JP6025002B2 - 骨形成または血管新生促進用ペプチドbfp4およびその用途 - Google Patents
骨形成または血管新生促進用ペプチドbfp4およびその用途 Download PDFInfo
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- A61K38/10—Peptides having 12 to 20 amino acids
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- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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Description
Phe−Phe−Lys−Ala−Thr−Glu−Val−His−Phe−Arg−Ser−Ile−Arg−Ser−Thr
本発明において、「骨形成」は、骨が発生する過程を意味し、骨芽細胞による骨基質形成とその石灰化現象を含む。
配列番号1のアミノ酸からなるペプチドは、公知の方法によって人為的に合成可能であるが、本実験のためには(株)ペプトロン(韓国)に依頼して製造した。下記のアミノ酸配列を有するペプチドをBFP4(bone forming peptide4)と命名した。
Phe−Phe−Lys−Ala−Thr−Glu−Val−His−Phe−Arg−Ser−Ile−Arg−Ser−Thr
前記合成されたBFP4の構造を商用プラグラムを用いて確認した結果、図1に示すように、1826.1の分子量を有する15個のアミノ酸配列を持つα−ヘリックス構造を持っていることを確認した(図1)。
10%FBS入りのDMEMに、1×104個のBalb/c mouse bone marrow stromal cellからクローニングされた中間葉幹細胞が入るように分注した後、約37℃の温度を維持する、5%の二酸化炭素が含有された大気中で約3日間培養し、本実験に使用される骨芽細胞として前記中間葉幹細胞を準備した。
中間葉幹細胞が骨芽細胞に分化するとカルシウムが蓄積されるので、アリザリンレッド(alinzarin red)染色によってミネラリゼーションを測定することにより、骨芽細胞の分化程度を確認した。すなわち、骨芽細胞に分化が促進されるほど、アリザリンレッドによって染色される部分が多くなるので、骨芽細胞分化培地にアリザリンレッドを入れてBFP4を処理した後、アリザリンレッドの染色程度から骨芽細胞の分化程度を確認することができる。このために、骨芽細胞分化培地に骨芽細胞、すなわち中間葉幹細胞を移して3日間培養した後、BFP4またはBMP7を0.001μg/mL、0.01μg/mL、0.05μg/mL、0.1μg/mLずつ添加して2日間さらに培養した。その後、培養された中間葉幹細胞を、氷で冷却させた70%エタノールで1時間固定し、アリザリンレッド−s(alizarin red−s)溶液で約10分間染色してカルシウムの沈着程度を確認し、図2に示した。
カルシウム蓄積に効果がある濃度でBFP4の細胞毒性有無を確認し、図3に示した。このために、MTT Cell Proliferation Assay Kit(Cayman Chemical)を用いて、会社から提供する方法に従って分析を行った。
骨芽細胞の分化で発現される骨芽細胞特定酵素であるアルカリホスファターゼ(ALP)の活性およびカルシウムの濃度をDALP−250 QuantiChrom Alkaline Phosphatase Assay Kit(Gentaur)およびDICA−500 QuantiChrom Calcium Assay Kit(Gentaur)を用いて確認し、図4に示した。
BFP4による骨芽細胞特異遺伝子であるRunx2、オステオカルシンおよびアルカリホスファターゼ遺伝子の発現を確認し、図5に示した。このために、ペプチドを処理した細胞からRNAを抽出し、DNAを合成した後、前記遺伝子の発現程度をPCRを行って電気泳動によって測定した。
中間葉幹細胞が骨芽細胞に分化されながら現れる特定の表面タンパク質CD44、CD51の発現に及ぼすBFP4の影響をFACS分析によって測定し、図6に示した。
BFP4による細胞表面マーカーCD44とCD51の発現を蛍光顕微鏡を介して観察し、図7に示した。このために、骨芽細胞分化過程中に細胞が生きていることを確認するために、DAPI染色、およびCD44、CD51に結合して赤色を帯びるCD44、CD51抗体を用いて蛍光顕微鏡で観察した。
BFP4が生体内で骨形成を促進するかを確認するために、マウスを用いた動物実験を行った(n=6)。まず、中間葉幹細胞の分化を誘導するために、ODMを3日にわたって2回処理した後、2回目にODMを添加するときにBMP7またはBFP4を処理し、24時間経過後に細胞を収集して同数の細胞数を測定した後、マウスの背部分にコラーゲンを支持体として用いて移植した。移植後4週目と8週目にX−rayを用いて骨形成を比較し、図8に示した。
BFP4の血管新生効果を確認するために、VEGFの発現に及ぼすBFP4の影響を観察した。このために、ペプチドを処理した細胞からタンパク質を抽出した後、タンパク質電気泳動を行い、しかる後に、VEGF抗体を用いて発現を測定した。
BFP4による生体内血管新生を確認するために、マトリゲルを用いたマウス動物実験を行った。このために、ペプチドを処理した細胞を獲得した後、マトリゲルと共によく混合し、マウスの背に移植させた後、8週目にマウスの背からマトリゲルをさらに摘出して血管新生を観察した。
Claims (9)
- 配列番号1のアミノ酸配列から成る、骨形成または血管新生促進用ペプチド。
<配列番号1>
Phe−Phe−Lys−Ala−Thr−Glu−Val−His−Phe−Arg−Ser−Ile−Arg−Ser−Thr - 前記配列番号1のアミノ酸配列がBMP7に由来する、請求項1に記載のペプチド。
- 前記ペプチドが骨芽細胞の分化またはVEGFの発現を促進する、請求項1に記載のペプチド。
- 前記ペプチドが骨形成および血管新生促進活性を有する、請求項1に記載のペプチド。
- 請求項1のペプチドをコードするポリヌクレオチド。
- 請求項5のポリヌクレオチドを含む組み換えベクター。
- 請求項1〜4のいずれか1項のペプチド、前記ペプチドをコードするポリヌクレオチド、または前記ポリヌクレオチドを含む組み換えベクターを有効成分として含む、骨疾患または虚血性疾患の予防または治療用薬学的組成物。
- 前記骨疾患は骨粗しょう症、骨関節炎、骨折および骨形成不全症よりなる群から選ばれる一つ以上の疾患である、請求項7に記載の組成物。
- 前記虚血性疾患は虚血性壊死、虚血性脳血管疾患、虚血性腎臓疾患、虚血性肺疾患、四肢の虚血性疾患、虚血性心臓疾患、脳卒中、脳梗塞、心筋梗塞、虚血性心不全および閉塞性動脈硬化症よりなる群から選ばれる一つ以上の疾患である、請求項7に記載の組成物。
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KR1020110054179A KR101274930B1 (ko) | 2011-06-03 | 2011-06-03 | 골 형성 또는 혈관신생 촉진용 펩타이드 bfp 4 및 이의 용도 |
KR10-2011-0054179 | 2011-06-03 | ||
PCT/KR2012/004346 WO2012165900A2 (ko) | 2011-06-03 | 2012-06-01 | 골 형성 또는 혈관신생 촉진용 펩타이드 bfp 4 및 이의 용도 |
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CN105273039A (zh) * | 2015-11-12 | 2016-01-27 | 河北智同生物制药有限公司 | 一种骨肽提取罐及其应用 |
KR102169782B1 (ko) | 2016-08-31 | 2020-10-27 | 가톨릭대학교 산학협력단 | 인간 잇몸-유래 줄기세포 및 골전구체 세포를 공동배양하여 형성된 세포 스페로이드 및 이로부터 혈관내피 성장인자의 생산량을 증가시키는 방법 |
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WO2000047114A1 (en) * | 1999-02-12 | 2000-08-17 | Collagenesis, Inc. | Injectable collagen-based delivery system for bone morphogenic proteins |
US20040067505A1 (en) * | 2001-09-26 | 2004-04-08 | Enrique Alvarez | Therapeutic polypeptides, nucleic acids encoding same, and methods of use |
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US20120309675A1 (en) | 2012-12-06 |
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US20140200174A1 (en) | 2014-07-17 |
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