JP2008540328A - 脱灰骨基質(demineralizedbonematrix)の活性化抽出 - Google Patents
脱灰骨基質(demineralizedbonematrix)の活性化抽出 Download PDFInfo
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Abstract
Description
本研究は、復員軍人援護局によって支援された。米国政府は、本発明において、特定の権利を有しうる。
発明の分野
本発明は、一般的に、造骨因子に関し、そしてより詳細には、脱灰骨基質(demineralized bone matrix)(「DBM」)および/または天然骨形成タンパク質(「nBMP」)、造骨活性の少なくとも1つの内因性阻害剤が除去されているDBMおよび/またはnBMPを含む組成物、DBMおよび/またはnBMPを含む製品、ならびに該組成物および該製品を用いて骨形成を誘導する方法に関する。
正常骨形成は、発生中に起こり、そして傷害後の修復を行い、そして成人の生活においては、骨格の完全性を保持するため、リモデリングが起こる。骨形成およびリモデリングは、一般的に、破骨細胞による骨吸収および骨芽細胞による骨形成を伴い、これらは増殖因子によって制御される。したがって、細胞分化、骨形成および骨吸収における平衡間のいかなる干渉も、骨形成、修復およびホメオスタシスに影響を及ぼしうる。
例えば、BMP作用の動力学または全体の造骨潜在能力を改善する活性化剤および物質を添加することによるか、あるいはBMP作用の阻害剤を除去することによって、DBMおよびnBMPを改善することが望ましい可能性もある。
本発明の1つの側面において、造骨活性の阻害剤のレベルを減少させるか、または該阻害剤を除去することによって、DBMまたはnBMPの造骨活性を増加させることが望ましく、そしてより具体的には、BMP作用の阻害剤を除去することが望ましい。
本発明はまた、骨形成を誘導するかまたは骨修復を増進するため、物質でコーティングされたか、または分化した細胞が植え付けられた、移植片などのデバイスも含むことも可能である。本発明はまた、骨形成または骨修復が望ましい部位での、物質または分化した細胞の適用も含むことも可能である。例えば、骨形成または骨修復を刺激することによって、骨折を固定するか、骨形成を増進するか、または人工装具移植片を安定化させるために用いられる、限定されるわけではないが、ピン、ねじおよびプレートを、移植片が含むことも可能である。
脱灰骨基質(DBM)およびそこから精製される天然骨形成タンパク質(nBMP)は、異所性軟骨内骨形成を誘導し、これは、いくつかの臨床的状況において、骨治癒を増進するのに使用可能である。これらの物質は、多くのタンパク質の複雑な混合物であり、そしていくつかの既知の骨形成タンパク質(BMP)、およびおそらくBMP結合性タンパク質またはBMPの阻害剤を含有する。したがって、造骨活性が増加したDBM関連物質が望ましい。
DBMからBMP活性の増進剤または阻害剤を除去する潜在能力に関して、化学抽出を試験する、一連の研究を行った。1つのこうした処理は、アルカリ尿素での一晩抽出であり、これを用いて、タンパク質の正味荷電に基づいて、DBMからタンパク質を除去した。抽出されたDBMの造骨活性を、等量の濃縮された抽出物が添加されているDBMのものに比較した。
材料および方法
脱灰骨基質の産生。脱灰骨基質(DBM)を、Urist(Urist, M.R., Huo, Y.K., Brownell, A.G., Hohl, W.M., Buyske, J., Lietze, A., Tempst, P., Hunkapiller, M.およびDeLange, R.J.(1984)「ヒドロキシアパタイト・クロマトグラフィーによる、ウシ骨形成タンパク質の精製」Proc. Natl. Acad. Sci. U.S.A. 81:371−375. Urist, M.R.「骨形成タンパク質の新たな概念」(1991):Fundamentals of Bone Growth: Methodology and Applications中, A.D. Dixon, B.G. Sarnat、およびD.A.N. Hoyte(監修), pp.189−198.(C.R.C. Press, ボストン))に先に記載されるように調製した。簡潔には、新鮮な骨を清浄にし、粉砕し、プロテアーゼ阻害剤の存在下で水で洗浄し、1:1(v/v)クロロホルム:メタノールで脱脂し、0.6M HClで脱灰し、再び洗浄し、そして凍結乾燥した。
結果
DBMの造骨活性に対する抽出物の影響。図1および2は、DBMの造骨活性に対する、等量(25mg)の水溶性抽出物の影響を放射線学的に示す。図1に示す結果は、DBM出発物質(図1、左側の2標本)および抽出されたDBM(図1、右側の2標本)の造骨活性を確認し、そして比較する。DMBおよび抽出されたDMBは、石灰化の広い領域に見られうるように、どちらも、異所性骨形成を誘導した(矢印で示す)。組織学的検査によって、石灰化が、造骨性の骨形成と関連し、そして単にジストロフィー性石灰化でないことが確認された。
Claims (35)
- カオトロピック溶媒で抽出されている脱灰骨基質(demineralized bone matrix)を含む組成物であって、抽出された脱灰骨基質が骨誘導活性を有し、そして抽出された脱灰骨基質が、天然の脱灰骨基質より少ない非造骨性タンパク質を有する、前記組成物。
- カオトロピック溶媒が、約1M〜約4.5Mの間の濃度で尿素を含む、請求項1の組成物。
- カオトロピック溶媒が、約6M尿素および0.1M KOHの間の濃度で尿素を含む、請求項1の組成物。
- 脱灰骨基質のカオトロピック溶媒での第一の抽出、およびカオトロピック溶媒、イオン性界面活性剤または非変性濃度の酸での第二の抽出由来の抽出されている非コラーゲン性タンパク質を含む組成物であって、該非コラーゲン性タンパク質が造骨活性を有し、そして等量の抽出されていないタンパク質より少ない非造骨性タンパク質を有する、前記組成物。
- 第二の抽出カオトロピック溶媒が、約4Mグアンジジン(guandidine)HClおよび約6M尿素を含む、請求項3の組成物。
- 第二の抽出イオン性界面活性剤が約1%ドデシル硫酸ナトリウムを含む、請求項3の組成物。
- 第二の抽出酸が約1〜2Mクエン酸を含む、請求項3の組成物。
- 脱灰骨基質または天然BMPを含み、非造骨性タンパク質を実質的に含まない、造骨活性を有する組成物。
- 脱灰骨基質または天然BMPを含み、天然DBMまたはBMPより少ない造骨阻害タンパク質を有する、造骨活性を有する組成物。
- 脱灰骨基質または天然BMPを含み、等量の天然DBMまたはBMPより少ないノギンを有する、造骨活性を有する組成物。
- BMPノギンなどの阻害性タンパク質を、減少したレベルで有するかまたは実質的に含まない、脱灰骨基質またはBMPを含む組成物。
- BMP−2、BMP−4またはBMP−7の少なくとも1つをさらに含む、請求項1、2または3の組成物。
- (a)骨組織からDBMを得て;
(b)DBMをカオトロピック溶媒で抽出して;
(c)生じたDBMを単離する
工程を含む、減少したレベルの造骨阻害因子を有するDBMを産生するための方法。 - 骨形成を増進する際に使用するための薬剤であって、療法的有効投薬量のDBMまたはBMPを含むか、あるいは等量の天然DBMまたはBMPに比較して減少したレベルのBMP阻害剤を有する、前記薬剤。
- 副甲状腺ホルモン、フッ化ナトリウム、インスリン様増殖因子I、インスリン様増殖因子IIまたはトランスフォーミング増殖因子ベータ、ビスホスホネート、エストロゲン受容体調節剤、カルシトニン、ビタミンDまたはカルシウムを含む群より選択される少なくとも1つの剤をさらに含む、請求項14の薬剤。
- BMP−2、BMP−4またはBMP−7の少なくとも1つの療法的有効投薬量をさらに含む、請求項14の薬剤。
- ノギンを実質的に含まないDBMまたはnBMPで、哺乳動物細胞を処理することを含む、骨形成を誘導する方法。
- BMP−2、BMP−4またはBMP−7の少なくとも1つで、哺乳動物細胞を処理することをさらに含む、請求項17の方法。
- 等量の天然DBMまたはnBMPに比較して減少したレベルのノギンを有するDBMまたはnBMPで、哺乳動物細胞を処理することを含む、骨形成を誘導する方法。
- BMP−2、BMP−4またはBMP−7の少なくとも1つで、哺乳動物細胞を処理することをさらに含む、請求項19の方法。
- 療法的に有効な用量の、副甲状腺ホルモン、フッ化ナトリウム、インスリン様増殖因子I、インスリン様増殖因子IIまたはトランスフォーミング増殖因子ベータ、ビスホスホネート、選択的エストロゲン受容体調節剤、カルシトニン、ビタミンD、またはカルシウムを含む群より選択される少なくとも1つの剤で、哺乳動物細胞を処理することをさらに含む、請求項19の方法。
- 哺乳動物細胞を刺激して、未処理細胞における生物学的マーカーのレベルより高いレベルで、骨形成の生物学的マーカーを発現させる方法であって、カオトロピック溶媒で抽出されており、そして天然DBMまたはBMPに比較し、等量の抽出されていないノギンに比較して、減少したレベルの造骨阻害タンパク質を有する、DBMまたはnBMPに、哺乳動物細胞を曝露することを含む、前記方法。
- BMP−2、BMP−4またはBMP−7の少なくとも1つで、哺乳動物細胞を処理することをさらに含む、請求項22の方法。
- 生物学的マーカーが、アルカリホスファターゼ活性、カルシウム取り込み、ミネラル化またはオステオカルシンmRNAの発現の少なくとも1つの増加である、請求項22の方法。
- 骨形成が望ましい場所に隣接した場所に、造骨性細胞を投与し;そして天然DBMまたはnBMPに比較して減少したレベルのノギンを有するDBMまたはBMPを、骨形成が望ましい場所に隣接した場所に投与することを含む、骨形成を誘導する方法。
- BMP−2、BMP−4またはBMP−7の少なくとも1つを投与することをさらに含む、請求項25の方法。
- 支持体を含む製品であって、前記支持体がDBMまたはBMPを含むか、あるいは前記DBMまたはnBMPが、天然DBMまたはBMPに比較して減少したレベルのノギンを有し、そして前記DBMまたはBMPが造骨活性を有する、前記製品。
- 固体支持体上に固定されたタンパク質をさらに含む、請求項27の製品であって、前記タンパク質が、BMP−2、BMP−4、BMP−7またはその断片の少なくとも1つを含み、前記断片が造骨活性を有する、前記製品。
- 表面を有する支持体を含む移植片であって、移植片表面の少なくとも一部が、等量の天然DBMまたはnBMPに比較して減少したレベルのノギンを有するDBMまたはBMPを、骨形成を増進するのに十分な量で含む、前記移植片。
- BMP−2、BMP−4またはBMP−7の少なくとも1つをさらに含む、請求項29の移植片。
- 支持体が、ピン、ねじ、プレート、または人工関節の形に形成されている、請求項29の移植片。
- 移植片の少なくとも表面に、造骨性哺乳動物細胞がさらに含まれる、請求項29の移植片。
- 増加したレベルの造骨阻害因子を有する組成物を産生する方法であって:
(a)骨組織からDBMを得て;
(b)カオトロピック溶媒でDBMを抽出し;
(c)造骨阻害因子を含む水溶性分画を単離する
工程を含む、前記方法。 - 造骨阻害因子がノギンである、請求項33の方法。
- DBMの造骨活性を阻害するためのタンパク質であって、脱灰骨基質のカオトロピック溶媒での抽出由来の水溶性抽出物(extractate)から得られている、前記タンパク質を含む、組成物。
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US7241874B2 (en) | 2002-06-26 | 2007-07-10 | Zimmer Ortho Biologics, Inc. | Rapid isolation of osteoinductive protein mixtures from mammalian bone tissue |
US8188219B2 (en) * | 2004-01-28 | 2012-05-29 | The Regents Of The University Of California | Bone morphogenic protein binding peptide |
US8415302B2 (en) | 2004-01-28 | 2013-04-09 | The Regents Of The University Of California | Surgical applications for BMP binding protein |
US8193312B2 (en) | 2004-01-28 | 2012-06-05 | The Regents Of The University Of California | Bone morphogenic protein binding peptide |
JP2008540328A (ja) | 2004-11-29 | 2008-11-20 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 脱灰骨基質(demineralizedbonematrix)の活性化抽出 |
EP2115465A4 (en) * | 2006-12-22 | 2011-08-10 | Univ California | SURGICAL APPLICATIONS FOR BMP-BINDING PROTEINS |
EP2445512B1 (en) | 2009-06-23 | 2018-08-29 | The Regents of The University of California | Enhancement of bmp retention |
AU2010328427B2 (en) | 2009-12-13 | 2014-06-05 | Advanced Biologics, Inc. | Bioactive grafts and composites |
CN109260224B (zh) * | 2018-11-27 | 2020-11-10 | 正大制药(青岛)有限公司 | 一种帕立骨化醇软胶囊及其制备方法 |
KR20230039937A (ko) * | 2021-09-15 | 2023-03-22 | 현대자동차주식회사 | 차량의 리어 범퍼 구조 |
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