Antagonists to TRPV1, ASICs and P2X have a potential role to prevent the triggering of regional bone metabolic disorder and pain-like behavior in tail-suspended mice

Hanaka, Megumi; Iba, Kousuke; Dohke, Takayuki; Kanaya, Kumiko; Okazaki, Shunichiro; Yamashita, Toshihiko

doi:10.1016/j.bone.2018.02.006

Cited by 24 publications

(16 citation statements)

References 27 publications

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“…Additionally, inhibition of TRPV1 by CPZ was able to ameliorate PWT of BCP rats, and a significant reduction in mechanical allodynia was observed from 8 h to 5 days after CPZ injection. This is consistent with the view that TRPV1 blockage or deletion is proved to be an effective method to attenuate chronic bone pain state ( Heo et al, 2017 ; Hanaka et al, 2018 ). Importantly, Metformin application could significantly reduce the up-regulated TRPV1 in both DRG and SDH of BCP rats as well as Vinorelbine treatment, suggesting that TRPV1 might mediate the analgesic effect of Metformin and Vinorelbine on BCP.…”

Section: Discussionsupporting

confidence: 91%

Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

Qian

Zhou

et al. 2021

Front. Pharmacol.

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Bone cancer pain (BCP) is a common pathologic pain associated with destruction of bone and pathological reconstruction of nervous system. Current treatment strategies in clinical is inadequate and have unacceptable side effects due to the unclear pathology mechanism. In the present study, we showed that transplantation of Walker 256 cells aggravated mechanical allodynia of BCP rats (**p < 0.01 vs. Sham), and the expression of ASIC3 (Acid-sensitive ion channel 3) and TRPV1 was obviously enhanced in L4-6 dorsal root ganglions (DRGs) of BCP rats (**p < 0.01 vs. Sham). ASIC3 and TRPV1 was mainly expressed in CGRP and IB4 positive neurons of L4-6 DRGs. While, TRPV1 but not ASIC3 was markedly upregulated in L4-6 spinal dorsal horn (SDH) of BCP rats (**p < 0.01 vs. Sham). Importantly, intrathecal injection of CPZ (a TRPV1 inhibitor) or Amiloride (an ASICs antagonist) markedly increased the paw withdraw threshold (PWT) of BCP rats response to Von Frey filaments (**p < 0.01 vs. BCP + NS). What’s more, intraperitoneally injection of Metformin or Vinorelbine markedly elevated the PWT of BCP rats, but reduced the expression of TRPV1 and ASIC3 in L4-6 DRGs and decreased the TRPV1 expression in SDH (*p < 0.05, **p < 0.01 vs. BCP + NS). Collectively, these results suggest an effective analgesic effect of Metformin on mechanical allodynia of BCP rats, which may be mediated by the downregulation of ASIC3 and TRPV1.

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Section: Discussionsupporting

confidence: 91%

Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

Qian

Zhou

et al. 2021

Front. Pharmacol.

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“… 91 Nociceptors respond to H + mainly through acid-sensing ion channel 3 (ASIC3) and transient receptor potential vanilloid type 1 (TRPV1), and inhibition of these receptors attenuates pain-related behaviors in experimental models of bone pain. 25 , 29 , 31 , 36 , 83 Osteoclasts can also produce other pronociceptive factors, including lipids, 51 chemokines, 98 and neurotrophic factors. 104 Hence, osteoclasts may contribute to pain-like behaviors in various ways.…”

Section: Introductionmentioning

confidence: 99%

Antibody-induced pain-like behavior and bone erosion: links to subclinical inflammation, osteoclast activity, and acid-sensing ion channel 3–dependent sensitization

Jurczak

Delay

Barbier

et al. 2021

Pain

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Several bone conditions, eg, bone cancer, osteoporosis, and rheumatoid arthritis (RA), are associated with a risk of developing persistent pain. Increased osteoclast activity is often the hallmark of these bony pathologies and not only leads to bone remodeling but is also a source of pronociceptive factors that sensitize the bone-innervating nociceptors. Although historically bone loss in RA has been believed to be a consequence of inflammation, both bone erosion and pain can occur years before the symptom onset. Here, we have addressed the disconnection between inflammation, pain, and bone erosion by using a combination of 2 monoclonal antibodies isolated from B cells of patients with RA. We have found that mice injected with B02/B09 monoclonal antibodies (mAbs) developed a long-lasting mechanical hypersensitivity that was accompanied by bone erosion in the absence of joint edema or synovitis. Intriguingly, we have noted a lack of analgesic effect of naproxen and a moderate elevation of few inflammatory factors in the ankle joints suggesting that B02/B09-induced pain-like behavior does not depend on inflammatory processes. By contrast, we found that inhibiting osteoclast activity and acid-sensing ion channel 3 signaling prevented the development of B02/B09-mediated mechanical hypersensitivity. Moreover, we have identified secretory phospholipase A2 and lysophosphatidylcholine 16:0 as critical components of B02/B09-induced pain-like behavior and shown that treatment with a secretory phospholipase A2 inhibitor reversed B02/B09-induced mechanical hypersensitivity and bone erosion. Taken together, our study suggests a potential link between bone erosion and pain in a state of subclinical inflammation and offers a step forward in understanding the mechanisms of bone pain in diseases such as RA.

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“…Early OD was activated by FSS, as confirmed by osterix (Osx) of early OD markers and staining of alkaline phosphatase (ALP) [18]. A previous study also demonstrated that TRPV1 is expressed in bone tissues, and the antagonists to TRPV1 downregulated the expression of osteoblast and osteoclast regulators in tail-suspended mice [19]. TRPV1 activation induced production of calcitonin gene-related peptide (CGRP), which is a neuropeptide widely distributed in the peripheral and central nervous systems [20].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effect of Sirtuin6 (SIRT6) on Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells

et al. 2019

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BackgroundThe imbalance between bone resorption and formation is the basic mechanism underlying osteoporosis in the elderly. Osteogenesis is the differentiation of human mesenchymal stem cells (hMSCs) into osteoblasts. Sirtuin6 (SIRT6) regulates various biological functions, including differentiation. Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a non-selective cation channel that can be activated by physical and chemical stimulation. However, experimental data supporting the role of SIRT6 in osteogenic differentiation (OD) of hMSCs are lacking.Material/MethodsDifferentiation of hMSCs was induced. The expressions of SIRT6, TRPV1, and CGRP were detected by Q-PCR, Western blot, and ELISA, respectively. SIRT6 was overexpressed in hMSCs by transfection. ALP activity and Alizarin Red staining were utilized to detect the effect of SIRT6 on hMSC OD. Then, capsaicin and capsazepine, the TRPV1 agonist and antagonist, respectively, were administrated to assess the role of TRPV1.ResultsSIRT6 expression was downregulated during hMSC differentiation. SIRT6 overexpression was accompanied by reduced expression of specific genes and alkaline phosphatase (ALP) activity in osteoblasts. Furthermore, TRPV1 channel was also reduced by SIRT6 overexpression via ubiquitinating TRPV1. Capsaicin was utilized in SIRT6-overexpressed cells. Capsaicin therapy counteracted the effect of SIRT6 overexpression on OD, and markedly decreased OD.ConclusionThe SIRT6-TRPV1-CGRP signal axis is the key to regulating OD in hMSCs, which could be a potential therapeutic target for osteoporosis and bone loss-related diseases.

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Antagonists to TRPV1, ASICs and P2X have a potential role to prevent the triggering of regional bone metabolic disorder and pain-like behavior in tail-suspended mice

Cited by 24 publications

References 27 publications

Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

Antibody-induced pain-like behavior and bone erosion: links to subclinical inflammation, osteoclast activity, and acid-sensing ion channel 3–dependent sensitization

Inhibitory Effect of Sirtuin6 (SIRT6) on Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells

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