Faculty Profiles - NISHIDA Keiichiro

Papers - NISHIDA Keiichiro

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Expression and localization of connective tissue growth factor (CTGF/Hcs24/CCN2) in osteoarthritic cartilage

S Omoto, K Nishida, Y Yamaai, M Shibahara, T Nishida, T Doi, H Asahara, T Nakanishi, H Inoue, M Takigawa

OSTEOARTHRITIS AND CARTILAGE 12 ( 10 ) 771 - 778 2004.10

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO LTD

Objective: The investigation of the expression and localization of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24/CCN family member 2 (CTGF/Hcs24/CCN2) in normal and osteoarthritic (OA) cartilage, and quantification of CTGF/Hcs24-positive cells.
Methods: Cartilage samples of patients (n = 20) with late stage CA were obtained at total joint replacement surgery. Morphologically normal cartilage was harvested for comparison purposes from the femoral heads of 6 other patients with femoral neck fracture. Paraffin -embedded sections were stained by Safranin O. The severity of the OA lesions was divided into four stages (normal, early, moderate, and severe). The localization of protein and mRNA for CTGF/Hcs24 was investigated by immunohistochemistry and in situ hybridization, respectively. The population of CTGF/Hcs24-positive chondrocytes in CA cartilage and chondro-osteophyte was quantified by counting the number of the cells under light microscopy.
Results: Signals for CTGF/Hcs24 were detected in a small percentage of chondrocytes throughout the layers of normal cartilage. In early stage CA cartilage, the CTGF/Hcs24-positive chondrocytes were localized mainly in the superficial layer. In moderate to severe OA cartilage, intense staining for CTGF/Hcs24 was observed in proliferating chondrocytes forming cell clusters next to the cartilage surface. In chondro-osteophyte, strong signals were found in the chondrocytes of the proliferative and hypertrophic zones.
Conclusion: CTGF/Hcs24 expression was detected in both normal and OA chondrocytes of human samples. The results of the current study suggested that expression of CTGF/Hcs24 was concomitant with development of CA lesions and chondrocyte differentiation in chondro-osteophyte. (C) 2004 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.joca.2004.06.009

Histone deacetylase inhibitor suppression of auto antibody-mediated arthritis in mice via regulation of p16(INK4a) and p21(WAF1/Cip1) expression

K Nishida, T Komiyama, S Miyazawa, ZN Shen, T Furumatsu, H Doi, A Yoshida, J Yamana, M Yamamura, Y Ninomiya, H Inoue, H Asahara

ARTHRITIS AND RHEUMATISM 50 ( 10 ) 3365 - 3376 2004.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

Objective. To examine whether depsipeptide (FK228), a histone deacetylase (HDA) inhibitor, has inhibitory effects on the proliferation of synovial fibroblasts from rheumatoid arthritis (RA) patients, and to examine the effects of systemic administration of FK228 in an animal model of arthritis.
Methods. Antoantibody-mediated arthritis (AMA) was induced in 19 male DBA/1 mice (6-7 weeks old); 10 of them were treated by intravenous administration of FK228 (2.5 mg/kg), and 9 were used as controls. The effects of FK228 were examined by radiographic, histologic, and immunohistochemical analyses and arthritis scores. RA synovial fibroblasts (RASFs) were obtained at the time of joint replacement surgery. In vitro effects of FK228 on cell proliferation were assessed by MTT assay. Cell morphology was examined by light and transmission electron microscopy. The effects on the expression of the cell cycle regulators p16(INK4a) and p21(WAF1/Cip1) were examined by real-time polymerase chain reaction and Western blot analysis. The acetylation status of the promoter regions of p16(INK4a) and p21(WAF1/Cip1) were determined by chromatin immunoprecipitation assay.
Results. A single intravenous injection of FK228 (2.5 mg/ml) successfully inhibited joint swelling, synovial inflammation, and subsequent bone and cartilage destruction in mice with AMA. FK228 treatment induced histone hyperacetylation in the synovial cells and decreased the levels of tumor necrosis factor a and interleukin-1beta in the synovial tissues of mice with AMA. FK228 inhibited the in vitro proliferation of RASFs in a dose-dependent manner. Treatment of cells with FK228 induced the expression of p16(INK4a) and up-regulated the expression of p21(WAF1/Cip1). These effects of FK228 on p16(INK4a) and p21(WAF1/Cip1) were related to the acetylation of the promoter region of the genes.
Conclusion. Our findings strongly suggest that systemic administration of HDA inhibitors may represent a novel therapeutic target in RA by means of cell cycle arrest in RASFs via induction of p16(INK4a) expression and increase in p21(WAF1/Cip1) expression.

DOI： 10.1002/art.20709

Influence of telomerase activity on bone and soft tissue tumors

N Umehara, T Ozaki, S Sugihara, T Kunisada, Y Morimoto, A Kawai, K Nishida, A Yoshida, T Murakami, H Inoue

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 130 ( 7 ) 411 - 416 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Purpose. Telomeres consisting of a repeating nucleotide sequence (TTAGGG)n are shortened in normal somatic cells. Telomerase is an enzyme that elongates the telomere sequence and is detected in most human cancers and usually not in normal somatic cells. Little is known about telomerase activity in bone and soft tissue tumors. The aim of this study was to investigate the relationship between telomerase activity and clinical factors in bone and soft tissue tumors. Methods. Telomerase activity was measured using the modified telomeric repeat amplification protocol (TRAP) assay in 115 bone and soft tissue tumors obtained through open biopsy or resection. Results. Telomerase activity was detected in 10% of benign tumors and 44% of malignant tumors (p<0.001). A higher incidence of telomerase activity was detected in high-grade tumors than in low-grade tumors (p=0.002). The cumulative metastasis-free and overall survival in telomerase-positive patients was significantly worse than in telomerase-negative patients (p=0.045 and p=0.048). Conclusion. Our study suggests that telomerase activity is associated with tumor aggressiveness and may be a useful parameter to predict the prognosis of patients with malignant bone and soft tissue tumors.

DOI： 10.1007/s00432-004-0553-z

抗炎症薬・抗アレルギー薬開発の最前線ヒストン脱アセチル化酵素阻害剤を用いた細胞周期制御による実験的関節炎の抑制

西田圭一郎, 小見山貴充, 宮澤慎一, 北村亜似, 申正男, 真鍋博規, 土井英之, 浅原弘嗣, 二宮善文, 大塚愛二, 井上一

炎症・再生 24 ( 4 ) 425 - 425 2004.7

Radiological follow-up study of rheumatoid wrists after radio-lunate limited arthrodesis with ulnar head resection

Kensuke Uchida, Keiichiro Nishida, Hiroyuki Hashizume, Shunsuke Omoto, Masutaka Watanabe, Yusuke Ota, Hajime Inoue

Modern Rheumatology 14 ( 1 ) 31 - 36 2004.3

Language：English Publishing type：Research paper (scientific journal)

Radio-lunate limited arthrodesis (RLA) is an established surgical intervention for damaged rheumatoid arthritis (RA) wrists. The goal of RLA is to conserve the range of motion (ROM) and level of activities of daily life (ADL) by delaying more extensive fusion. In this study, we retrospectively reviewed the outcome of RLA with ulnar head resection (UHR) in terms of pain score, ROM, and radiographic parameters, including carpal height ratio, ulnar translation ratio, and palmar subluxation. The clinical factors, such as dose of corticosteroids per day and laboratory examination data before surgery, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF), did not influence the results of the surgery. The changes in these clinical factors were also statistically analyzed in relation to the Schulthess classification of preoperative radiographs of wrists reported by Simmen and Huber: Type I (ankylosis type), Type II (osteoarthritis type), and Type III (disintegration type). This study hypothesized that RLA with UHR would provide no significant improvement in Type III wrists. The results showed that RLA with UHR resulted in stable wrists with excellent pain relief and with limited, but temporary, functional ROM, suggesting that this procedure seems to be applicable for all types of wrists within this group of patients. © Springer-Verlag Tokyo 2004.

DOI： 10.1007/s10165-003-0262-5

Spontaneous "spaghetti" flexor tendon ruptures in the rheumatoid wrist

Hiroyuki Hashizume, Keiichiro Nishida, Kazuo Fujiwara, Hajime Inoue

Modern Rheumatology 14 ( 3 ) 257 - 259 2004

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Japan

A 54-year-old woman who had been treated for rheumatoid arthritis for 12 years developed spontaneous multiple flexor tendon ruptures during a 5-month period. Radiography revealed volar subluxation of the lunate bone. Surgery was performed 5 months after the first onset of tendon rupture. All eight flexors, except the flexor pollicis longus tendons, had ruptured, and the damage resembled spaghetti. Four flexor digitorum profundus tendons were reconstructed by bridge graft using their respective sublimis tendons. Wrist joint fusion and tenolysis were performed 3 months after the first operation. Each finger achieved a good range of motion 2 years and 6 months after be second operation. © Japan College of Rheumatology and Springer-Verlag Tokyo 2004.

DOI： 10.3109/s10165-004-0303-8

Biomechanical analysis of the mechanism of elbow fracturedislocations by compression force

H Wake, H Hashizume, K Nishida, H Inoue, N Nagayama

JOURNAL OF ORTHOPAEDIC SCIENCE 9 ( 1 ) 44 - 50 2004

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

Fracture-dislocations of the coronoid and olecranon were produced experimentally, and their onset mechanisms were analyzed to clarify the effects of compression force on the coronoid and olecranon. The study used two-dimensional finite element method (2D-FEM) simulations and static loading experiments. The latter applied axial force distally to 40 cadaveric elbows. Posterior fracture-dislocations occurred between 15degrees of extension and 30degrees of flexion, anterior or posterior fracture-dislocations at 60degrees, and only anterior fracture-dislocations at 90degrees. Injuries were mainly to anterior or posterior support structures. The 2D-FEM simulations showed that the stress concentration areas moved from the coronoid process to the olecranon as position changed from extension to flexion. The very high frequency of concurrent fracture-dislocations of radial head or neck in the current study indicated that the radial head may also function as a stabilizer in the anterior support system.

DOI： 10.1007/s00776-003-0735-6

Arthroscopic surgery for traumatic triangular fibrocartilage complex injury

H Miwa, H Hashizume, K Fujiwara, K Nishida, H Inoue

JOURNAL OF ORTHOPAEDIC SCIENCE 9 ( 4 ) 354 - 359 2004

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

Clinical characteristics, diagnostic imaging, arthroscopic findings, and surgical results of arthroscopic treatment are reported in 62 hands with traumatic triangular fibrocartilage complex (TFCC) injury treated between 1995 and 2002. This retrospective study also describes and compares the results of a novel arthroscopic suture technique for repairing tears with Palmer's class 1B and 1D tears. According to Palmer's classification, there were 10 class 1A, 27 1B, 81C, and 17 1D injuries. The arthroscopic suture and debridement treatments were done under brachial plexus block as a L-day in-hospital procedure. Class ID tears required transradial fixation to anchor the TFCC. Surgical results of suture groups according to Minami's criteria were excellent in 16 hands, good in 15 hands, fair in 1 hand, and poor in 1 hand. The results of the debridement group were excellent in 16 hands, good in 10 hands, fair in 2 hands, and poor in 1 hand. The results of the current study indicate that the novel suture technique were easy to perform, provided strong, tight repair for class 1D injuries, and was applicable for class 1B injuries in this small case series.

DOI： 10.1007/s00776-004-0796-1

Hoechst 33342 is a useful cell tracer for a long-term investigation of articular cartilage repair.

Keisuke Kawasaki, Shinsuke Sugihara, Keiichiro Nishida, Toshifumi Ozaki, Aki Yoshida, Aiji Ohtsuka, Hajime Inoue

Archives of histology and cytology 67 ( 1 ) 13 - 9 2004

Language：English Publishing type：Research paper (scientific journal)

The repair process of a full-thickness osteochondral defect was observed in a rat model using Hoechst 33342 as a cell tracer. The osteochondral defect was created at the medial femoral condyle of the right knee joints of twelve 11 week old male rats. Three weeks after the surgery, Hoechst 33342 was injected into the same knee joints. Calcein, a marker of the mineralization front, was then injected subcutaneousely twice at seven days and one day before harvesting of the tissue. At six, ten, and fourteen weeks and one year after the surgery, femoral condyles were obtained from the operated knee joints, fixed by alcohol, and embedded in polymethylmethacrylate. The sections were examined by fluorescent and then light microscopy. In the lateral femoral condyle cartilage, Hoechst 33342 labeling of chondrocyte nuclei was observed in all layers of the intact cartilage, and the dye never infiltrated beneath the subchondral bone plate. At 6 weeks after the surgery, Hoechst 33342-positive cells were observed not only in the regenerated fibrous cartilage, but also in the newly formed mineralized tissue in the medial femoral condyle. Interestingly, Hoechst 33342 labeling remained undiminished even one year after the intra-articular injection. The findings of the present study suggest that intra-articular injection of Hoechst 33342 is a useful tracer for long-term investigations of chondrocyte differentiation in vivo.

DOI： 10.1679/aohc.67.13

Development of a bone cutting robot for total knee arthroplasty. Reviewed

Mamoru Mitsuishi, Shin'ichi Warisawa, Naohiko Sugita, N. Suzuki, Masahiko Suzuki, Hideshige Moriya, Kazuo Fujiwara, Nobuhiro Abe, Keiichiro Nishida, Hiroyuki Hashizume, H. Inoue, Takayuki Inoue, Koichi Kuramoto, Yoshio Nakashima

2004 IEEE/RSJ International Conference on Intelligent Robots and Systems, Sendai, Japan, September 28 - October 2, 2004 4 3302 - 3308 2004

Publishing type：Research paper (international conference proceedings) Publisher：IEEE

In total knee joint replacement, the femur and the tibia must be precisely shaped to ensure that they firmly mate with the artificial joint. The normal procedure is to manually cut the bones using a bone saw and mechanical jigs. A 9-axis bone cutting machine tool has been developed by the authors to increase cutting accuracy and reduce the hospital stay required for recuperation. As developed, the cut plane is determined by a 5 degree-of-freedom mechanism and the femur and tibia are cut by moving two translational and one rotational degrees of freedom, a system that provides a cutter path which avoids cutting the ligament. A preoperative planning system based on CAD/CAM principles and an overview of a system for total knee arthroplasty are also discussed. Experimental results showed the effectiveness of the developed robot and the system.

DOI： 10.1109/IROS.2004.1389926

Blood loss in patients for total knee arthroplasty

N Abe, H Fujimoto, T Ozaki, K Asaumi, H Kato, K Nishida, Y Takahara, H Inoue

ANNALS OF THE RHEUMATIC DISEASES 62 497 - 497 2003.7

Vascular endothelial growth factor principally acts as the main angiogenic factor in the early stage of human osteoblastogenesis

T Furumatsu, ZN Shen, A Kawai, K Nishida, H Manabe, T Oohashi, H Inoue, Y Ninomiya

JOURNAL OF BIOCHEMISTRY 133 ( 5 ) 633 - 639 2003.5

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE BIOCHEMICAL SOC

Vascular endothelial growth factor (VEGF)-mediated angiogenesis is essential for bone formation. However, the effect of VEGF on osteoblastic cells during osteoblastogenesis is still controversial. The aim of this,study was to clarify the relationship between osteoblastic cells derived from human mesenchymal stem cells (MSCs). and VEGF -in the early stage of osteoblastic differentiation. Continuous dexamethasone treatment with a low concentration stimulated osteoblastogenesis of MSCs and the expression of VEGF121 mRNA. The VEGF secretion from osteoblastic cells also increased along with osteoblastogenesis. Neuropilin-1, which mainly binds VEGF165, was detected at all stages during early osteoblastogenesis, but VEGF receptor-1 and -2 were not detected on RT-PCR analyses. In this study, VEGF had no direct effect on the proliferation of osteoblastic cells. However, the secreted VEGF in the conditioned medium of osteoblastic cells exhibited high angiogenic power as to endothelial cell proliferation. Our findings indicated that VEGF121 principally acts as the main angiogenic factor in the early stage of human osteoblastogenesis. The present study also demonstrated the differential expression of VEGF121 during osteoblastogenesis. The increase of VEGF in the early stage might be a useful marker of induction of bone formation due to human MSCs.

DOI： 10.1093/jb/mvg081

リウマチ教室の経験

篠田潤子, 西田圭一郎, 千田益生, 濱田全紀, 堅山佳美, 井上一, 難波良文

リハビリテーション医学 40 ( Suppl. ) S292 - S292 2003.5

Effect of NOS2 gene deficiency on the development of autoantibody mediated arthritis and subsequent articular cartilage degeneration

H Kato, K Nishida, A Yoshida, Takada, I, C McCown, M Matsuo, T Murakami, H Inoue

JOURNAL OF RHEUMATOLOGY 30 ( 2 ) 247 - 255 2003.2

Language：English Publishing type：Research paper (scientific journal) Publisher：J RHEUMATOL PUBL CO

Objective. To determine the effect of NOS2 gene deletion on articular cartilage degradation in autoantibody mediated arthritis (AMA).
Methods. Female C57BL/6Ai-[ko] NOS2 N5 (NOS2-/-) mice (7-8 weeks old) and the counterpart C57/B16 Crj mice (wild-type, WT) were studied, Arthritis was induced by intraperitoneal injection of 4 mg of an arthritogenic cocktail of 4 monoclonal antibodies raised against type II collagen twice on Day 0 and Day 1 followed by intraperitoneal injection of 50 mug of lipopolysaccharide on Day 2. Individual limbs were scored for arthritis in 4 grades; the total maximum score per mouse was 16. Femoral condyles and tibial plateaus of both knee joints were collected on Day 15 for immunohistological studies on nitrotyrosine and matrix metalloproteinase (MMP)-3 and -9. DNA fragmentation in chondrocytes was detected by the nick-end labeling (TUNEL) method. Blood was also collected on Day 15 to determine serum levels of nitrite/nitrate and interleukin 1beta (IL-1beta).
Results. Both NOS2-/- and WT mice with AMA developed clinically apparent arthritis. In WT mice, the arthritis progressed rapidly and reached the peak score 11.4 +/- 2.9 on Day 12, whereas the arthritis in NOS2-/- mice was milder and the peak score was 7.7 +/- 2.8 on Day 13 (p < 0.05). The serum nitrite/nitrate levels, histological grades of articular cartilage degradation, and numbers of apoptotic chondrocytes and nitrotyrosine positive chondrocytes were significantly lower in NOS2-/- mice with AMA than in WT mice with AMA. Conversely, significant differences were not observed in MMP-3 or -9 expression in chondrocytes, or in serum IL-1β levels between these 2 groups of mice.
Conclusion. NOS2 gene deletion did not affect the inflammatory responses, but reduced the cartilage degradation.

Blood loss in patients for total knee arthroplasty

Fujimoto, H., Ozaki, T., Asaumi, K., Kato, H., Nishida, K., Takahara, Y., Abe, N., Inoue, H.

Knee Surgery, Sports Traumatology, Arthroscopy 11 ( 3 ) 2003

Hepatopancreatic arterial ring: Bilateral symmetric typology in human celiaco-mesenteric arterial system

M Kosaka, K Horiuchi, K Nishida, T Taguchi, T Murakami, A Ohtsuka

ACTA MEDICA OKAYAMA 56 ( 5 ) 245 - 253 2002.10

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

The celiac and mesenteric arterial system including the left gastric, splenic, common hepatic, and superior mesenteric arteries shows various types of origins, courses, ramifications and anastomoses. In order to explain the various expressions of this system, we have proposed a typological model, in which celiacomesenteric arteries develop as paired or bilaterally symmetrical primordial vessels originated from the anterior aspect of the aorta, and these vessels anastomose each other with longitudinal and horizontal pathways. Here, we report 3 unusual cases characterized by arterial rings, formed by the left gastric, left accessory hepatic, proper hepatic, anterior pancreaticoduodenal, and dorsal pancreatic arteries. The dorsal pancreatic and anterior pancreaticoduodenal arteries are located to the right and left of the embryonic pancreas developing in the dorsal mesentery, respectively. Such hepatopancreatic arterial rings simultaneously containing right and left elements can only be explained using our typological model, in which the concept of paired arteries or bilateral symmetry is introduced.

DOI： 10.18926/AMO/31711

Inhibition of human chondrosarcoma cell growth via apoptosis by peroxisome proliferator-activated receptor-gamma

K Nishida, T Furumatsu, Takada, I, A Kawai, A Yoshida, T Kunisada, H Inoue

BRITISH JOURNAL OF CANCER 86 ( 8 ) 1303 - 1309 2002.4

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

A rare immunohistochemical study using 28 surgical sections of human chondrosarcoma revealed that 67.9% of tumour cells had weak (10-40%) or strong (> 40%) positive immunoreaction for peroxisome proliferator-activated receptor-gamma. The expression of peroxisome proliferator-activated receptor-mRNA and protein in human chondrosarcoma cell line OUMS-27 was also determined by reverse transcription-polymerase chain reaction and immunocytochemistry, respectively. Furthermore, the effects of peroxisome proliferator-activated receptor-gamma ligands on cell proliferation and survival were investigated in OUMS-27 cells. Pioglitazone, a selective ligand for peroxisome proliferator-activated receptor-gamma, and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a putative endogenous ligand for peroxisome proliferator-activated receptor-gamma, inhibited the proliferation of OUMS-27 cells in a dose-dependent manner. The mechanism of cytotoxic effects of 15d-PGJ(2) was via apoptosis as shown by DNA fragmentation using TUNEL stain and DNA ladder formation, and by ultrastructural analysis using transmission electron microscopy. Flow-cytometric analysis using annexin-V-fluorescein and propidium iodide detected the early change of apoptosis, as well as necrosis of OUMS-27 cells at 4 h after co-incubation with 15d-PGJ(2). These results suggest that peroxisome proliferator-activated receptor-gamma may play a significant role in the pathogenesis of chondrosarcoma, and peroxisome proliferator-activated receptor-gamma ligands, especially 15d-PGJ(2), may be of therapeutic value in the treatment of human chondrosarcoma. (C) 2002 dCancer Research UK.

DOI： 10.1038/sj/bjc/6600241

Endostatin inhibits adhesion of endothelial cells to collagen I via alpha(2)beta(1) integrin, a possible cause of prevention of chondrosarcoma growth

T Furumatsu, N Yamaguchi, K Nishida, A Kawai, T Kunisada, M Namba, H Inoue, Y Ninomiya

JOURNAL OF BIOCHEMISTRY 131 ( 4 ) 619 - 626 2002.4

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE BIOCHEMICAL SOC

Endostatin derived from collagen XVIII is a potent endogenous anti-angiogenic factor that induces regression of various tumors of epithelial origin. Endostatin has been shown to inhibit endothelial cell functions, however, its effect remains controversial. We first attempted here to apply the inhibitory effect of recombinant human endostatin on chondrosarcomas, which originate from the mesenchyme, in nude mice. Endostatin induced reduction of chondrosarcoma growth and tumor angiogenesis in vivo. However, endostatin showed no effect on the proliferation and migration of chondrosarcoma cells in vitro. Next, we investigated the interactions between endostatin and endothelial cells in detail. Endostatin inhibited the migration on and attachment to collagen I but did not affect the proliferation of endothelial cells. Although the migration of endothelial cells was stimulated by angiogenic factors such as basic fibroblast growth factor and vascular endothelial growth factor, endostatin showed similar inhibitory effects on it in the presence and absence of the stimulants. Moreover, the inhibitory effect against endothelial cell attachment to collagen I was attenuated or modulated in the presence of neutralizing antibodies of alpha(2), alpha(5)beta(1), and alpha(V)beta(3) integrins but not that of alpha(1) integrin. Our results suggest that endostatin might suppress the alpha(2)beta(1) integrin function of endothelial cells via alpha(5)beta(1), or alpha(V)beta(3), integrin. We propose here that endostatin might be effective for anti-angiogenic therapy for human chondrosarcomas through the suppression of alpha(2)beta(1) integrin functions in endothelial cells.

DOI： 10.1093/oxfordjournals.jbchem.a003142

Human chondrosarcoma secretes vascular endothelial growth factor to induce tumor angiogenesis and stores basic fibroblast growth factor for regulation of its own growth

T Furumatsu, K Nishida, A Kawai, M Namba, H Inoue, Y Ninomiya

INTERNATIONAL JOURNAL OF CANCER 97 ( 3 ) 313 - 322 2002.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are well-known factors that induce neovascularization in many tumors. The molecular mechanisms that regulate tumor angiogenesis in human chondrosarcoma are not clear. We assessed in this work the angiogenic activities of a human chondrosarcoma cell line (OUMS-27) In vivo and determined the efficacies of angiogenic factors derived from OUMS-27 cells on human umbilical vein endothelial cells (HUVECs) in vitro. Tumor xenografts induced an increase in the formation of neovessels, but the distributions of Ki-67 antigen, VEGF and bFGF were unaffected. We also demonstrated that OUMS-27 cells secreted VEGF(165) into the culture medium and that it was the maximal angiogenic factor to stimulate endothelial proliferation and migration in chondrosarcoma. Anti-VEGF antibodies induced an approximately 70% inhibition of these responses of HUVECs, but did not have any effect on OUMS-27 cells. Anti-bFGF antibodies suppressed not only the activities of HUVECs but also the growth of tumor cells in vitro. We indicate that angiogenesis is principally elicited by VEGF(165) and that tumorigenesis is mainly regulated by bFGF stored in the extracellular matrix of OUMS-27 cells. The present study may offer the availability of combination therapies for inhibition of VEGF and bFGF action on vascular endothelial cells and chondrosarcoma cells, respectively. (C) 2002 Wiley-Liss, Inc.

DOI： 10.1002/ijc.1607

Changes in LPIA D-dimer levels after total hip or knee arthroplasty relevant to deep-vein thrombosis diagnosed by bilateral ascending venography

Naofumi Shiota, Toru Sato, Keiichiro Nishida, Masatsugu Matsuo, Yasuhiro Takahara, Shigeru Mitani, Takuro Murakami, Hajime Inoue

Journal of Orthopaedic Science 7 ( 4 ) 444 - 450 2002

Language：English Publishing type：Research paper (international conference proceedings) Publisher：Springer Japan

The purpose of the current retrospective study was to determine the most sensitive and specific cutoff value of plasma D-dimer level associated with deep-vein thrombosis (DVT) after total hip (THA) or knee (TKA) joint arthroplasty. Diagnosis of DVT was determined by bilateral ascending venography pre- and postoperatively. Plasma D-dimer levels were measured by a latex photometric immunoassay system (LPIA) preoperatively and postoperatively on days 1, 3, 7, 10, 14, and 21. Postoperative DVT diagnosed by venography was found in 22 patients (40.1%) after THA and in 18 patients (64.3%) after TKA. Plasma D-dimer levels were significantly higher (P &lt
0.01) in patients with DVT than in those without DVT on days 1, 7, and 10 after THA, but only on day 7 after TKA. Statistical analysis confirmed that a cutoff value of 10.0 μg/ml for D-dimer on day 7 was most sensitive (THA, 95.5%
TKA, 94.4%) and most specific (THA, 96.9%
TKA, 90.0%) in the diagnosis of DVT after THA as well as TKA. It was concluded that over 10 μg/ml of LPIA D-dimer on post-operative day 7 appears to be an indication of the occurrence of DVT after THA and TKA.

DOI： 10.1007/s007760200077

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