JP2006503819A - 骨形成を増進するための作用剤および方法 - Google Patents
骨形成を増進するための作用剤および方法 Download PDFInfo
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- JP2006503819A JP2006503819A JP2004531921A JP2004531921A JP2006503819A JP 2006503819 A JP2006503819 A JP 2006503819A JP 2004531921 A JP2004531921 A JP 2004531921A JP 2004531921 A JP2004531921 A JP 2004531921A JP 2006503819 A JP2006503819 A JP 2006503819A
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- hydroxycholesterol
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Abstract
【解決手段】 本発明は、造骨細胞の細胞分化を誘導する作用剤および方法、並びに、患者を処置する、骨の質量を維持する、骨の形成及び/又は骨の修復を増進するための、作用剤および方法の使用を開示する。好適な作用剤としては、オキシステロール、単独あるいは特定のオキシステロール、または骨の形成を助長する既知の他の作用剤との組み合わせが挙げられる。本発明は、さらに、骨の障害の治療のためのオキシステロール含有薬剤、オキシステロールまたは細胞の局所的な注入、及び、骨の修復を促進するための作用剤または細胞を有するインプラントを含む。
Description
この研究は、米国立衛生研究所/米国立衛生研究所により後援されており、米国立衛生研究所/米国立衛生研究所により グラント番号P60 AG 10415-11 が授与されている。アメリカ合衆国政府は本発明に関して一定の権利を有する。
、799塩基対のPCR生成物を産生。PCR生成物は、ゲル精製し、UCLA配列決定コアで配列決定したところ、それらの各GenBankのエントリーに対する最高の類似度が示された。ハイブリッド形成後、室温で、2X SSC+0.1%SDSによりブロットを2度洗浄し、次いで、0.5X SSC+0.1%SDSにより60℃で2度洗浄し、X線フィルムに曝露した。濃度測定により、遺伝子発現誘導の程度を判定した。
Claims (41)
- 哺乳類の間葉幹細胞の造骨細胞分化を誘導する方法であって、少なくとも一つのオキシステロールにより哺乳類の間葉細胞を処置する工程を含むことを特徴とする方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、プレグネノロン、及び、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、及びプレグネノロンのうちの任意の一つの活性部分を含む群から選択されることを特徴とする請求項1に記載の方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロールと22R−ヒドロキシコレステロール、または20S−ヒドロキシコレステロールと22S−ヒドロキシコレステロール、を含む群から選択されるオキシステロールの組合せであることを特徴とする請求項1に記載の方法。
- さらに、副甲状腺ホルモン、弗化ナトリウム、インスリン様成長因子I、インスリン様成長因子IIまたはトランスフォーミング成長因子ベータを含む群から選択される少なくとも一つの二次作用剤により、該哺乳類の間葉細胞を処置する工程を含むことを特徴とする請求項1に記載の方法。
- さらに、チトクロームP450阻害剤、ホスホリパーゼ活性化剤、アラキドン酸、COX酵素活性化剤、造骨性プロスタノイドまたはERK活性化剤を含む群から選択される少なくとも一つの二次作用剤により、該哺乳類の間葉細胞を処置する工程を含むことを特徴とする請求項1に記載の方法。
- 哺乳類の細胞を刺激して、未処置の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の造骨細胞分化の生物学的マーカーを発現させる方法であって、哺乳類の細胞を、選択された投与量の少なくとも一つのオキシステロールに曝露する工程を含むことを特徴とする方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、プレグネノロン、及び、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、及びプレグネノロンのうちの任意の一つの活性部分を含む群から選択されることを特徴とする請求項6に記載の方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロールと22R−ヒドロキシコレステロール、または20S−ヒドロキシコレステロールと22S−ヒドロキシコレステロール、を含む群から選択されるオキシステロールの組合せであることを特徴とする請求項6に記載の方法。
- さらに、副甲状腺ホルモン、弗化ナトリウム、インスリン様成長因子I、インスリン様成長因子IIまたはトランスフォーミング成長因子ベータを含む群から選択される少なくとも一つの二次作用剤により、該哺乳類の間葉細胞を処置する工程を含むことを特徴とする請求項6に記載の方法。
- さらに、チトクロームP450阻害剤、ホスホリパーゼ活性化剤、アラキドン酸、COX酵素活性化剤、造骨性プロスタノイドまたはERK活性化剤を含む群から選択される少なくとも一つの二次作用剤により、該哺乳類の間葉細胞を処置する工程を含むことを特徴とする請求項6に記載の方法。
- 該生物学的マーカーが、アルカリ性ホスファターゼの活性度、カルシウムの取込み、石灰化またはオステオカルシンのmRNAの発現のうちの少なくとも一つの増大であることを特徴とする請求項6に記載の方法。
- 該哺乳類の細胞が、間葉幹細胞、骨前駆体細胞または頭蓋冠器官培養細胞を含む群から選択されることを特徴とする請求項6に記載の方法。
- 哺乳類の間葉幹細胞の脂肪細胞分化を阻害する方法であって、少なくとも一つのオキシステロールにより、哺乳類の間葉細胞を処置する工程を含むことを特徴とする方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、プレグネノロン、及び、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、及びプレグネノロンのうちの任意の一つの活性部分を含む群から選択されることを特徴とする請求項13に記載の方法。
- 患者を処置して骨髄ストローマ細胞の造骨細胞への分化を増大させる方法であって、少なくとも一つのオキシステロールを、治療的に有効な投与量で、有効な投与形態で、選択された間隔で、投与して、骨組織に存在する造骨細胞の数を増大させる工程を含むことを特徴とする方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、プレグネノロン、及び、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、及びプレグネノロンのうちの任意の一つの活性部分を含む群から選択されることを特徴とする請求項15に記載の方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロールと22R−ヒドロキシコレステロール、または20S−ヒドロキシコレステロールと22S−ヒドロキシコレステロール、を含む群から選択されるオキシステロールの組合せであることを特徴とする請求項15に記載の方法。
- さらに、副甲状腺ホルモン、弗化ナトリウム、インスリン様成長因子I、インスリン様成長因子IIまたはトランスフォーミング成長因子ベータを含む群から選択される少なくとも一つの二次作用剤により、該患者を処置する工程を含むことを特徴とする請求項15に記載の方法。
- 患者を処置して骨の形成を誘導する方法であって、少なくとも一つのオキシステロールを、治療的に有効な投与量で、有効な投与形態で、選択された間隔で、投与して、骨の質量を増大させる工程を含むことを特徴とする方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、プレグネノロン、及び、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、及びプレグネノロンのうちの任意の一つの活性部分を含む群から選択されることを特徴とする請求項19に記載の方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロールと22R−ヒドロキシコレステロール、または20S−ヒドロキシコレステロールと22S−ヒドロキシコレステロール、を含む群から選択されるオキシステロールの組合せであることを特徴とする請求項19に記載の方法。
- さらに、副甲状腺ホルモン、弗化ナトリウム、インスリン様成長因子I、インスリン様成長因子IIまたはトランスフォーミング成長因子ベータを含む群から選択される少なくとも一つの二次作用剤により、治療的に有効な投与量で、該患者を処置する工程を含むことを特徴とする請求項19に記載の方法。
- さらに、ビスホスホン酸塩、選択的エストロゲン受容体モジュレータ、カルシトニン、またはビタミンDおよびカルシウムを含む群から選択される少なくとも一つの二次作用剤により、治療的に有効な投与量で、患者を処置する工程を含むことを特徴とする請求項19に記載の方法。
- 骨粗鬆症の臨床的な症候を示す患者を処置する方法であって、少なくとも一つのオキシステロールを、治療的に有効な投与量で、有効な投与形態で、選択された間隔で、投与して、骨粗鬆症の症候を寛解する工程を含むことを特徴とする方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、プレグネノロン、及び、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、及びプレグネノロンのうちの任意の一つの活性部分を含む群から選択されることを特徴とする請求項24に記載の方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロールと22R−ヒドロキシコレステロール、または20S−ヒドロキシコレステロールと22S−ヒドロキシコレステロール、を含む群から選択されるオキシステロールの組合せであることを特徴とする請求項24に記載の方法。
- さらに、副甲状腺ホルモン、弗化ナトリウム、インスリン様成長因子I、インスリン様成長因子IIまたはトランスフォーミング成長因子ベータを含む群から選択される少なくとも一つの二次作用剤により、治療的に有効な投与量で、該患者を処置する工程を含むことを特徴とする請求項25に記載の方法。
- さらに、ビスホスホン酸塩、選択的エストロゲン受容体モジュレータ、カルシトニン、またはビタミンDおよびカルシウムを含む群から選択される少なくとも一つの二次作用剤により、治療的に有効な投与量で、患者を処置する工程を含むことを特徴とする請求項25に記載の方法。
- 患者を処置して、骨の形成を誘導する方法であって、
哺乳類の間葉幹細胞を収集する工程;
該哺乳類の間葉細胞を少なくとも一つの作用剤により処置する工程であって、該少なくとも一つの作用剤は、該間葉幹細胞を誘導して、少なくとも一つの造骨細胞分化の細胞マーカーを発現させることを特徴とする工程;及び
該患者に該分化した細胞を投与する工程
を含む方法。 - 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、プレグネノロン、及び、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、及びプレグネノロンのうちの任意の一つの活性部分を含む群から選択されることを特徴とする請求項29に記載の方法。
- 該少なくとも一つのオキシステロールが、20S−ヒドロキシコレステロールと22R−ヒドロキシコレステロール、または20S−ヒドロキシコレステロールと22S−ヒドロキシコレステロール、を含む群から選択されるオキシステロールの組合せであることを特徴とする請求項29に記載の方法。
- さらに、少なくとも一つのオキシステロールを、治療的に有効な投与量で、有効な投与形態で、選択された間隔で、投与する工程を含むことを特徴とする請求項29に記載の方法。
- さらに、副甲状腺ホルモン、弗化ナトリウム、インスリン様成長因子I、インスリン様成長因子IIまたはトランスフォーミング成長因子ベータを含む群から選択される少なくとも一つの二次作用剤により、治療的に有効な投与量で、該患者を処置する工程を含むことを特徴とする請求項29に記載の方法。
- さらに、ビスホスホン酸塩、選択的エストロゲン受容体モジュレータ、カルシトニン、またはビタミンDおよびカルシウムを含む群から選択される少なくとも一つの二次作用剤により、治療的に有効な投与量で、患者を処置する工程を含むことを特徴とする請求項29に記載の方法。
- さらに、該分化した細胞を該患者に全身的な注入によって投与する工程を含むことを特徴とする請求項29に記載の方法。
- さらに、該分化した細胞を骨の形成が望まれる選択された部位への該細胞の適用によって該患者に投与する工程を含むことを特徴とする請求項29に記載の方法。
- ヒトの身体内で使用するためのインプラントであって、表面を有する基体を含み、該インプラントの少なくとも該表面が、周辺の骨組織内に骨形成を誘導するのに十分な量の少なくとも一つのオキシステロールを含むことを特徴とするインプラント。
- 該基体は、ピン、ネジ、板、または補綴関節の形に形成されていることを特徴とする請求項37に記載のインプラント。
- ヒトの身体内で使用するためのインプラントであって、表面を有する基体を含み、該インプラントの少なくとも該表面が、造骨細胞分化が可能な哺乳類細胞を含むことを特徴とするインプラント。
- ヒトの身体内で使用するためのインプラントであって、表面を有する基体を含み、該インプラントの少なくとも該表面は、造骨細胞の哺乳類細胞を含むことを特徴とするインプラント。
- 骨の障害の処置に使用するための薬物であって、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、プレグネノロン、及び、20S−ヒドロキシコレステロール、22S−ヒドロキシコレステロール、22R−ヒドロキシコレステロール、25−ヒドロキシコレステロール、及びプレグネノロンのうちの任意の一つの活性部分を含む群から選択される少なくとも一つのオキシステロールを治療的に有効な投与量含有することを特徴とする薬物。
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