Tumor angiogenesis, the formation of new blood capillaries by vascular endothelial cells from existing vessels, is an important mechanism for supplying nutrients, oxygen, growth factors and others to tumor cells. Tumor cells trigger angiogenesis by secreting angiogenic factors, especially vascular endothelial growth factor (VEGF-A), 1) which plays an important role in the regulation of normal and abnormal angiogenesis.2) VEGF-A (commonly known as VEGF) was first reported as a vascular permeability-inducing factor secreted by tumor cells, and referred to as vascular permeability factor (VPF). Reactive oxygen species (ROS) are suggested to play an important role in angiogenesis. 10) Furthermore, there is increasing evidence of the involvement of H 2 O 2 in the regulation of angiogenesis.9,11-13) As well, a variety of cell lines derived from human tumors has been shown to produce large amounts of H 2 O 2 .14) Constitutive surveillance for cellular protection against oxidative stress is conferred by intracellular antioxidative agents.15) Excess amounts of ROS are toxic and cause a reduction of intracellular antioxidant levels.16) It has been reported that pretreatment of the heart with exogenous antioxidants improved its condition as a result of reducing ROS production.17) The VEGF-A gene is one that has its expression regulated by ROS, especially by H 2 O 2 . Additional data support that VEGF-A mRNA is up-regulated by H 2 O 2 in a dose-and time-dependent manner. 18,19) Taken together, these suggest that some endogenous as well as exogenous antioxidative agents can be used to regulate VEGF-A gene expression and/or H 2 O 2 production for therapeutic purposes.Electrolyzed reduced water (ERW) has attracted much attention because of its antioxidative potential. Water electrolysis typically produces two forms of water: reduced or alkaline (high pH) water near the cathode and an oxidized or acid (low pH) water near the anode. Applications of oxidized

Between May 2002 and October 2006, 19 patients (17 men and 2 women; average age 57.2; range 47-71 years) received anterior corpectomy and fusion for severe ossification of the posterior longitudinal ligament (OPLL) in our department. Preoperative radiological evaluation showed the narrowing by the OPLL exceeded 50% in all cases, and OPLL extended from one to three vertebrae. We followed-up all patients for 12-36 months (mean 18 months). The Japanese Orthopaedic Association (JOA) score before surgery was 9.3±1.8 (range 5-12) which significantly increased to 14.2±1.3 (range 11-16) points at the last follow-up (P<0.01). The improvement rate (IR) of neurological function ranged from 22.2-87.5%, with a mean of 63.2%±15.2%. The operation also provided a significant increase in the cervical lordosis and the cord flatting rate (P< 0.01). No severe neurological complication developed. We therefore concluded that anterior decompression and fusion was effective and safe in the treatment of the selected patients, although OPLL exceeded 50% diameter of the spinal canal.

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Osteogenic factors are often used in orthopedics to promote bone growth, improve fracture healing, and induce spine fusion. Osteogenic oxysterols are naturally occurring molecules that were shown to induce osteogenic differentiation in vitro and promote spine fusion in vivo. The purpose of this study was to identify an osteogenic oxysterol more suitable for clinical development than those previously reported, and evaluate its ability to promote osteogenesis in vitro and spine fusion in rats in vivo. Among more than 100 oxysterol analogues synthesized, Oxy133 induced significant expression of osteogenic markers Runx2, osterix (OSX), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OCN) in C3H10T1/2 mouse embryonic fibroblasts and in M2-10B4 mouse marrow stromal cells. Oxy133-induced activation of an 8×-Gli luciferase reporter, its direct binding to Smoothened, and the inhibition of Oxy133-induced osteogenic effects by the Hedgehog (Hh) pathway inhibitor, cyclopamine, demonstrated the role of Hh pathway in mediating osteogenic responses to Oxy133. Oxy133 did not stimulate osteogenesis via BMP or Wnt signaling. Oxy133 induced the expression of OSX, BSP, and OCN and stimulated robust mineralization in primary human mesenchymal stem cells. In vivo, bilateral spine fusion occurred through endochondral ossification and was observed in animals treated with Oxy133 at the fusion site on xray after 4 weeks and confirmed with manual assessment, micro CT (μCT), and histology after 8 weeks, with equal efficiency to recombinant human bone morphogenetic protein-2 (rhBMP-2). Unlike rhBMP-2, Oxy133 did not induce adipogenesis in the fusion mass and resulted in denser bone evidenced by greater BV/TV ratio and smaller trabecular separation. Findings here suggest that Oxy133 has significant potential as an osteogenic molecule with greater ease of synthesis and improved time to fusion compared to previously studied oxysterols. Small molecule osteogenic oxysterols may serve as the next generation of bone anabolic agents for therapeutic development.

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