title: Peripheral TGF-β1 signaling is a critical event in bone cancer-induced hyperalgesia in rodents.
abstract: Pain is the most common symptom of bone cancer. TGF-β, 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-β1 is critical for bone cancer-induced pain sensitization. We found that, after the progression of bone cancer, TGF-β1 was highly expressed in tumor-bearing bone, and the expression of its receptors, TGFβRI and TGFβRII, 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-β receptors by the TGFβRI antagonist SD-208 robustly suppressed bone cancer-induced thermal hyperalgesia on post-tumor day 14 (PTD 14). Peripheral injection of TGF-β1 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-β1 significantly potentiated TRPV1 currents and increased [Ca(2+)]i in DRG neurons. Pharmacological studies revealed that the TGF-β1 sensitization of TRPV1 and the induction of thermal hyperalgesia required the TGF-βR-mediated Smad-independent PKCε and TGF-β activating kinase 1-p38 pathways. These findings suggest that TGF-β1 signaling contributes to bone cancer pain via the upregulation and sensitization of TRPV1 in primary sensory neurons and that therapeutic targeting of TGF-β1 may ameliorate the bone cancer pain in advanced cancer.
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.forename: Xiao-Meng
authors.initials: XM
authors.lastname: Zhang
authors.forename: Kai-Zheng
authors.initials: KZ
authors.lastname: Duan
authors.forename: Xi-Yao
authors.initials: XY
authors.lastname: Gu
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.forename: Ben-Long
authors.initials: BL
authors.lastname: Liu
authors.forename: Zhi-Qi
authors.initials: ZQ
authors.lastname: Zhao
authors.forename: Yu-Qiu
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000150:complications*; D002279:Carcinoma 256, Walker / Q000473:pathology; D055724:Electrophysiological Phenomena; D005260:Female; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D007150:Immunohistochemistry; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D017933:Peripheral Nervous System / Q000503:physiopathology*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000235:genetics / Q000502:physiology; D050916:TRPV Cation Channels / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000502:physiology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D011493:Protein Kinase C; D051785:Smad Proteins; D050916:TRPV Cation Channels; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C494484:TRPV1 receptor
keywords: TGF-β; TRPV1; bone cancer pain; dorsal root ganglion; patch clamp; thermal hyperalgesia