JP2016124813A - 軟骨変性抑制剤および変形性関節症抑制剤 - Google Patents
軟骨変性抑制剤および変形性関節症抑制剤 Download PDFInfo
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Abstract
【解決手段】軟骨変性抑制剤は、カルシトニン遺伝子関連ペプチド受容体拮抗剤を含む。この場合、前記カルシトニン遺伝子関連ペプチド受容体拮抗剤は、オルセゲパントであってもよい。あるいは、前記カルシトニン遺伝子関連ペプチド受容体拮抗剤は、カルシトニン遺伝子関連ペプチド抗体であってもよい。また、変形性関節症抑制剤は、カルシトニン遺伝子関連ペプチド受容体拮抗剤を含む。
【選択図】図7
Description
本発明の第1の観点に係る軟骨変性抑制剤は、
カルシトニン遺伝子関連ペプチド受容体拮抗剤を含む。
オルセゲパントである、
こととしてもよい。
カルシトニン遺伝子関連ペプチド抗体である、
こととしてもよい。
カルシトニン遺伝子関連ペプチド受容体拮抗剤を含む。
(実施の形態)
実施の形態について詳細に説明する。本実施の形態に係る軟骨変性抑制剤は、CGRP受容体拮抗剤を含む。CGRP受容体は、GPCR calcitonin receptor−like receptor(CLR)、Receptor Activity Modifying Protein(RAMP)および細胞内のReceptor Component Protein(RCP)から構成されるヘテロ三量体タンパク質である。37個のアミノ酸からなるペプチドであるCGRPがCGRP受容体に結合すると、細胞内のcAMPが増加し、血管拡張などの作用をもたらす。
以下の手順でOAモデルマウスを作製した。まず、10週齢のC57/BL6マウスの右膝関節の内側側副靭帯を切離するOA手術を行った。軟骨下骨の早期変化を評価するために、OA手術を施したマウスを過剰量の麻酔で2日後および7日後に安楽死させた(各時点においてn=6)。擬似手術(sham)を施したマウスも同様に安楽死させた(n=6)。
図1は、OAモデルマウスの膝関節から作製した切片の画像を示す。内側側副靭帯を切離したOAモデルマウスでは、2日、7日と経時的に軟骨下骨の骨形成が進み、骨髄腔の減少がみられた。また、OAモデルマウスでは、経時的に軟骨変性が進行していた。なお、以下で説明する図中のバーは100μmの長さを示す。
第2継代および第3継代のヒト骨髄間葉幹細胞(MSC)(Life Technologies社製)を、10%ウシ胎児血清(FBS)および1%ペニシリン/ストレプトマイシンを含むMSC成長培地(StemPro MSC SFM、Life Technologies社製)で増殖させた。第4継代のMSCを12穴プレートに播種し、骨形成を誘導した。10%FBSおよび1%ペニシリン/ストレプトマイシンを含む骨形成誘導培地(StemPro osteogenesis differentiation kit、Life Technologies社製)を、1週間に2回交換し、21日間インキュベートした。なお、100nMのCGRP(ペプチド研究所製)をさらに含む骨形成誘導培地、および100nMのCGRPとBIBN4096とをさらに含む骨形成誘導培地でも同様に骨形成を誘導した。
図15は、オステオカルシンの発現量およびALP活性を示す。CGRP存在下で、骨形成の誘導によるオステオカルシンの発現が増加した。一方、BIBN4096を加えることで、オステオカルシンの発現量が有意に低下した。同様に、CGRP存在下では、ALP活性が増加した。一方、BIBN4096を加えることで、ALP活性が有意に低下した。
12穴プレートで、Raw 264.7細胞を、10%FBSおよび1%ペニシリン/ストレプトマイシンを含むα−ミニマル・エッセンシャル培地で培養した。破骨細胞形成を評価するために、3日ごとに50ng/mLのM−CSF(和光純薬工業社製)および50ng/mLのRANKL(和光純薬工業社製)を含む培地に交換し、1週間培養した。なお、100nMのCGRPをさらに含む培地、および100nMのCGRPとBIBN4096とをさらに含む培地でも同様に培養した。7日目に、和光純薬工業社製の上記キットを用いて、細胞のTRAPを染色した。4個以上の核を有するTRAP陽性多核細胞を破骨細胞として同定した。200倍拡大の顕微鏡観察下で、各ウェルで顕微鏡の10視野における破骨細胞を計数した。すべての実験は3重に、少なくとも3回行った。
TRAPを染色した細胞の画像を図16に示す。破骨細胞への分化誘導によって確認されたTRAP陽性細胞が、CGRPを加えることで減少した。一方、BIBN4096を加えると、TRAP陽性細胞が増加した。図17は、TRAP陽性細胞(破骨細胞)の個数を示す。BIBN4096を加えることで、TRAP陽性細胞の個数が有意に増加した。
上記OAモデルマウスに、ビスフォスフォネートの1種であるリセドロネートを、OA手術後に0.06mg/kg/100μlの投与量で静脈内に投与した。投与から1週間後および4週間後に、膝関節を回収し、上記実施例1と同様に組織学的評価を行った。
図18は、リセドロネートの投与から1週間後および4週間後のサフラニン−O ファストグリーン法で染色した膝関節の切片の画像を示す。図7のBIBN4096投与群の1週および4週と比較して、軟骨下骨の骨硬化および軟骨変性の進行が認められる。ビスフォスフォネートは、破骨細胞の機能を抑制するため、軟骨下骨の骨硬化および軟骨変性を抑制できないと考えられる。
Claims (4)
- カルシトニン遺伝子関連ペプチド受容体拮抗剤を含む、
軟骨変性抑制剤。 - 前記カルシトニン遺伝子関連ペプチド受容体拮抗剤は、
オルセゲパントである、
請求項1に記載の軟骨変性抑制剤。 - 前記カルシトニン遺伝子関連ペプチド受容体拮抗剤は、
カルシトニン遺伝子関連ペプチド抗体である、
請求項1に記載の軟骨変性抑制剤。 - カルシトニン遺伝子関連ペプチド受容体拮抗剤を含む、
変形性関節症抑制剤。
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Citations (4)
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JP2005519917A (ja) * | 2002-02-01 | 2005-07-07 | オメロス コーポレイション | 軟骨分解の全身阻害のための組成物および方法 |
JP2008502609A (ja) * | 2004-06-17 | 2008-01-31 | オステオロジックス エイ/エス | リウマチおよび関節性疾患の治療改善方法 |
JP2009515827A (ja) * | 2005-10-18 | 2009-04-16 | ユニバーシティ・オブ・シェフィールド | 治療薬 |
JP2011513386A (ja) * | 2008-03-04 | 2011-04-28 | ファイザー・リミテッド | 炎症性疼痛を治療する方法 |
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JP2005519917A (ja) * | 2002-02-01 | 2005-07-07 | オメロス コーポレイション | 軟骨分解の全身阻害のための組成物および方法 |
JP2008502609A (ja) * | 2004-06-17 | 2008-01-31 | オステオロジックス エイ/エス | リウマチおよび関節性疾患の治療改善方法 |
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