Peripheral TGF-β1 Signaling Is a Critical Event in Bone Cancer-Induced Hyperalgesia in Rodents

Xu, Qian; Zhang, Xiaomeng; Duan, Kaizheng; Gu, Xiechong; Han, Mei; Liu, Benlong; Zhao, Zhi‐Qi; Zhang, Yu‐Qiu

doi:10.1523/jneurosci.4852-12.2013

Cited by 66 publications

(64 citation statements)

References 45 publications

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“…Emerging evidence has highlighted that CXCL12/ CXCR4 signaling is responsible for pleiotropic aspects of metastatic cancer progression including homing, survival, proliferation, and angiogenesis in bone marrow microenvironment (Sun et al 2010;Shi et al 2014). It is well known that, after metastasized to bone, the secondary tumors in the advanced stage subsequently result in BCP (Duan et al 2012;Xu et al 2013). Interestingly, we further found that, in a rat model of tibia metastasis, CXCL12/CXCR4 signaling in the spinal dorsal horn was also responsible for BCP development, in addition to its oncogenic roles in tumor-burdened bone.…”

Section: R E T R a C T E Dmentioning

confidence: 99%

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Liu

Zhang

et al. 2015

Journal of Neurochemistry

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The activation of MAPK pathways in spinal cord and subsequent production of proinflammatory cytokines in glial cells contribute to the development of spinal central sensitization, the basic mechanism underlying bone cancer pain (BCP). Our previous study showed that spinal CXCL12 from astrocytes mediates BCP generation by binding to CXCR4 in both astrocyters and microglia. Here, we verified that CXCL12/CXCR4 signaling contributed to BCP through a MAPK-mediated mechanism. In na€ ıve rats, a single intrathecal administration of CXCL12 considerably induced pain hyperalgesia and phosphorylation expression of spinal MAPK members (including extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase), which could be partially prevented by pre-treatment with CXCR4 inhibitor AMD3100. This CXCL12-induced hyperalgesia was also reduced by MAPK inhibitors. In bone cancer rats, tumor cell inoculation into the tibial cavity caused prominent and persistent pain hyperalgesia, and associated with up-regulation of CXCL12 and CXCR4, activation of glial cells, phosphorylation of MAPKs, and production of proinflammatory cytokines in the spinal cord. These tumor cell inoculation-induced behavioral and neurochemical alterations were all suppressed by blocking CXCL12/CXCR4 signaling or MAPK pathways. Taken together, these results demonstrate that spinal MAPK pathways mediated CXCL12/CXCR4-induced pain hypersensitivity in bone cancer rats, which could be druggable targets for alleviating BCP and glia-derived neuroinflammation. Keywords: astrocytes, bone cancer pain, chemokine, mitogenactivated protein kinase, microglia, neuroinflammation. Bone cancer pain (BCP) caused by primary tumors or bone metastases is the most common source of moderate and severe cancer pain, which not only makes patients less confident to receive therapeutic plan but also discourages tumor-burdened people from desiring to live (Knopp et al. 2011). With effective treatment strategies depending on a better understanding of BCP, intensive studies of underlying pathogenic mechanisms of BCP and development of novel analgesic targets are highly anticipated in the basic and clinical research communities.Following local inoculation of primary or metastatic bone tumor in the bone microenvironment, cellular and neurochemical alterations take place abundantly in the spinal cord, triggering hyperalgesic behaviors (Medhurst et al. 2002). In this complex pathophysiologic process, glial cells (especially astrocytes and microglia) react and release various proinflammatory cytokines, including tumor necrosis factor a (TNF-a), interleukin 1b (IL-1b) and IL-6, which enhance central sensitization and thus evoking pain hypersensitivity (Falk and Dickenson 2014). Indeed, inhibiting functional activation of astrocytes and microglia at the spinal level is sufficient to suppress BCP and these glia-derived mediators Moreover, numerous studies have shown that all three MAPK members are prone to be phosphorylated following the activation of certain GPCRs, especially che...

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Section: R E T R a C T E Dmentioning

confidence: 99%

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Liu

Zhang

et al. 2015

Journal of Neurochemistry

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“…signaling sensitizes TRPV1 in primary sensory neurons. [14][15][16] ] i increase. Thus, another possibility mediating the acute effects of TGF-β1 is that calcium released from intracellular calcium pools as a second message opens one or more non-selective cation channels in direct or indirect ways, thus resulting in robust depolarization and discharges.…”

Section: Discussionmentioning

confidence: 96%

“…Evidence suggests that TGF-β1 has protective effects against neuropathic pain in the central nervous system, 11,12 while in peripheral nervous system, TGF-β1 is recently reported as an algogenic substance that contributes to peripheral sensitization by downregulation of the KCNA4 gene, 13 or activation of cyclin-dependent kinase-transient receptor potential vanilloid type 1 (Cdk5-TRPV1) signaling 14,15 and transforming growth factor β activated kinase 1 (TAK1)/protein kinase C (PKC)-TRPV1 signaling. 16 As mentioned in those studies, [13][14][15][16] TGF-β1 is a complex modulator of sensory neuronal function, and its signaling pathway in the induction and development of pancreatic pain in rats with chronic pancreatitis was not fully understood. Therefore, the roles of TGF-β1 and its receptors were re-explored in the setting of chronic pancreatitis.…”

Section: Introductionmentioning

confidence: 99%

Acute Effects of Transforming Growth Factor-β1 on Neuronal Excitability and Involvement in the Pain of Rats with Chronic Pancreatitis

Zhang

Zheng

et al. 2016

J Neurogastroenterol Motil

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Background/AimsThis study was to investigate whether transforming growth factor-β1 (TGF-β1) plays a role in hyperalgesia in chronic pancreatitis (CP) and the underlying mechanisms. MethodsCP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Abdominal hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. Dil dye injected into the pancreas was used to label pancreas-specific dorsal root ganglion (DRG) neurons. Whole cell patch clamp recordings and calcium imaging were performed to examine the effect of TGF-β1 on acutely isolated pancreas-specific DRG neurons. Western blot analysis was carried out to measure the expression of TGF-β1 and its receptors. ResultsTNBS injection significantly upregulated expression of TGF-β1 in the pancreas and DRGs, and TGF-β1 receptors in DRGs (T9-T13) in CP rats. Intrathecal injection of TGF-β receptor I antagonist SB431542 attenuated abdominal hyperalgesia in CP rats. TGF-β1 application depolarized the membrane potential and caused firing activity of DRG neurons. TGF-β1 application also reduced rheobase, hyperpolarized action potential threshold, and increased numbers of action potentials evoked by current injection of pancreas-specific DRG neurons. TGF-β1 application also increased the concentration of intracellular calcium of DRG neurons, which was inhibited by SB431542. Furthermore, intrathecal injection of TGF-β1 produced abdominal hyperalgesia in healthy rats. ConclusionsThese results suggest that TGF-β1 enhances neuronal excitability and increases the concentration of intracellular calcium. TGF-β1 and its receptors are involved in abdominal hyperalgesia in CP. This and future study might identify a potentially novel target for the treatment of abdominal pain in CP.

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“…63 Attempts to develop or identify antagonists devoid of temperature effects have not been successful. In this context, it is noted that recent studies have shown that the expression and activity of TRPV1 on the DRG sensory neurons are upregulated by TGF-b1 64 and IGF-1. 65 Further, these studies showed that inhibition of TGF-b or IGF receptor signaling reduced CABP through suppression of TRPV1 activation.…”

Section: Cancer-colonized Bonementioning

confidence: 99%

Acidic microenvironment and bone pain in cancer-colonized bone

Yoneda¹,

Hiasa²,

Nagata³

et al. 2015

BoneKEy Reports

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Solid cancers and hematologic cancers frequently colonize bone and induce skeletal-related complications. Bone pain is one of the most common complications associated with cancer colonization in bone and a major cause of increased morbidity and diminished quality of life, leading to poor survival in cancer patients. Although the mechanisms responsible for cancer-associated bone pain (CABP) are poorly understood, it is likely that complex interactions among cancer cells, bone cells and peripheral nerve cells contribute to the pathophysiology of CABP. Clinical observations that specific inhibitors of osteoclasts reduce CABP indicate a critical role of osteoclasts. Osteoclasts are proton-secreting cells and acidify extracellular bone microenvironment. Cancer cell-colonized bone also releases proton/lactate to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Thus, extracellular microenvironment of cancer-colonized bone is acidic. Acidosis is algogenic for nociceptive sensory neurons. The bone is densely innervated by the sensory neurons that express acid-sensing nociceptors. Collectively, CABP is evoked by the activation of these nociceptors on the sensory neurons innervating bone by the acidic extracellular microenvironment created by bone-resorbing osteoclasts and bone-colonizing cancer cells. As current treatments do not satisfactorily control CABP and can elicit serious side effects, new therapeutic interventions are needed to manage CABP. Understanding of the cellular and molecular mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and by which the expression and function of the acid-sensing nociceptors on the sensory neurons are regulated would facilitate to develop novel therapeutic approaches for the management of CABP.

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Peripheral TGF-β1 Signaling Is a Critical Event in Bone Cancer-Induced Hyperalgesia in Rodents

Cited by 66 publications

References 45 publications

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Acute Effects of Transforming Growth Factor-β1 on Neuronal Excitability and Involvement in the Pain of Rats with Chronic Pancreatitis

Acidic microenvironment and bone pain in cancer-colonized bone

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