Hsi-Kai Tsou

Percutaneous pulsed radiofrequency in the treatment of cervical and lumbar radicular pain

BACKGROUND Previous reports of the efficacy of percutaneous pulsed radiofrequency have been confounded by fewer case numbers, poor patient selection, and limited data on cervical or lumbar radicular pain. We used percutaneous pulsed radiofrequency for cervical and lumbar radicular pain, and the study has more than 100 cases for the analysis of the efficacy of percutaneous pulsed radiofrequency. METHODS We collected 154 cases of patients with lumbar or cervical radicular pain due to a herniated intervertebral disk or previous failed surgery. They underwent pulsed radiofrequency therapy in 2 to 4 spinal levels unilaterally. Follow-up period was from 1 week to 1 year postoperatively. RESULTS Twenty-six (53.06%) of 49 patients and 59 (50.86%) of 116 patients after cervical and lumbar pulsed radiofrequency stimulation, respectively, had an initial improvement of 50% or more in the first week of follow-up. Twenty-seven (55.10%) of 49 patients and 52 (44.83%) of 116 patients after cervical and lumbar pulsed radiofrequency stimulation, respectively, had pain relief of 50% or more at the follow-up period of 3 months. In the analysis of patients with pain relief of 50% or more for at least 1 month, the most effective period was during postoperation 1 month later. No complication was found among these patients. CONCLUSIONS The results of this retrospective analysis showed that the application of pulsed radiofrequency is a safe and useful intervention for cervical and lumbar radicular pain. The satisfactory pain relief obtained by most of our patients justifies the start of this study for at least 6 months. Although pulsed radiofrequency appears to provide intermediate-term relief of pain, further studies with long-term follow-up are necessary.

Leptin enhances cell migration in human chondrosarcoma cells through OBRl leptin receptor.

Leptin, an adipocyte-derived cytokine that is closely associated with obesity, has recently been shown to be involved in carcinogenesis and cancer progression. Integrins are the major adhesive molecules in mammalian cells and have been associated with metastasis of cancer cells. In this study, we found that leptin increased the migration and the expression of alphavbeta3 integrin in human chondrosarcoma cells. We also found that human chondrosarcoma tissues and chondrosarcoma cell lines had significant expression of the long form (OBRl) leptin receptor, which was higher than that in normal cartilage and human primary chondrocyte. Leptin-mediated migration and integrin upregulation were attenuated by OBRl receptor antisense oligonucleotide. Activations of insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), Akt and nuclear factor-kappaB (NF-kappaB) pathways after leptin treatment were demonstrated, and leptin-induced expression of integrin and migration activity was inhibited by the specific inhibitor, small-interfering RNA and mutant of IRS-1, PI3K, Akt and NF-kappaB cascades. Taken together, our results indicated that leptin enhances the migration of chondrosarcoma cells by increasing alphavbeta3 integrin expression through the OBR1/IRS-1/PI3K/Akt/NF-kappaB signal transduction pathway.

Thrombin enhanced migration and MMPs expression of human chondrosarcoma cells involves PAR receptor signaling pathway

Thrombin is a multifunctional protease that can activate hemostasis and coagulation through the cleavage of fibrinogen to form fibrin clots. Thrombin also plays a crucial role in migration and metastasis of human cancer cells. However, the effect of thrombin on migration activity in human chondrosarcoma cells is mostly unknown. Here, we found that thrombin increased the migration and expression of matrix metalloproteinase (MMP)‐2 and MMP‐13 in human chondrosarcoma cells (JJ012 and SW1353 cells). By using pharmacological inhibitors or activators or genetic inhibition by the protease‐activated receptor (PAR), we found that the PAR1 and PAR4 receptor but not PAR3 receptor are involved in thrombin‐mediated cell migration and MMPs expression. Thrombin‐mediated migration and MMPs up‐regulation was attenuated by phospholipase C (PLC), protein kinase C, and c‐Src inhibitor. Activations of PLCβ, PKCα, c‐Src, and NF‐κB pathways after thrombin treatment was demonstrated, and thrombin‐induced MMPs expression and migration activity was inhibited by the specific inhibitors and mutants of PLC, PKC, c‐Src, and NF‐κB cascades. Taken together, our results indicated that thrombin enhances the migration of chondrosarcoma cells by increasing MMP‐2 and MMP‐13 expression through the PAR/PLC/PKCα/c‐Src/NF‐κB signal transduction pathway. J. Cell. Physiol. 223:737–745, 2010.

Hepatocyte Growth Factor Increases Osteopontin Expression in Human Osteoblasts through PI3K, Akt, c-Src, and AP-1 Signaling Pathway

Background Hepatocyte growth factor (HGF) has been demonstrated to stimulate osteoblast proliferation and participated bone remodeling. Osteopontin (OPN) is a secreted phosphoglycoprotein that belongs to the SIBLING family and is present during bone mineralization. However, the effects of HGF on OPN expression in human osteoblasts are large unknown. Methodology/Principal Findings Here we found that HGF induced OPN expression in human osteoblasts dose-dependently. HGF-mediated OPN production was attenuated by c-Met inhibitor and siRNA. Pretreatment of osteoblasts with PI3K inhibitor (Ly294002), Akt inhibitor, c-Src inhibitor (PP2), or AP-1 inhibitor (curcumin) blocked the potentiating action of HGF. Stimulation of osteoblasts with HGF enhanced PI3K, Akt, and c-Src activation. In addition, incubation of cells with HGF also increased c-Jun phosphorylation, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the OPN promoter. HGF-mediated AP-1-luciferase activity and c-Jun binding to the AP-1 element was reduced by c-Met inhibitor, Ly294002, Akt inhibitor, and PP2. Conclusions/Significance Our results suggest that the interaction between HGF and c-Met increases OPN expression in human osteoblasts via the PI3K, Akt, c-Src, c-Jun, and AP-1 signaling pathway.

CTGF increases IL-6 expression in human synovial fibroblasts through integrin-dependent signaling pathway.

Background Connective tissue growth factor (CTGF; also known as CCN2) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. CTGF is abundantly expressed in osteoarthritis (OA). However, the relationship between CTGF and IL-6 in OA synovial fibroblasts (OASFs) is mostly unknown. Methodology/Principal Findings OASFs showed significant expression of CTGF, and expression was higher than in normal SFs. OASFs stimulation with CTGF induced concentration-dependent increases in IL-6 expression. CTGF mediated IL-6 production was attenuated by αvβ5 integrin neutralized antibody and apoptosis signal-regulating kinase 1 (ASK1) shRNA. Pretreatment with p38 inhibitor (SB203580), JNK inhibitor (SP600125), AP-1 inhibitors (Curcumin and Tanshinone IIA), and NF-κB inhibitors (PDTC and TPCK) also inhibited the potentiating action of CTGF. CTGF-mediated increase of NF-κB and AP-1 luciferase activity was inhibited by SB203580 and SP600125 or ASK1 shRNA or p38 and JNK mutant. Conclusions/Significance Our results suggest that CTGF increased IL-6 production in OASFs via the αvβ5 integrin, ASK1, p38/JNK, and AP-1/NF-κB signaling pathways.

Plasma electrolytic oxidation of titanium and improvement in osseointegration

Reducing the osseointegration time for biomedical titanium implants in surgical patients is an important goal. However, a huge controversy exists over the effectiveness of osseointegration of the surface layer by plasma electrolytic oxidation (PEO), which is a widely favored surface modification for titanium-based implants. In this study, various surface coatings, including anatase-TiO2 (A-TiO2 ), rutile-TiO2 (R-TiO2 ), hydroxyapatite (HAp), strontium-containing hydroxyapatite (Sr-HAp), and dual-phase HAp-TiO2 were synthesized on titanium implants by PEO. A comparative study of osseointegration performance (both in vitro and in vivo) and bone/implant adhesion strength conducted using push-out thrust tests were demonstrated. The in vitro experimental test results agree strongly with the in vivo test results: the dual-phase HAp-TiO2 coating exhibits the superior cell adhesion and differentiation condition among all of the coatings in the in vitro tests and therefore has the highest push-out bonding strength of 5.37 MPa after 12 wk of implantation in the in vivo test. The HAp-containing coatings benefit from its bioactivity and therefore perform the others in terms of long-term osteocyte growth (from the in vitro results) and the extent of osseointegration (from the in vivo results). The dual-phase HAp-TiO2 coating provides the advantages of both the bioactive HAp and structural enhancement by the TiO2 , effectively promoting osseointegration.

Percutaneous pulsed radiofrequency applied to the L-2 dorsal root ganglion for treatment of chronic low-back pain: 3-year experience

OBJECT The authors assessed the effectiveness of percutaneous pulsed radiofrequency treatment for providing pain relief in patients with chronic low-back pain with or without lower-limb pain. METHODS Data were obtained in 127 patients who had chronic low-back pain with or without lower-limb pain due to a herniated intervertebral disc or previous failed back surgery and who underwent pulsed radiofrequency treatment. Their conditions were proven by clinical features, physical examination, and imaging studies. Low-back pain was treated with pulsed radiofrequency applied to the L-2 dorsal root ganglion (DRG) and lower-limb pain was treated with pulsed radiofrequency applied to the L3-S1 DRG. Patients underwent uni- or bilateral treatment depending on whether their low-back pain was unilateral or bilateral. A visual analog scale was used to assess pain. The patients were followed up for 3 years postoperatively. RESULTS In patients without lower-limb pain (Group A), 27 (55.10%) of 49 patients had initial improvement >or= 50% at 3-month follow-up. At 1-year follow-up, 20 (44.44%) of 45 patients in Group A had pain relief >or= 50%. An analysis of patients with pain relief >or= 50% for at least 1 month showed that the greatest effect was at 3 months after treatment. In patients with low-back pain and lower-limb pain (Group B), 37 (47.44%) of 78 patients had initial improvement >or= 50% at 3-month follow-up. At 1-year follow-up, 34 (45.95%) of 74 patients had pain relief effect >or= 50%. An analysis of patients in Group B with pain relief >or= 50% for at least 1 month showed that the greatest effect was at 1 month after treatment. CONCLUSIONS The results of this prospective analysis showed that treatment with pulsed radiofrequency applied at the L-2 DRG is safe and effective for treating for chronic low-back pain. Satisfactory pain relief was obtained in the majority of patients in Group A with the effect persisting for at least 3 months. The results indicate that pulsed radiofrequency provided intermediate-term relief of low-back pain. Further studies with long-term follow-up are necessary.

Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells

Chondrosarcomas are a type of primary malignant bone cancer, with a potent capacity for local invasion and distant metastasis. Brain-derived neurotrophic factor (BDNF) is commonly upregulated during neurogenesis. The aim of the present study was to examine the mechanism involved in BDNF-mediated vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells. Here, we knocked down BDNF expression in chondrosarcoma cells and assessed their capacity to control VEGF expression and angiogenesis in vitro and in vivo. We found knockdown of BDNF decreased VEGF expression and abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in vivo in the chick chorioallantoic membrane and Matrigel plug nude mouse models. In addition, in the xenograft tumor angiogenesis model, the knockdown of BDNF significantly reduced tumor growth and tumor-associated angiogenesis. BDNF increased VEGF expression and angiogenesis through the TrkB receptor, PLCγ, PKCα, and the HIF-1α signaling pathway. Finally, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of BDNF and VEGF protein in 56 chondrosarcoma patients was significantly higher than in normal cartilage. In addition, the high level of BDNF expression correlated strongly with VEGF expression and tumor stage. Taken together, our results indicate that BDNF increases VEGF expression and enhances angiogenesis through a signal transduction pathway that involves the TrkB receptor, PLCγ, PKCα, and the HIF-1α. Therefore, BDNF may represent a novel target for anti-angiogenic therapy for human chondrosarcoma.

Improved osteoblast compatibility of medical-grade polyetheretherketone using arc ionplated rutile/anatase titanium dioxide films for spinal implants.

Titanium dioxide (TiO(2)), known to exhibit good biocompatibility, is applied in this study as a thin film formed onto polyetheretherketone (PEEK) substrate, which has been widely used in spinal interbody fusion cages. For successful deposition, an arc ionplating (AIP) technique was applied to deposit TiO(2) at low deposition temperature without damaging PEEK substrate, while providing satisfactory film adhesion. This study systematically investigates the effects of TiO(2) thin film phase composition and surface characteristics, controlled by using different target current and substrate bias, on osteoblast compatibility. Experimental results showed that anatase phase (A-TiO(2)) and/or rutile phase (R-TiO(2) ) TiO(2) coatings, respectively, can be prepared in appropriate deposition conditions. Overall, the TiO(2)-coated PEEK presented better osteoblast compatibility than the bare PEEK material in terms of cell adhesion, cell proliferation, and cell differentiation abilities, as well as osteogenesis performance (as determined by levels of osteopontin, osteocalcin, and calcium content). Surface roughness and hydrophilicity of the AIP-TiO(2) films were found to be responsible for significant osteoblast cell growth. It is also noticeable that the R-TiO(2) exhibited better osteoblast compatibility than the A-TiO(2) due to the presence of negatively charged hydroxyl groups on R-TiO(2) (110) surface in nature.

HGF and c-Met interaction promotes migration in human chondrosarcoma cells.

Chondrosarcoma is a type of highly malignant tumor with a potent capacity for local invasion and causing distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Hepatocyte growth factor (HGF) has been demonstrated to stimulate cancer proliferation, migration, and metastasis. However, the effect of HGF on migration activity of human chondrosarcoma cells is not well known. Here, we found that human chondrosarcoma tissues demonstrated significant expression of HGF, which was higher than that in normal cartilage. We also found that HGF increased the migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells. c-Met inhibitor and siRNA reduced HGF-increased cell migration and MMP-2 expression. HGF treatment resulted in activation of the phosphatidylinositol 3′-kinase (PI3K)/Akt/PKCδ/NF-κB pathway, and HGF-induced expression of MMP-2 and cell migration was inhibited by specific inhibitors or siRNA-knockdown of PI3K, Akt, PKCδ, and NF-κB cascades. Taken together, our results indicated that HGF enhances migration of chondrosarcoma cells by increasing MMP-2 expression through the c-Met receptor/PI3K/Akt/PKCδ/NF-κB signal transduction pathway.