JP4394718B2 - 骨芽細胞の発生及び使用 - Google Patents
骨芽細胞の発生及び使用 Download PDFInfo
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Description
本発明は、脂肪組織から骨芽細胞への間質細胞の分化のための方法および組成、ならびにその使用に関する。
骨粗鬆症は、毎年アメリカ合衆国内における約150万件の骨折の原因であり、そのうち約300,000件は股関節部骨折である。股関節部骨折患者の50〜75%は自立して生活することができず、その結果、介護の費用が増大する。骨粗鬆症は、加齢による正常を上回る骨密度の損失を特徴とする。この疾患は、西欧およびアジア文化圏において高頻度(60才を超える女性の30%以上)で発生する。これらの骨修復障害の正確な原因は不明であるが、骨改造作用の動的過程が、骨芽細胞(骨産生細胞)活性の低下および破骨(骨分解細胞)活性の増進を特徴とする過程によって中断されることは明白である(Parfitt(1992)Triangle31:99−110,Parfitt(1992)In Bone, volume 1,B.K.Hall ed. Teleford Press and CRC Press,Boca Raton,FL,p.351−429)。
本発明は、脂肪組織からの間質細胞を、骨芽細胞特性を有する細胞に分化させる方法および組成物、ならびに被験対象の骨組織を改善する方法を提供する。本方法は、脂肪組織からの間質細胞を上記細胞を骨芽細胞に分化させるのに十分な時間、βグルセロリン酸およびアスコルビン酸またはアスコルビン酸2リン酸あるいはそれらの両方中で培養する工程を含む。このような方法および組成物は、手術部位または障害における骨に自家移植するための骨芽細胞の産生に有用である。この組成物は、脂肪間質細胞、線維芽細胞の成長を支持することができる培地ならびに分化を誘導する量のβグリセロリン酸およびアスコルビン酸またはアスコルビン酸2リン酸、あるいはそれらの両方を含む。
本発明は、脂肪間質細胞を骨芽細胞に分化させる方法を提供する。本発明の方法によって産生される骨芽細胞は、手術部位または骨折部位における研究または被験対象の骨に移植するための、もとの骨芽細胞を提供するのに有用である。したがって1つの態様において、本発明は脂肪間質細胞を骨芽細胞に分化させる方法であって、線維芽細胞の成長を支持することができる培地と、分化を誘導する量のβグリセロリン酸およびアスコルビン酸またはアスコルビン酸2リン酸、あるいはそれらの両方とを含む組成物中で、上記細胞を培養する工程を含む方法を提供する。
Rodbell(1964)J Bioll Chem 239:375およびHaunerら(1989)J Clin Invest 84:1663−1670に記載の方法に従って、ヒトの間質細胞を脂肪組織から単離した。簡潔に記載すると、脂肪吸引手術によって皮下貯留物からヒト脂肪組織を取り出した。ついで、この脂肪組織を脂肪吸引カップから500mlの滅菌ビーカーに移し、約10分間静置した。沈殿した血液を吸引により除去した。容量125ml(以下)の組織を250mlの遠心管に移し、次いでこの遠心管にクレブスリンゲル緩衝液(Krebs−Ringer Buffer)を満たした。組織および緩衝液を約3分間または明らかに分離するまで静置し、吸引によって緩衝液を除去した。組織をクレブスリンゲル緩衝液で洗浄し、さらに4、5回または組織が黄橙色になり且つ緩衝液が淡い黄褐色になるまで、洗浄した。
実施例1に記載の通りに脂肪間質細胞を単離し、下記の通りに処理して、骨芽細胞に分化させる。1cm2あたり約22,000細胞の密度で間質細胞培地(上記参照)に懸濁した間質細胞を、24ウェルまたは6ウェル、あるいはそれらの両方の組織培養プレートで平板培養した。24時間後、間質細胞培地に骨芽細胞分化培地(10%のウシ胎仔血清(v/v)を添加したDMEM、10mMのβグリセロリン酸、50μg/mlのアスコルビン酸2リン酸、60U/mlのペニシリン、60U/mlのストレプトマイシン、15μg/mlのアンホテリシンB)と交換した。3日ごとに3週間、骨芽細胞分化培地を新たな培地と交換した。培地を変えるとき、1mlの馴化培地を採取し、分泌された因子を後で分析するために、−80℃で保存した。あるいは、脂肪組織から単離された間質細胞を、Hauner et al. (1989 J Clin Invest 34:1663−1667)の方法に従って、脂肪細胞分化培地で処理することにより分化させた。
実施例1に記載の方法に従って脂肪組織から単離された間質細胞の培養体を使用して、本発明の化合物が骨芽細胞分化に及ぼす作用を試験した。本発明の化合物の存在下および非存在下におくこと以外は実施例2に記載の通りに、脂肪間質細胞から骨芽細胞を分化させた。分泌したオステオカルシン用のアッセイによって、分化を測定した。この実施例の方法を使用して、骨芽細胞分化に対して陽性に影響を及ぼすことが確認された化合物としては、骨形態発生タンパク質4およびオステオポンチンIが挙げられる(データ表示せず)。以上の結果は、先のWozney et al. 1988 Science 242:1528−1534,Asahina et al. 1996 Exp Cell Res 222:38−47およびCook et al. 1996 Clin Orthop.324:29−38の結果と一致する。下記の通骨芽細胞分化を増進する化合物を使用して、被験対象の骨構造を強化することが可能である。
実施例1に記載の方法を使用して、非治癒性骨折または骨粗鬆症性骨折に罹っている患者からの脂肪吸引により、脂肪組織から間質細胞を単離する。実施例2に記載の方法を使用して、in vitroで、前脂肪細胞を骨芽細胞に分化させる。7〜21日後、たとえばトリプシン処理により、あるいは分化した細胞を組織培養プレートから機械的に擦り取ることにより、分化した骨芽細胞を収穫し、次いで無菌条件下で4〜20℃にて3000×gで10分間遠心分離することにより濃縮する。収穫した細胞を、コラーゲンまたはMatrigel(商標)溶液中に再懸濁し、次いで、20ゲージ以上の穿孔針を使用して、骨折部位または手術部位に直接注入する。あるいは、注入前に細胞を、DBMあるいは、ProOsteon2000(商標)(InterporeCross社製,Irvine,CA)もしくはCollgraft(商標)(ZimmerInc.製,Warsaw,IN)等のセラミックマトリックスと混合する。使用する細胞の量は、骨折の表面積および骨折の性質によって異なる。所望する骨折の回復速度に応じて、複合治療を必要とする場合もある。結果として治癒までの時間が短縮し、骨折部位の周りの骨密度が上昇した。
実施例1に記載の通りに間質細胞を単離し、塩化カルシウム等の標準形質導入法(Manistis et al. (1982)MolecularCloning:A Laboratory Manual,Cold Spring Harbor Press,Cold Spring Harbor,NY)を使用して、遺伝物質(たとえば、プロモーターに作動可能に連結した骨形態発生タンパク質等の有用な遺伝子産物をコードするDNA)を間質細胞に導入する。Effectene試薬を使用した、このようなプロトコルが開発されており、本明細書に記載されている。微量遠心管内で、0.1〜2.0μgのpCMV−βgal(Stratagene,Inc.製,La Jolla,CA)を150μlの緩衝液EC(Qiagen Effectene(商標)キット、カタログ番号301425、QiagenCorp.製)に加える。こうすることにより、DNAを凝縮することが可能である。この凝縮したDNAに8μlのエンハンサー(QiagenEffectenキット)を加える。次いで、凝縮したDNAが入っている遠心管を1秒間ボルテックスし、室温で2〜5分間インキュベートする。この遠心管を短時間遠心分離して、遠心管の上部の滴を除去する。10μlのEffectene(商標)を加え、遠心管を10秒間ボルテックスし、室温で5〜10分間インキュベートする。5〜10分間インキュベートした後、DNA混合物に培地の1mlを加える。
Claims (28)
- ウシ胎仔血清と、分化を誘導する量のβグリセロリン酸およびアスコルビン酸及び/又はアスコルビン酸2リン酸とを含む培地(但し、さらに添加されたグルココルチコイドを含む培地を除く)を含む組成物中で、脂肪間質細胞を培養する工程を含む、脂肪間質細胞を骨芽細胞に分化させる方法。
- 前記量が、2〜20mMのβグリセロリン酸、および20〜75μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である請求項1に記載の方法。
- 前記量が、5〜15mMのβグリセロリン酸、および40〜60μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である請求項2に記載の方法。
- 前記量が、10mMのβグリセロリン酸、および50μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である請求項3に記載の方法。
- 前記培地が、DMEM、αMEM及びBMEからなる群から選択される請求項1に記載の方法。
- 前記培地が、5〜20%のウシ胎仔血清を含む請求項1に記載の方法。
- 前記培地が1種または複数の骨形態発生タンパク質をさらに含む請求項1に記載の方法。
- 前記細胞が哺乳動物のものである請求項1に記載の方法。
- a)骨芽細胞分化に対する影響について試験すべき化合物の存在下および非存在下で、ウシ胎仔血清と、分化を誘導する量のβグリセロリン酸およびアスコルビン酸及び/又はアスコルビン酸2リン酸とを含む培地(但し、さらに添加されたグルココルチコイドを含む培地を除く)を含む組成物中で、脂肪間質細胞を培養する工程と、
b)前記化合物の存在下で培養した前記細胞における骨芽細胞分化を、前記化合物の非存在下で培養した前記細胞の骨芽細胞分化と比較する工程と
を含む骨芽細胞の分化に影響を与える化合物を同定する方法。 - 前記量が、2〜20mMのβグリセロリン酸、および20〜75μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である請求項9に記載の方法。
- 前記量が、5〜15mMのβグリセロリン酸、および40〜60μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である請求項10に記載の方法。
- 前記量が、10mMのβグリセロリン酸、および50μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である請求項11に記載の方法。
- ウシ胎仔血清と、分化を誘導する量のβグリセロリン酸、およびアスコルビン酸及び/又はアスコルビン酸2リン酸とを含む培地(但し、さらに添加されたグルココルチコイドを含む培地を除く)を含む組成物中で脂肪間質細胞を培養する工程
を含む被験対象の骨構造改善のための細胞を処理する方法。 - 前記量が、2〜20mMのβグリセロリン酸、および20〜75μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である請求項13に記載の方法。
- 前記量が、5〜15mMのβグリセロリン酸、および40〜60μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である、請求項14に記載の方法。
- 前記量が、10mMのβグリセロリン酸、および50μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である、請求項15に記載の方法。
- 前記脂肪間質細胞が前記被験対象から単離される、請求項13に記載の方法。
- 前記培地が、DMEMと、αMEMと、BMEとからなる群から選択される、請求項13に記載の方法。
- 前記培地が、5〜20%のウシ胎仔血清を含む請求項13に記載の方法。
- 前記培地が、1種または複数の骨形態発生タンパク質をさらに含む請求項13に記載の方法。
- 前記被験対象が哺乳動物である、請求項13に記載の方法。
- 前記骨芽細胞が、骨創傷または骨欠損または骨障害あるいはそれらのすべての修復に有用な組成物と混合して導入される、請求項13に記載の方法。
- 所望の核酸配列が前記脂肪間質細胞または骨芽細胞に導入される、請求項13に記載の方法。
- ウシ胎仔血清と、間質細胞を骨芽細胞に分化させるのに十分な量のβグリセロリン酸およびアスコルビン酸及び/又はアスコルビン酸2リン酸とを含む培地(但し、さらに添加されたグルココルチコイドを含む培地を除く)と、脂肪間質細胞とを含む組成物。
- 前記量が、2〜20mMのβグリセロリン酸、および20〜75μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である、請求項24に記載の組成物。
- 前記量が、5〜15mMのβグリセロリン酸、および40〜60μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である、請求項25に記載の組成物。
- 前記量が、10mMのβグリセロリン酸、および50μMのアスコルビン酸及び/又はアスコルビン酸2リン酸である、請求項26に記載の組成物。
- 前記間質細胞がヒトのものである、請求項24に記載の組成物。
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JP2008099708A (ja) | 2008-05-01 |
CN1584020A (zh) | 2005-02-23 |
CA2312847C (en) | 2014-09-30 |
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CA2312847A1 (en) | 1999-06-10 |
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CN1280612A (zh) | 2001-01-17 |
US20020119126A1 (en) | 2002-08-29 |
WO1999028444A1 (en) | 1999-06-10 |
JP4222726B2 (ja) | 2009-02-12 |
HK1075062A1 (en) | 2005-12-02 |
DE69841850D1 (de) | 2010-09-30 |
EP1036163A1 (en) | 2000-09-20 |
JP2001525165A (ja) | 2001-12-11 |
US20160068813A1 (en) | 2016-03-10 |
US9200255B2 (en) | 2015-12-01 |
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