Angiogenesis plays an essential role in a wide range of physiologic and pathologic states. Numerous factors are reported to be involved in angiogenesis. Among them, vascular endothelial growth factor (VEGF), a homodimer-secreted protein, is one of the most important factors. VEGF was initially termed vascular permeability factor (VPF) and was shown to induce vascular permeability, as well as to promote angiogenesis. There are three tyrosine kinase-type VEGF receptors, Fit-1 (VEGFR-1), KDR/Flk-1 (VEGFR-2), and Flt -4 (VEGFR-3) . Flt -1 and KDR/Flk-1 are expressed in vascular endothelial cells (ECs), whereas Flt -4 is preferentially expressed in lymphatic ECs. VEGF binds to Flt -1 and KDR/Flk-1, and to a membrane protein neuropilin-1 on ECs. Neuropilin-1 does not contain a tyrosine kinase domain, but is functionally associated with VEGF receptors. The VEGF-KDR/Flk-1 mediated signal is indispensable for the differentiation of ECs and blood cells in embryo. The VEGF-KDR/Flk-1 mediated signal also play an important role in adult, and stimulates protease synthesis in ECs and promotes EC migration and proliferation. VEGF-induced angiogenesis results beneficial effects in several animal models of myocardial or limb ischemia. Currently, several clinical trials are ongoing to test the hypothesis that VEGF-induced angiogenesis may be beneficial for these conditions.

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Apoptosis occurs in a variety of physiologic situations, including embryogenesis, and plays a crucial role in normal tissue homeostasis, however, a breakdown in the delicate balance between cell survival and apoptosis has been implicated in the pathogenesis of a number of rheumatic diseases. Recent studies have revealed that the signals leading to apoptotic cell death are regulated by the molecular interactions among a set of gene products, thus, it is possible to speculate that the expression of apoptosis-related molecules in situ is modulated by various humoral and/or cellular factors, which may contribute to the characteristic phenotype of each human autoimmune disease. Rheumatoid arthritis (RA) is a joint-affecting disease, which is characterized by the hyperplasia of synovial tissues with periarticular bone destruction (bone loss), thus, the impaired synovial cell apoptosis with the increased susceptibility toward osteoblast apoptosis have been speculated.
We are going to discuss in this review the apoptosis mechanisms involving in the synovial cell hyperplasia, as well as therapeutic implication of apoptosis induction, in patients with RA.

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Recently, several studies have demonstrated feasibility of cell transplantation for the therapy of failing heart. However, little has been considered for blood supply indispensable to cell transplantation. This study is an investigation to evaluate the feasibility of in advance angiogenesis by gelatin microspheres incorporating basic fibroblast growth factor (bFGF) for cell therapy of cardiomyocytes with an ischemic cardiomyopathy model. Our previous study revealed that the gelatin microspheres achieved controlled release of bFGF. Rats with myocardial infarction received the intramuscular injection of culture medium (Control), fetal cardiomyocytes (TX), gelatin microspheres incorporating bFGF (FGF), and gelatin microspheres incorporating bFGF followed by that of fetal cardiomyocytes 1 week later (FGF-TX) . Left ventricle (LV) function of rat hearts was assessed by echocardiography and cardiac catheterization 4 week later. The TX, FGF, and FGF-TX groups showed better fractional shortening than the Control group. LV maximum timevarying elastance was significantly higher in the FGF-TX group than other groups. These results indicate that the combination of bFGF-induced angiogenesis and cardiomyocyte transplantation is a promising procedure to improve the LV function in rats with myocardial infarction.

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Self renewing epidermis are characterized by a fine balance between growth and differentiation of immature keratinocytes including stem cells. Recent progress showed various molecules that played important roles for this control. Here we focus on two molecules, cyclin-dependent kinase inhibitor p 21 and Notch receptor. First, p21 has been shown to the contribution to proliferation and differentiation of keratinocytes. Recently we know that loss of p21 function increases the pluripotent keratinocyte population with multi-potential (stem cells) . Second, Notch was identified as one of key molecules for cell fate decision in Drosophila. Even in mammalian Notch homologues have important functions for the control of cell fate decision and growth/differentiation due to cell-cell communication. In keratinocytes Notch 1 signaling leads to growth arrest via p21 activation and differentiation. These works will advance our knowledge on controlling mechanism for homeostasis and tumor formation in not only epidermis but also other epithelia tissue.

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Recent development of biotechnology has brought extensive advance in medical care and supplies. Especially, the tissue engineering is one of the most attractive approaches to regenerate the damaged organs. For example, it is now possible to reconstruct the bone tissue by culturing bone marrow derived mesenchymal stem cells. Tissue Engineering Research Center (TERC) at the National Institute of Advanced Industrial Science and Technology (AIST) was established in April, 2001. The TERC has clean rooms (class 10, 000 and 1, 000) handling only human cells for clinical applications. We report herein about culture technique and safety of the tissue engineering products in repect of clinical application in Orthopedic fields.

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Various extracts of the Chinese herbal remedy Tripterygium wilfordii Hook. f. (TWHF) have been reported to be therapeutically effective for rheumatoid arthritis (RA) in China, but their action mechanism has not been understood well. In this review, we describe the novel chondroprotective and immunosuppressive effects of triptolide, a diterpenoid triepoxide from TWHF.
Triptolide suppresses the IL-1 α-induced production of proMMPs-1 and -3 along with decrease in their mRNAs in human synovial fibroblasts. In contrast, the IL-1 α-mediated production of tissue inhibitors of metalloproteinases (TIMP) -1 and -2 was further augmented by triptolide in human synovial fibroblasts. Triptolide also inhibits the IL-1 α-induced PGE₂ production by selectively suppressing the gene expression and production of cycloxygenase-2. Furthermore, the gene expression of IL-1 α, IL-1 β, TNF-α and IL-6, and the production of IL-1 β and IL-6 are effectively inhibited in the triptolide-treated mouse macrophages.
These data suggest that the therapeutic effects of TWHF in RA are in part due to the novel chondroprotective effects of triptolide via suppression of proMMP production and up-regulation of TIMPs. The interference in the production of proinflammatory cytokines and COX-2 are also very likely to be effective.

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We conducted a preliminary study to evaluate the efficacy and safety of FK 506 for rheumatoid arthritis (RA) patients. Subjects were 29 RA patients in an active state. The trial was of an open, uncontrolled design, with a comparison of 2 treatment schedules. An intermittent administration group, 11 patients, received biweekly doses of 5 mg/time for 4 weeks, 7 mg/time for next 4 weeks and then 9mg/time for 16 weeks. A daily administration group, 18 patients, received doses of 3mg/day for 4 weeks, 4mg/day for next 4 weeks and then 5 mg/day for 16 weeks. The clinical efficacy was assessed by numbers of swollen and tender joints, morning stiffness, grip strength, ESR, CRP, rheumatoid factor, Lansbury index and ADL. Moderate to marked improvement on the final global assessment was obtained in 36.4% of the patients in the intermittent administration group and in 76.5% of the patients in the daily administration group. BSR and CRP were significantly decreased by the 4^th or 8^th week of treatment in the daily administration group, but not in the intermittent administration group. Adverse events were mainly gastrointestinal symptoms, cardiovascular symptoms, increased serum levels of BUN, uric acid, glucose and creatinine. In the daily administration group, 1 of 7 patients who received 3mg/day during the trial without increasing doses and 5 of 11 patients who received 4-5mg/day showed the elevation of 0.3mg/dl or more in the serum level of creatinine. Daily administration of F 506 at the dose of 3mg/day or less might have a salutary therapeutic effect on RA patients.

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