modulating the CGRP and AC-PKA/PKC/MAPK signaling pathways in the dorsal root ganglion [70]. Besides, TRPA1 and RPV4 are closely associated with modulation of mechanical pain in OA.…”

Section: Receptors Of Mechanical Load In Cartilagementioning

confidence: 99%

Molecular mechanisms of mechanical load-induced osteoarthritis

Fang

Zhou

Jin

et al. 2021

International Orthopaedics (SICOT)

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Introduction Mechanical loading enhances the progression of osteoarthritis. However, its molecular mechanisms have not been established. Objective The aim of this review was to summarize the probable mechanisms of mechanical load-induced osteoarthritis. Methods A comprehensive search strategy was used to search PubMed and EMBASE databases (from the 15th of January 2015 to the 20th of October 2020). Search terms included “osteoarthritis”, “mechanical load”, and “mechanism”. Results Abnormal mechanical loading activates the interleukin-1β, tumour necrosis factor-α, nuclear factor kappa-B, Wnt, transforming growth factor-β, microRNAs pathways, and the oxidative stress pathway. These pathways induce the pathological progression of osteoarthritis. Mechanical stress signal receptors such as integrin, ion channel receptors, hydrogen peroxide-inducible clone-5, Gremlin-1, and transient receptor potential channel 4 are present in the articular cartilages. Conclusion This review highlights the molecular mechanisms of mechanical loading in inducing chondrocyte apoptosis and extracellular matrix degradation. These mechanisms provide potential targets for osteoarthritis prevention and treatment.

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Section: Receptors Of Mechanical Load In Cartilagementioning

confidence: 99%

Molecular mechanisms of mechanical load-induced osteoarthritis

Fang

Zhou

Jin

et al. 2021

International Orthopaedics (SICOT)

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“…[65][66][67][68] As a downstream molecule of Ca 2+ -dependent signaling pathways, PKC is a ubiquitous serotonin protein kinase that catalyzes the phosphorylation of many cell proteins [67]. Additionally, the activation of MAPK is recognized as a pathogenic mechanism in chronic pain [69]. In recent years, exploring the multiple functions of signaling pathways and interactions between targets have gradually become a research focus, and PKC/p38 MAPK is no exception.…”

Section: Discussionmentioning

confidence: 99%

Corydalis saxicola Bunting total alkaloids attenuate paclitaxel-induced peripheral neuropathy through PKCε/p38 MAPK/TRPV1 signaling pathway

Xue

Liu

et al. 2021

Chin Med

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Background Corydalis saxicola Bunting, affiliated with the Papaveraceae Juss., has been proven to work well in anti-inflammation, hemostasis, and analgesia. This study was designed to observe the effect and potential mechanism of Corydalis saxicola Bunting total alkaloids (CSBTA) on paclitaxel-induced peripheral neuropathy (PIPN). Materials and methods Rats were injected 2 mg/kg paclitaxel 4 times and administrated with 30 or 120 mg/kg CSBTA. Mechanical and thermal allodynia and hyperalgesia were tested. After 40 days, serum was collected to detect PGE2, TNF-α, and IL-1β by ELISA. The L4-L6 segment spinal cord, DRG, and plantar skin were harvested, and Western-blot or RT-qPCR analyzed protein and gene levels of pro-inflammatory cytokines, p38 MAPK, PKCε, and TRPV1. The PIPN cell model was established with paclitaxel (300 nM, 5 d) in primary DRG neurons. We examined the effect of CSBTA (25 μg/ml or 50 μg/ml) by measuring the mRNA levels in PGE2, TNF-α and CGRP, and the protein expression on the PKCε/p38 MAPK/TRPV1 signaling pathway in the PIPN cell model. Results The results showed that CSBTA effectively ameliorated allodynia and hyperalgesia, and regulated cytokines' contents (PGE2, TNF-α, and IL-1β) and neuropeptides (CGRP and SP) in different tissues in vivo. In addition, CSBTA significantly decreased cytokine gene levels of DRG neurons (PGE2, TNF-α, and CGRP) and the protein expressions of PKCε/p38 MAPK/TRPV1 signaling pathway in vivo and in vitro. Conclusion Therefore, CSBTA has a perspective therapeutic effect on the treatment of paclitaxel-induced peripheral neuropathy.

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“…The upregulated expression of CACNA2D1 contributed to chronically maintain neuropathic pain by enhancing VGCCs activation, neuronal excitability, and neurotransmission ( Yusaf et al, 2001 ; Gribkoff, 2006 ; Li et al, 2006 , 2014 ). Moreover, CACNA2D1 could modulate CGRP and AC-PKA/protein kinase C (PKC)/MAPK signaling pathways in the dorsal root ganglion (DRG) in chronic pain process ( Sun et al, 2020 ). Fundamentally, CACNA2D1 gene performs these functions by the genetic translation product—the α2δ1 protein.…”

Section: The α2δ1 Subunit and Its Role In Neuropathic Painmentioning

confidence: 99%

“…These findings indicate that TSP4 contributes to the process of neuropathic pain by increasing the concentration of intracellular Ca 2+ via binding to Cavα2δ1 and activating the downstream PKC signaling pathway ( Figure 4 ). Cavα2δ1 contributes to the occurrence and development of neuropathic pain by modulating the PKA/PKC/MAPK signaling pathways in the DRG ( Sun et al, 2020 ). GBP significantly attenuates neuropathic pain by binding to Cavα2δ1 and regulating the intracellular PKC signaling pathway in the SDH of rats ( Sun et al, 2020 ).…”

Section: Cavα2δ1 Contributes To Neuropathic Pain By Activating Its Downstream Protein Kinase C Targetmentioning

confidence: 99%

“…Cavα2δ1 contributes to the occurrence and development of neuropathic pain by modulating the PKA/PKC/MAPK signaling pathways in the DRG ( Sun et al, 2020 ). GBP significantly attenuates neuropathic pain by binding to Cavα2δ1 and regulating the intracellular PKC signaling pathway in the SDH of rats ( Sun et al, 2020 ). Moreover, our recent study showed that the phosphorylation of PKC was increased in the TG after pT-ION, and the PKC inhibitor GF109203X (0.2 mg/kg) significantly attenuated the mechanical allodynia and cold hyperalgesia induced by trigeminal nerve injury ( Cui et al, 2020 ).…”

Section: Cavα2δ1 Contributes To Neuropathic Pain By Activating Its Downstream Protein Kinase C Targetmentioning

confidence: 99%

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The Calcium Channel α2δ1 Subunit: Interactional Targets in Primary Sensory Neurons and Role in Neuropathic Pain

Cui

et al. 2021

Front. Cell. Neurosci.

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Neuropathic pain is mainly triggered after nerve injury and associated with plasticity of the nociceptive pathway in primary sensory neurons. Currently, the treatment remains a challenge. In order to identify specific therapeutic targets, it is necessary to clarify the underlying mechanisms of neuropathic pain. It is well established that primary sensory neuron sensitization (peripheral sensitization) is one of the main components of neuropathic pain. Calcium channels act as key mediators in peripheral sensitization. As the target of gabapentin, the calcium channel subunit α2δ1 (Cavα2δ1) is a potential entry point in neuropathic pain research. Numerous studies have demonstrated that the upstream and downstream targets of Cavα2δ1 of the peripheral primary neurons, including thrombospondins, N-methyl-D-aspartate receptors, transient receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid family 1 (TRPV1), and protein kinase C (PKC), are involved in neuropathic pain. Thus, we reviewed and discussed the role of Cavα2δ1 and the associated signaling axis in neuropathic pain conditions.

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Effect and mechanism of the CACNA2D1-CGRP pathway in osteoarthritis-induced ongoing pain

Cited by 15 publications

References 41 publications

Molecular mechanisms of mechanical load-induced osteoarthritis

Molecular mechanisms of mechanical load-induced osteoarthritis

Corydalis saxicola Bunting total alkaloids attenuate paclitaxel-induced peripheral neuropathy through PKCε/p38 MAPK/TRPV1 signaling pathway

The Calcium Channel α2δ1 Subunit: Interactional Targets in Primary Sensory Neurons and Role in Neuropathic Pain

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