Summary of Research Project Results Under the JSPS FY2000
"Research for the future Program"



1.Research Institution Tokyo Medical and Dental University
 
2.Research Area Integrated Fields
 
3.Research Field Tissue Engineering
 
4.Term of Project FY1996〜FY2000
 
5.Project Number 96I00205
 
6.Title of Project Tissue Engineering for Hard Tissues

7.Projetct Leader
Name Institution,Department Title of Position
Shoji Enomoto Tokyo Med&Dent. Univ. Oral Surgery Professor

8.Core Members

Names Institution,Department Title of Position
Isao Ishikawa Tokyo Med&Dent. Univ Periodontics Professor
Kenichi Shinomiya Tokyo Med&Dent. Univ Orthopaedics Professor
Masaki Noda Tokyo Med&Dent. Univ Molecular Pharmacology Professor

9.Cooperating Researchers

Names Institution,Department Title of Position
Izumi Asahina Tokyo Med&Dent. Univ Oral Surgery Assist Professor
Soichiro Ito Tokyo Med&Dent. Univ Orthopaedics Assist Professor
Shigeru Oda Tokyo Med&Dent. Univ Periodontics Assist Professor

10.Summary of Research Results

Bone Morphogenetic Protein (BMP) has been expected to be utilized for the repair of bone defects because of its bone inductive activity. We have already confirmed that the implantation of BMP with a carrier regenerate the bone defects in rats and dogs. Whereas, contrary to our expectation, the graft of BMP alone did not reconstruct the mandibular bone defects in primates, which were closer species to humans. One of the reasons for the discrepancy in these results may be a lower response of the cells to BMP due to aging. However, we found that the combination graft of BMP and bone marrow, or culture expanded osteoprogenitor cells, reconstructed mandibular bones in primates This method is a reliable way to regenerate bony defects. The carriers of BMP play important role in BMP-inducing bone formation. Therefore, we tried to develop new carriers of BMP and we confirmed that PLLA sponge and biphasic calcium phosphate worked well as the carriers. Additionally, we developed a new artificial bone substitute, a collagen/hydroxyapatite composite. The material was strong enough to support the stress loading, and it had a direct bond to bone and is gradually substituted by the newly formed bone. Furthermore, we found that this new material was a good carrier of BMP. To understand the fundamental mechanism of bone formation, we analyzed the mRNA expression of Cbfa1, a transcriptional factor, concerned to bone formation. We found that Cbfa1 was expressed constitutionally in osteoblasts and chondrocytes and BMP enhanced its expression. Additionally, we identified several new genes, transcriptional factors related to the differentiation of osteoblast and chondrocyte. These results will lead us to develop new therapy which contribute to patients who suffered from osseous diseases.

11.Key Words

(1)Bone Morphogenetic protein、(2)Osteoblast, Chondrocyte、(3)Carrier
(4)Tissue Engineering

12.References

[Reference Articles]
Author Title of Article
Yamashita T Retardation in bone resorption after bone marrow ablation in klotho mutant mice.
Journal Volume Year Pages Concerned
Endocrinology 141 2000 438-445

Author Title of Article
Takazawa Y CBFA1, IS Constitutively expressed in chondrocytic cell line, TC6, and its expression is upregulated byBMP2.
Journal Volume Year Pages Concerned
Journal of Endocrinology 165 2000 579-586

Author Title of Article
Sekiya I SOX9 enhances aggrecan gene promoter/enhancer activity and is upregulated by Retinoic Acid in a Cartilage-Derived Cell Line, TC6.
Journal Volume Year Pages Concerned
Journal of Biological Chemistry 275 2000 10738-10744

Author Title of Article
Tsuji K Identification and Expression of a novel 3'-exon of mouse Runx1/Pebp2 α B/Cbfa2/AML1 gene.
Journal Volume Year Pages Concerned
Biochemical and Biophysical Research Communications 274 2000 171-176

Author Title of Article
Kawaguchi N Mitf is expressed in osteoclast progenitors in vitro.
Journal Volume Year Pages Concerned
Experimental Cell Research 260 2000 284-291

Author Title of Article
Furuya K. Overexpression of Cas-interactiong zinc finger protein (CIZ) suppresses proliferation and enhances expression of type I collagen gene in osteoblast-like MC3T3E1 cells.
Journal Volume Year Pages Concerned
Experimental Cell Research 261 2000 329-335

Author Title of Article
I Ishikawa Regeneration of periodontal tissues Now and Future
Journal Volume Year Pages Concerned
J. Japanese dental medicine 19 2000 112-115

Author Title of Article
S Oda, The effect of EMDOGAIN
Journal Volume Year Pages Concerned
J. Japanese Dentist 52 2000 115

Author Title of Article
A Kinoshita Regeneration of Periodontal tissues
Journal Volume Year Pages Concerned
The Journal of Dental Engineering 134 2000 9-12

Author Title of Article
Kikuchi M Self-Organization Mechanism in a Bone-like Hydroxyapatite / Collagen Nanocomposite Synthesized in vitro and Its Biological Reaction in vivo.
Journal Volume Year Pages Concerned
Biomaterials,   2000 in press

Author Title of Article
Kikuchi M Preparation of Hydroxyapatite / Collagen Composites using Biomimetic Process and Their Biocompatibility.
Journal Volume Year Pages Concerned
Mater. Res. Soc. Sym. Proc. 599 2000 51-53

Author Title of Article
Takakuda K Bone Reconstruction with Hydroxyapatite / Collagen.
Journal Volume Year Pages Concerned
Proc. Internat. WS on Bio- integrated Mater. & Tissue Eng.   2000 72-73

Author Title of Article
Miki T, Experience with freeze-dried PGLA/HA/rhBMP-2 as a bone graft substitute.
Journal Volume Year Pages Concerned
Journal of Cranio-Maxillofacial Surgery. 28 2000  

Author Title of Article
Kikuchi M Hap/Collagen Biomimetic synthesis has bone morphigenetic ability
Journal Volume Year Pages Concerned
Intelligent Materials 10 2000 14-18

Author Title of Article
Manabe A Pateulized autogenous bone graft for reconstruction after resection of osteosarcoma
Journal Volume Year Pages Concerned
Orthopaedic Surgery and Traumatology 43 2000 1089-1096

Author Title of Article
Seto I Reconstruction of Primate Mandible by the Combination graft of Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) and Bone Marrow.
Journal Volume Year Pages Concerned
American Journal of Oral and Maxillofacial Surgery. 59 2001 53-61

Author Title of Article
Md. Imranul Alam Comparative study of biphasic calcium phosphate ceramics impregnated with rhBMP-2 as bone substitutes.
Journal Volume Year Pages Concerned
Journal of Biomedical Materials Research 54 2001 129-138

Author Title of Article
Md. Imranul Alam Evaluation of ceramics composed of different hydroxyapatite to tricalcium phosphate ratios as carriers for rhBMP-2
Journal Volume Year Pages Concerned
Biomaterials   2001  

Author Title of Article
Moriyama T Development of cultured oral mucosa utilizing collagen sponge matrix and contracted collagen gel A preliminary study for clinical applications
Journal Volume Year Pages Concerned
Tissue Engineering   2001 in press

Author Title of Article
Md. Imranul Alam Prefabricated vascularized bone flap: a tissue transformation technique for bone reconstruction.
Journal Volume Year Pages Concerned
Plastic and Reconstructive Surgery.   2001 in press

Author Title of Article
Yonezawa H Effect of Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) on Distraction Osteogenesis:An Experimental Study in Rabbit Mandible.
Journal Volume Year Pages Concerned
The Asian Jounal of Oral and Maxillofacial Surgery.   2001 81-90

Author Title of Article
Ishii Y Experimental Study of Secondary Bone Graft of Alveolar Clefts using Bone Morphogenetic Protein (BMP).
Journal Volume Year Pages Concerned
The Journal of the Stomatological Society, Japan. 68,1 2001 111-124

Author Title of Article
Oda M Prefabrication of vascularized bone flap using bone morphogenetic protein
Journal Volume Year Pages Concerned
The Journal of the Stomatological Society, Japan. 68,1 2001 in press

Author Title of Article
Itoh S Enhancement of bone ingrowth in a titanium fiber mesh implant by rhBMP-2 and hyaluronic acid.
Journal Volume Year Pages Concerned
J Materials Science: Materials in Medicine   2001 in press

Author Title of Article
Itoh S The biocompatibility and osteoconductive activity of a novel hydroxyapatite/collagen composite biomaterial, and its function as a carrier of rhBMP-2.
Journal Volume Year Pages Concerned
J Biomedical Materials Research 54 2001 445-453

Author Title of Article
Itoh S A study on induction of nerve regeneration using bioabsorbable tubes.
Journal Volume Year Pages Concerned
J reconstr microsurg 17(2) 2001 in press

Author Title of Article
Kuroda K Improvement autogenous bone graft for reconstruction after resection of osetosarcoma
Journal Volume Year Pages Concerned
J. East. Jpn. Orthop. Traumatol 13 2001 in press

Author Title of Article
Itoh S Investigation of Collagen cross link technique
Journal Volume Year Pages Concerned
Microsurgery 14(1) 2001 in press

Author Title of Article
Kawaguchi N Spontaneous mutation in Mitf gene causes osteopetrosis in silver homozygote quail.
Journal Volume Year Pages Concerned
Developmental Dynamics   2001 in press

Author Title of Article
Nemoto H Osteopontin deficiency reduces experimental tumor cell metastasis to bone and soft tissues.
Journal Volume Year Pages Concerned
Journal of Bone and Mineral Research. 16 2001 in press

Author Title of Article
Asou Y Osteopontin facilitates angiogenesis, accumulation of osteoclasts and resorption in ectopic bone.
Journal Volume Year Pages Concerned
Endocrinology 142 2001 in press

Author Title of Article
Yamashita T Klotho-deficient mice are resistant to bone loss induced by unloading due to sciatic neurectomy
Journal Volume Year Pages Concerned
Journal of Endocrinology 168 2001 in press

Author Title of Article
Ishijima M Enhancement Of Osteoclastic Bone Resorption And Supression Of Osteoblastic Bone Formation In Response To Reduced Mechanical Stress Do Not Occur In The Absence Of Osteopontin.
Journal Volume Year Pages Concerned
The Journal Of Experimental Medicine 193 2001 399-404

Author Title of Article
Ihara H Parathyroid hormone-induced bone resorption does not occur in the absence of osteopontin.
Journal Volume Year Pages Concerned
Journal of Biological Chemistry   2001 in press

Author Title of Article
Tsuji K Transient Suppression of Cbfal Expression by Basic Fibroblast Growth Factor (bFGF) in Rat Osteoblast-like Osteosarcoma ROS17/2.8 Cells.
Journal Volume Year Pages Concerned
Journal of Bone and Mineral Metabolism.   2001 in press


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