JP2017105798A - オーラプテン類縁化合物を有効成分とする骨芽細胞分化促進剤、骨形成促進用医薬組成物及び保健機能食品 - Google Patents
オーラプテン類縁化合物を有効成分とする骨芽細胞分化促進剤、骨形成促進用医薬組成物及び保健機能食品 Download PDFInfo
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Landscapes
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Abstract
Description
下記の式1:
で表される精製されたクマリン類化合物からなる骨芽細胞分化促進剤が提供される。R4は、好ましくはイソブテニル基、プレニル基又はゲラニル基である。
1.以下の式2で表されるオーラプテン(2H−1−ベンゾピラン−2−オン,7−[[(2E)−3,7−ジメチル−2,6−オクタジエン−1−イル]オキシ]−;別名:7−(ゲラニルオキシ)クマリン)
また、上記各化合物は、強力な骨形成促進作用が知られるサイトカインの骨形成因子(Bone morphogenetic protein 2;BMP−2)に匹敵する強力な骨芽細胞分化促進作用を有する。BMPは強力な骨形成誘導作用があることから、多くの骨減少性疾患への応用が期待されるが、タンパク質であるために(1)製造に非常にコストがかかる、(2)安定性の問題や品質管理が難しい等の問題がある。これに対し、本発明において使用されるオーラプテン及び類縁クマリン化合物は、天然由来の低分子化合物であり、安定性も高いため、取り扱い・品質管理が容易であるうえ、低コストで製造することができる。したがって、BMPと同等の作用が得られうる本発明の骨芽細胞分化促進剤及び骨形成促進用医薬組成物等は、骨減少性疾患の予防や治療にきわめて有用である。
また、本発明の骨芽細胞分化促進剤は、食品添加物としても利用でき、骨強化機能を有する保健機能食品、飲食品、衛生用品(歯磨き粉等の医薬部外品も含む)等にも応用可能である。
を含有する。
オーラプテンは、和光純薬工業(株)(Lkt Labs. Inc)より購入した。その他の被検化合物は、すべて住商ファーマインターナショナル(株)より購入した。MC3T3−E1細胞(マウス胎児頭蓋骨由来前骨芽細胞株、cell番号RCB1126)は、RIKEN Cell Bankより購入した。また、α−最少必須培地(α-minimum essential medium;α−MEM)は、INVITROGEN社(カタログ番号11900-024)より購入した。その他の試薬は和光純薬工業(株)又はSIGMA社より購入した。96ウェルマイクロプレートは、Nunc社(カタログ番号161093)より購入した。
骨芽細胞の増殖に対する効果を、以下のようにして調べた。
MC3T3−E1細胞をα−MEMに縣濁して、96ウェルマイクロプレートの各ウェルに、2×103 cells/wellとなるようにまいた。37℃、5%CO2条件で10%ウシ胎仔血清(FBS)含有α−MEMにて一晩培養後、培養液を、1、3、10又は30μMの各濃度の化合物を含む10%FBS含有α−MEMに交換して3日間培養した。同量の溶媒のみを含む培養液を用いて同様に培養したものをコントロール(対照)とした。
マウス前骨芽細胞株であるMC3T3−E1細胞をα−MEMに縣濁して、96ウェルマイクロプレートの各ウェルに、5×103 cells/wellとなるようにまいた。37℃、5%CO2条件で10%FBS含有α−MEMにて2日間前培養後、培養液を、1、3、10、30又は100μMの各濃度の化合物を含む10%FBS含有α−MEMに交換して6日間培養した。培養期間中、培養液は3日に一度交換した。クマリン類化合物を含まない培養液を用いて同様に培養したものをコントロール(対照)とした。
MC3T3−E1細胞をα−MEMに縣濁して、96ウェルマイクロプレートの各ウェルに、5×103 cells/wellとなるようにまき、37℃、5%CO2条件で10%FBS含有α−MEMにて2日間前培養した。その後、培養液を1、3、10又は30μMの各濃度の各化合物、及び50μg/ml アスコルビン酸及び10mM β−グリセロリン酸を含む10%FBS含有α−MEMに交換して10日間培養した。培養期間中、培養液は3ないし4日に一度交換した。
上記(「2.骨芽細胞の初期分化に対する効果」)と基本的に同様にして、公知の骨芽細胞分化促進剤である骨形成因子(BMP−2)の作用との比較及びBMP阻害剤であるノギン(Noggin)、ドルソモルフィン(Dorsomorphin)による阻害作用を調べた。
BMP−2は25ng/ml、オーラプテンは30μMで添加し、サンプル添加時にBMPの阻害剤であるノギン 10ng/ml又はI型BMPレセプター(ALK)の阻害剤であるドルソモルフィン 1μM(上記濃度はいずれも最終濃度)存在下又は非存在下で6日間培養し、上記と同様にALP活性を測定した。BMP−2、ノギン、ドルソモルフィンはいずれも和光純薬工業(株)より購入した。
BMPは、強力な骨形成促進因子と知られるサイトカインである。オーラプテン(30μM)処理によって、BMP−2(25ng/ml)と同等又はそれ以上のALP活性促進作用が認められた(図4)。このことは、オーラプテンはBMP−2に匹敵する強力な骨芽細胞分化促進作用を持つことを示す。
したがって、天然由来の低分子化合物であって安全性・安定性も高いうえ、BMPと同等の作用が得られうる本発明の骨芽細胞分化促進剤及び骨形成促進用医薬組成物等は、骨減少性の多くの疾患、例えば、骨粗鬆症、関節リウマチ、歯周病、ページェット病、がんの骨転移等の予防や治療に有用な作用を示すことが期待でき、きわめて有用である。
骨芽細胞分化に関わる各種遺伝子の発現に対する作用を、リアルタイムRT−PCR法にて解析した。
ΔCt=(標的遺伝子のCt)−(内因性コントロール遺伝子のCt)
ΔΔCt=(目的サンプルのΔCt)−(対照サンプルのΔCt)
対照サンプルに対する目的サンプルの標的遺伝子の相対的発現量=2(−ΔΔCt)
(1)骨芽細胞分化のマーカー遺伝子の発現
ポジティブコントロールであるBMP−2処理(「B」)と同様に、オーラプテン処理(「Aur」)によって、骨芽細胞の初期の分化マーカーとして知られるALP、及び後期の分化マーカーとして知られるマウスオステオカルシン(Osteocalcin)の遺伝子の発現がいずれもコントロール(「-」)と比較して増加した(図5A、図5B)。
ノックアウトマウスを用いた解析等から、転写因子であるRunx2及びオステリックス(Osterix)が骨芽細胞分化に重要な役割を果たすことが知られている。ポジティブコントロールであるBMP−2処理(「B」)と同様に、オーラプテン処理(「Aur」)によって、Runx2及びオステリックスの遺伝子の発現がいずれもコントロール(「-」)と比較して増加した(図5C、図5D)。
BMP類は強力な骨芽細胞分化促進サイトカインであり、種々の化合物による骨芽細胞分化促進作用に、BMP類の発現が関与しているとの報告がある。オーラプテン処理によって、BMP−2及びBMP−4の遺伝子の発現がいずれもコントロール(「-」)と比較して増加した(図5E、図5F)。
卵巣摘出による閉経後骨粗鬆症モデルマウスを作製し、骨量が低下したマウスに対して被検化合物を投与し、骨形成に対する生体レベルにおける作用を検討した。
採取した大腿骨について、pQCT(peripheral Quantitative Computed Tomography )骨密度測定装置(商品名「XCT Research SA+」、STRATEC社製)によって骨塩量等の測定を行った。
卵巣摘出手術(「OVX」)群の1ヶ月後(「30days」)の海綿骨塩量(図6A)及び全骨塩量(図6B)は、偽手術(「Sham」)群と比較して有意に低下した。その後、1ヶ月間(「30+30days」)オーラプテンを投与した群(「OVX−AUR」)は、卵巣摘出手術後溶媒のみを投与した群(「OVX−Con」)と比較して、海綿骨塩量(図6A)及び全骨塩量(図6B)が高い傾向が認められた。
骨吸収に対する作用を明らかにするために、骨吸収を担う細胞である破骨細胞の分化に対する作用を検討した。
ディッシュを乾燥後、分化の指標として、破骨細胞のマーカー酵素である酒石酸耐性酸ホスファターゼ(TRAP)の活性を以下のように測定した。
また、同様に培養後、MTT試薬を用いて定法により細胞数を測定し、コントロールを100とした時の値を示した。
Claims (7)
- 以下の式1:
で表される精製されたオーラプテン又はその類縁クマリン化合物からなる骨芽細胞分化促進剤。 - 式1で表される化合物が、以下の式2〜9:
- 以下の式2、3、5、6又は9:
- 請求項1〜3のいずれか1項記載の骨芽細胞分化促進剤を有効成分として含有する骨形成促進用医薬組成物。
- 請求項1〜3のいずれか1項記載の骨芽細胞分化促進剤を含有する食品添加物。
- 請求項5記載の食品添加物を添加された飲食品。
- 請求項1〜3のいずれか1項記載の骨芽細胞分化促進剤を含有する保健機能食品。
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