| First Author | Xu Q | Year | 2013 |
| Journal | J Neurosci | Volume | 33 |
| Issue | 49 | Pages | 19099-111 |
| PubMed ID | 24305807 | Mgi Jnum | J:315331 |
| Mgi Id | MGI:6830122 | Doi | 10.1523/JNEUROSCI.4852-12.2013 |
| Citation | Xu Q, et al. (2013) Peripheral TGF-beta1 signaling is a critical event in bone cancer-induced hyperalgesia in rodents. J Neurosci 33(49):19099-111 |
| abstractText | Pain is the most common symptom of bone cancer. TGF-beta, a major bone-derived growth factor, is largely released by osteoclast bone resorption during the progression of bone cancer and contributes to proliferation, angiogenesis, immunosuppression, invasion, and metastasis. Here, we further show that TGF-beta1 is critical for bone cancer-induced pain sensitization. We found that, after the progression of bone cancer, TGF-beta1 was highly expressed in tumor-bearing bone, and the expression of its receptors, TGFbetaRI and TGFbetaRII, was significantly increased in the DRG in a rat model of bone cancer pain that is based on intratibia inoculation of Walker 256 mammary gland carcinoma cells. The blockade of TGF-beta receptors by the TGFbetaRI antagonist SD-208 robustly suppressed bone cancer-induced thermal hyperalgesia on post-tumor day 14 (PTD 14). Peripheral injection of TGF-beta1 directly induced thermal hyperalgesia in intact rats and wide-type mice, but not in Trpv1(-/-) mice. Whole-cell patch-clamp recordings from DRG neurons showed that transient receptor potential vanilloid (TRPV1) sensitivity was significantly enhanced on PTD 14. Extracellular application of TGF-beta1 significantly potentiated TRPV1 currents and increased [Ca(2+)]i in DRG neurons. Pharmacological studies revealed that the TGF-beta1 sensitization of TRPV1 and the induction of thermal hyperalgesia required the TGF-betaR-mediated Smad-independent PKCepsilon and TGF-beta activating kinase 1-p38 pathways. These findings suggest that TGF-beta1 signaling contributes to bone cancer pain via the upregulation and sensitization of TRPV1 in primary sensory neurons and that therapeutic targeting of TGF-beta1 may ameliorate the bone cancer pain in advanced cancer. |
