Bone-derived IGF-1 enhances bone pain through activation of acid-sensing nociceptors in bone metastases of breast cancer Export

@article{citeulike:3508484, abstract = {Bone cancer pain is one of the most common complications by patients with breast cancer. However, precise molecular mechanism of bone pain is still elusive. Recent studies have shown that the acid-sensing nociceptors (ASNs) such as the transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channels (ASICs) expressed in calcitonin gene-related protein (CGRP)-positive nociceptive fibers play a role in transducing peripheral pain signals to CNS. Of note, IGF-1 is found to regulate TRPV1 activation. Since IGF is released from bone due to increased bone resorption during the progression of bone metastases, we reasoned bone-derived IGF modulates bone pain. To approach this, we established a mouse model of cancer-induced bone pain by inoculating the 4T1 mouse breast cancer cells into the marrow cavity of tibiae. Tumor-inoculated tibiae showed significantly increased pain behaviors compared with the non-tumor-bearing tibiae, indicating 4T1 cells induced bone pain. Immunohistochemical examination revealed substantial expression of TRPV1/CGRP-positive fibers and increased proportion of these fibers in the tumor-bearing tibiae. RT-PCR showed elevated mRNA expression of TRPV1, ASIC3 and CGRP in the ipsi-lateral dorsal root ganglions (DRGs) which were the the cell body of primary sensory neurons innervating bone. Since c-fos, pERK and p38 were widely-accepted markers of neural activation, we examined these expression in the DRGs. RT-PCR showed elevated mRNA expression of c-fos, and western blotting showed elevated pERK and p38 expression in the ipsi-lateral tumor-bearing DRGs compared with the contra-lateral DRGs, respectively. To study the role of bone-derived IGF-1 in vitro, we established organ cultures of mouse DRGs. The culture supernatants harvested from the mouse neonatal calvariae up-regulated TRPV1, ASIC3, CGRP and c-fos expression in mouse DRGs. AG1024, a specific inhibitor of IGF receptor tyrosine kinase, decreased the expression of these molecules. IGF-1 up-regulated TRPV1, ASIC3 and CGRP mRNA expression in DRGs, while TGFb, another abundant growth factor in bone, showed no effects. IGF-1 also elevated mRNA expression of c-fos in the F-11 rat DRG-like cells. These results collectively suggest that bone-derived IGF-1 influences bone pain. To verify this, we tested AG1024 in vivo. AG1024 significantly reduced pain behaviors in tumor-bearing tibiae. In addition, mRNA expression of TRPV1, ASIC3 and CGRP and c-fos was decreased by AG1024 in the ipsi-lateral DRGs. Moreover, the expression of pERK and p38 were also decreased by AG1024 in the ipsi-lateral DRGs. These results demonstrated IGF-1 up-regulates mRNA expression of TRPV1 and ASIC3 and also activated TRPV1 and ASIC3. In conclusion, our results suggest that bone-derived IGF-1 enhances breast cancer-induced bone pain through stimulating ASN expression and activation and that inhibition of bone resorption may reduce bone pain by limiting IGF release from bone.}, author = {Sakurai, T. and Umemura, T. and Yono, H. and Williams, P. and Farias, A. and Yoneda, T.}, citeulike-article-id = {3508484}, citeulike-linkout-0 = {http://www.abstracts2view.com/sabcs/view.php?nu=SABCS07L_70}, day = {14}, keywords = {asic3, bone, igf-1, pain, trpv1}, month = {December}, posted-at = {2008-11-13 12:29:44}, priority = {3}, title = {Bone-derived IGF-1 enhances bone pain through activation of acid-sensing nociceptors in bone metastases of breast cancer}, url = {http://www.abstracts2view.com/sabcs/view.php?nu=SABCS07L_70}, year = {2007} }

TY - JOUR ID - citeulike:3508484 L3 - citeulike-article-id:3508484 N2 - Bone cancer pain is one of the most common complications by patients with breast cancer. However, precise molecular mechanism of bone pain is still elusive. Recent studies have shown that the acid-sensing nociceptors (ASNs) such as the transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channels (ASICs) expressed in calcitonin gene-related protein (CGRP)-positive nociceptive fibers play a role in transducing peripheral pain signals to CNS. Of note, IGF-1 is found to regulate TRPV1 activation. Since IGF is released from bone due to increased bone resorption during the progression of bone metastases, we reasoned bone-derived IGF modulates bone pain. To approach this, we established a mouse model of cancer-induced bone pain by inoculating the 4T1 mouse breast cancer cells into the marrow cavity of tibiae. Tumor-inoculated tibiae showed significantly increased pain behaviors compared with the non-tumor-bearing tibiae, indicating 4T1 cells induced bone pain. Immunohistochemical examination revealed substantial expression of TRPV1/CGRP-positive fibers and increased proportion of these fibers in the tumor-bearing tibiae. RT-PCR showed elevated mRNA expression of TRPV1, ASIC3 and CGRP in the ipsi-lateral dorsal root ganglions (DRGs) which were the the cell body of primary sensory neurons innervating bone. Since c-fos, pERK and p38 were widely-accepted markers of neural activation, we examined these expression in the DRGs. RT-PCR showed elevated mRNA expression of c-fos, and western blotting showed elevated pERK and p38 expression in the ipsi-lateral tumor-bearing DRGs compared with the contra-lateral DRGs, respectively. To study the role of bone-derived IGF-1 in vitro, we established organ cultures of mouse DRGs. The culture supernatants harvested from the mouse neonatal calvariae up-regulated TRPV1, ASIC3, CGRP and c-fos expression in mouse DRGs. AG1024, a specific inhibitor of IGF receptor tyrosine kinase, decreased the expression of these molecules. IGF-1 up-regulated TRPV1, ASIC3 and CGRP mRNA expression in DRGs, while TGFb, another abundant growth factor in bone, showed no effects. IGF-1 also elevated mRNA expression of c-fos in the F-11 rat DRG-like cells. These results collectively suggest that bone-derived IGF-1 influences bone pain. To verify this, we tested AG1024 in vivo. AG1024 significantly reduced pain behaviors in tumor-bearing tibiae. In addition, mRNA expression of TRPV1, ASIC3 and CGRP and c-fos was decreased by AG1024 in the ipsi-lateral DRGs. Moreover, the expression of pERK and p38 were also decreased by AG1024 in the ipsi-lateral DRGs. These results demonstrated IGF-1 up-regulates mRNA expression of TRPV1 and ASIC3 and also activated TRPV1 and ASIC3. In conclusion, our results suggest that bone-derived IGF-1 enhances breast cancer-induced bone pain through stimulating ASN expression and activation and that inhibition of bone resorption may reduce bone pain by limiting IGF release from bone. TI - Bone-derived IGF-1 enhances bone pain through activation of acid-sensing nociceptors in bone metastases of breast cancer KW - asic3 KW - bone KW - igf-1 KW - pain KW - trpv1 AU - Sakurai, T AU - Umemura, T AU - Yono, H AU - Williams, P AU - Farias, A AU - Yoneda, T PY - 2007/12/14/ UR - http://www.abstracts2view.com/sabcs/view.php?nu=SABCS07L_70 ER -