KR101595063B1 - 세포결합 서열, 헤파린 결합 도메인 및 오스테오칼신 도메인을 포함하는 융합단백질 및 이를 포함하는 약학 조성물 - Google Patents
세포결합 서열, 헤파린 결합 도메인 및 오스테오칼신 도메인을 포함하는 융합단백질 및 이를 포함하는 약학 조성물 Download PDFInfo
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Abstract
피브로넥틴 유래 세포결합에 관여하는 RGD(Arg-Gly-Asp) 서열 및 헤파린 결합 도메인(heparin-binding domain, HBD)과 오스테오칼신 도메인을 포함하여, 세포결합, 세포증식 및 골형성 분화를 현저하게 촉진시킬 수 있는 효과를 나타내는 융합 단백질, 상기 융합 단백질을 코딩하는 폴리뉴클레오티드, 상기 폴리뉴클레오티드를 포함하는 융합단백질 발현용 벡터, 상기 벡터가 도입되어, 상기 융합단백질을 생산할 수 있는 형질전환체, 상기 형질전환체를 이용하여 상기 융합단백질을 생산하는 방법, 상기 융합 단백질을 포함하는 골질환 예방 또는 치료용 약학 조성물 및 상기 융합 단백질을 포함하는 골 또는 치아 재생용 약학 조성물에 관한 것이다. 본 발명의 융합단백질은 RGD 서열 뿐만 아니라 헤파린 결합 도메인을 포함하여, RGD 서열만을 포함하는 종래의 융합단백질에 비하여, 세포결합, 세포증식 및 골형성 분화와 같은 다양한 세포활성을 더욱 활성화시킬 수 있음을 확인하였으므로, 골질환의 예방 또는 치료 뿐만 아니라, 손상된 골 또는 치아를 재생하는데에도 널리 활용될 수 있을 것이다.
Description
본 발명은 세포결합 서열, 헤파린 결합 도메인 및 오스테오칼신 도메인을 포함하는 융합단백질 및 그의 용도에 관한 것으로, 보다 구체적으로 본 발명은 피브로넥틴 유래 세포결합에 관여하는 RGD(Arg-Gly-Asp) 서열 및 헤파린 결합 도메인(heparin-binding domain, HBD)과 오스테오칼신 도메인을 포함하여, 세포결합, 세포증식 및 골형성 분화를 현저하게 촉진시킬 수 있는 효과를 나타내는 융합 단백질, 상기 융합 단백질을 코딩하는 폴리뉴클레오티드, 상기 폴리뉴클레오티드를 포함하는 융합단백질 발현용 벡터, 상기 벡터가 도입되어, 상기 융합단백질을 생산할 수 있는 형질전환체, 상기 형질전환체를 이용하여 상기 융합단백질을 생산하는 방법, 상기 융합 단백질을 포함하는 골질환 예방 또는 치료용 약학 조성물 및 상기 융합 단백질을 포함하는 골 또는 치아 재생용 약학 조성물에 관한 것이다.
대량 골 결손의 치료는 현대 의학에서 중요한 과제이다. 재생 의학 및 조직공학에 대한 연구가 계속되고 있으며, 줄기세포 기반의 치료가 임상에서의 골 재생을 위해 고려되고 있다. 이는 부분적 골 결손이 이미 상당히 진행되었거나 조직이 노화된 환자에게서 초기 조골세포 획득이 어렵다는 문제를 극복하였다. 중간엽 줄기세포(MSCs)는 뼈 형성 단백질과 같은 적절한 영양분이 공급되는 경우 조골세포의 표현형으로 바로 분화한다.
골 조직 공학에 적용하기 위한 스캐폴드는, 숙주 조직의 최적화된 조직 형성을 위해 핵심적인 몇 가지 조건을 만족해야 한다. 이 조건은 세포 친화력, 영양분과 산소가 투과하기 위한 적절한 공극률, 세포 부착 및 분화를 촉진시키기 위한 계면 활성 등을 포함한다. 또한, 이상적으로 스캐폴드는 연속적으로 분해되어 숙주세포에 의해 대체되어야 한다. 콜라겐과 같은 세포외 기질(ECM)분자가 적절한 스캐폴드 재료이다. 그러나, 폴리유산(PLA), 폴리카프로락톤(PCL) 및 이의 공중합체와 같은 합성 분해성 플라스틱은 자연발생 물질에 비하여 정확한 가공이 가능하고, 보다 경제적이어서 임상적으로 널리 사용할 수 있다는 장점이 있다.
그러나, 합성 생체 고분자는 낮은 골 생체활성, 높은 소수성, 생체 단백질 및 세포에 대한 낮은 친화력을 가지기 때문에, 합성 생체고분자 스캐폴드는 골 조직 공학에 적합하도록 최적화 될 필요가 있다. 따라서, 생체활성을 증가시키기 위해 친수성 물질을 이용한 표면 개질과 같은 여러 시도가 있어왔다. 접착 단백질은 합성 고분자의 표면에 공유결합 하여 초기 세포 부착을 증가시킨다. 이러한 접착 단백질은 콜라겐이나 피브로넥틴을 포함한다. 그러나, 접착 단백질을 스캐폴드에 연결하는 것은 줄기세포가 조골세포로 분화하여 기능적인 골 조직을 형성하기 위해 적절한 표면 조건을 충분히 제공하지 못한다. 하이드록시아파타이트(HA) 또는 트리칼슘 포스페이트(TCP)와 같은 생체활성 세라믹과 PCL로 이루어진 복합 스캐폴드가 골 재생에 있어서 증가된 생물학적 수용력, 즉 개선된 세포 접착력, 조골세포의 기능 분화, 골 형성을 보여준다. 따라서, 생체활성 세라믹과 PCL의 복합 스캐폴드가 골 조직 공학에 있어 바람직하지만, 이는 초기 세포 반응 및 미분화된 줄기세포에 대해서는 선호되지 않을 수 있다. 이상적으로, 생체모방 환경은 초기 줄기 세포 접착 및 성장, 및 조골세포의 표현형으로 성숙하기 위한 연속적 분화 모두에 적합한 것이 바람직하다.
이에 초기 중간엽 줄기 세포의 부착 및 연속적인 골형성 모두에 적합한 스캐폴드를 개발하기 위하여, 다양한 연구가 수행되어 왔다. 예를 들어, 한국특허공개 제2012-0036217호에는 합성 생체고분자에 젤라틴-아파타이트를 혼합하여 얻은 혼합물을 전기방사함으로써 젤라틴-아파타이트-생체고분자로 구성된 복합체 골 조직 재생용 나노섬유를 제조하는 방법이 개시되어 있고, 한국특허공개 제2012-0036218호에는 반대 상으로서 캠핀을 사용하는 상분리법을 이용하여 나노섬유상 구조의 생체 고분자를 제조하는 방법과, 반대 상으로서 캠핀을 사용하는 상분리법을 이용하고 일반적인 스캐폴딩 방법을 적용함으로써 나노섬유상 구조를 가지는 3D 스캐폴드를 제조하는 방법이 개시되어 있으며, 한국특허공개 제2012-0057429호에는 피브로넥틴 도메인 및 오스테오칼신 도메인을 포함하는 융합 단백질, 및 상기 단백질을 포함하는 뼈 또는 치아 재생용 조성물 및 뼈 질환 예방 또는 치료용 조성물이 개시되어 있고, 한국특허등록 제1317515호에는 고분자 스캐폴드 표면에 코팅된 하이드록시아파타이트 및 하이드록시아파타이트와 결합된 피브로넥틴-오스테오칼신 융합단백질을 포함하는 뼈 재생용 스캐폴드 및 이의 제조 방법이 개시되어 있다.
특히, RGD 서열을 포함하는 피브로넥틴 도메인과 오스테오칼신 도메인을 포함하는 융합 단백질의 경우, 이에 포함된 오스테오칼신으로 인하여, 피브로넥틴 자체가 갖는 세포결합 활성이 현저하게 증진되었음을 확인하였다.
이러한 배경하에서, 본 발명자들은 피브로넥틴 도메인과 오스테오칼신 도메인을 포함하는 융합 단백질이 나타내는 세포결합 활성 등의 세포활성이 보다 향상된 융합단백질을 개발하고자 예의 연구노력한 결과, 종래의 RGD 서열 이외의 헤파린 결합 도메인(heparin-binding domain, HBD)을 포함하는 피브로넥틴 도메인과 오스테오칼신 도메인을 포함하는 융합 단백질이, RGD 서열만을 포함하는 피브로넥틴 도메인과 오스테오칼신 도메인을 포함하는 융합 단백질 보다도 향상된 세포활성을 나타냄을 확인하고, 본 발명을 완성하였다.
본 발명의 하나의 목적은 피브로넥틴 유래 RGD(Arg-Gly-Asp) 서열과 헤파린 결합 도메인(heparin-binding domain, HBD), 및 오스테오칼신 도메인을 포함하는 융합 단백질을 제공하는 것이다.
본 발명의 다른 목적은 상기 융합 단백질을 코딩하는 폴리뉴클레오티드를 제공하는 것이다.
본 발명의 또 다른 목적은 상기 폴리뉴클레오티드를 포함하는 융합단백질 발현용 벡터를 제공하는 것이다.
본 발명의 또 다른 목적은 상기 벡터가 도입되어, 상기 융합단백질을 생산할 수 있는 형질전환체를 제공하는 것이다.
본 발명의 또 다른 목적은 상기 형질전환체를 이용하여 상기 융합단백질을 생산하는 방법을 제공하는 것이다.
본 발명의 또 다른 목적은 상기 융합 단백질을 포함하는 골질환 예방 또는 치료용 약학 조성물을 제공하는 것이다.
본 발명의 또 다른 목적은 상기 융합 단백질을 포함하는 골 또는 치아 재생용 약학 조성물을 제공하는 것이다.
본 발명자들은 조골세포에 대한 결합 및 유지를 촉진시키고, 조골세포의 분화를 향상시킬 수 있는 효과를 나타내는, RGD 서열을 포함하는 피브로넥틴 도메인과 오스테오칼신 도메인을 포함하는 융합 단백질을 개발한 바 있다(한국특허공개 제2012-0057429호). 상기 개발된 융합 단백질이 나타내는 세포결합 활성 등의 세포활성이 보다 향상된 융합단백질을 개발하고자, 상기 융합단백질에 부가하기 위한 다양한 융합파트너에 대한 연구를 수행하던 중, 헤파린 결합 도메인(heparin-binding domain, HBD)에 주목하게 되었다. 상기 HBD는 제3형 피브로넥틴 12 내지 14번 도메인에 의해 구성되는 도메인으로서, 헤파린에 대한 결합활성을 나타낸다고 알려져 있다. 본 발명자들은 앞서 개발한 융합 단백질과 유사한 형태를 갖도록 RGD 서열을 포함하는 제3형 피브로넥틴 9번 및 10번 도메인과 오스테오칼신 도메인을 포함하는 융합단백질(rhOC-FNIII9-10); 및 RGD 서열을 포함하는 제3형 피브로넥틴 9번 내지 11번 도메인, HBD를 포함하는 제3형 피브로넥틴 12 내지 14번 도메인 및 오스테오칼신 도메인을 포함하는 융합단백질(rhOC-FNIII9-14)을 각각 제조하고, 전조골세포(preosteoblastic cell)의 일종인 MC3T3-E1 세포의 다양한 세포활성(세포결합 활성, 세포증식 활성 및 골형성 분화활성)에 미치는 이들 각 융합단백질의 효과를 비교하였다. 그 결과, HBD를 포함하는 융합단백질(rhOC-FNIII9-14)이 HBD를 포함하지 않는 융합단백질(rhOC-FNIII9-10) 보다, 다양한 세포활성(세포결합 활성, 세포증식 활성 및 골형성 분화활성)을 높은 수준으로 향상시킬 수 있는 효과를 나타냄을 확인하였다.
따라서, 본 발명에서 제공하는 HBD를 포함하는 융합단백질(rhOC-FNIII9-14)은 세포결합, 세포증식 및 골형성 분화를 현저하게 촉진시킬 수 있는 효과를 나타내어, 골질환의 예방 또는 치료용 약학조성물 또는 골 또는 치아 재생용 약학 조성물의 유효성분으로 사용할 수 있음을 알 수 있었다.
상술한 본 발명의 목적을 달성하기 위한 일 실시양태로서, 본 발명은 피브로넥틴 유래 RGD(Arg-Gly-Asp) 서열과 헤파린 결합 도메인(heparin-binding domain, HBD), 및 오스테오칼신 도메인을 포함하는 융합 단백질을 제공한다.
본 발명의 용어 "피브로넥틴(fibronectin, FN)"이란, 고등 동물의 세포 표면, 혈액, 세포외기질 등에 존재하고, 220 내지 250kDa의 분자량을 갖는 당단백질을 의미하는데, 이황화결합으로 인하여 이량체 또는 사량체의 형태로 존재한다. 상기 FN은 주로 간에서 합성되어 혈액으로 분비되는 이중합체 형태의 혈장 피브로넥틴과 섬유아세포에서 합성되어 세포외기질 또는 세포막으로 분비되는 사중합체 형태의 세포성 피브로넥틴으로 구별된다. 상기 FN을 코딩하는 유전자는 한 종류이지만, 상기 유전자는 RNA 스플라이싱이 발생하는 지역이 3개 부위에서 발생할 수 있어, 가능한 조합으로는 약 20종류의 단백질을 합성할 수 있다(도 1). 도 1에서 보듯이, 피브로넥틴을 코딩하는 유전자는 구조적으로 6개의 제1형 피브로넥틴 도메인, 3개의 제2형 피브로넥틴 도메인, 제3형 피브로넥틴 1 내지 14번 도메인, IIICS 도메인, 제3형 피브로넥틴 15번 도메인 및 3개의 제1형 피브로넥틴 도메인으로 구성된다. 상기 구성요소 중에서 제3형 피브로넥틴 7 내지 11번 도메인은 중앙 세포결합 도메인(central cell-binding domain, CCBD)를 구성하고, 제3형 피브로넥틴 10번 도메인은 세포 결합에 관여하는 RGD 서열을 포함하며, 제3형 피브로넥틴 12 내지 14번 도메인은 헤파린 결합 도메인(heparin-binding domain, HBD)를 구성한다고 알려져 있어, 이러한 구조로 인하여, 콜라겐, 젤라틴, 헤파린, 피브린, 인테그린 등의 물질과 결합할 수 있다고 알려져 있다. 기능적인 측면에서 FN은 세포결합, 세포증식, 세포형태 조절, 세포이동, 손상회복 등의 다양한 생리적 작용에 관여한다고 알려져 있다. 상기 피브로넥틴의 구체적인 아미노산 서열 또는 그를 코딩하는 유전자의 염기서열 정보는 NCBI의 GenBank 등 공지의 데이터베이스(GenBank Accession No. NP_002017, NP_001263337, NM_002026, NM_001276408 등)에서 얻을 수 있는데, 예를 들어, 피브로넥틴은 서열번호 1의 아미노산 서열로 표시될 수 있다.
본 발명에 있어서, 상기 피브로넥틴으로부터 유래된 RGD(Arg-Gly-Asp) 서열과 헤파린 결합 도메인(heparin-binding domain, HBD)를 사용하여 융합단백질을 구성할 수 있다.
본 발명의 용어 "피브로넥틴 유래 RGD 서열"이란, 상기 피브로넥틴을 구성하는 제3형 피브로넥틴 10번 도메인에 포함된 서열로서 세포결합 활성을 나타내는 도메인을 의미한다. 예를 들어, RGD 서열은 피브로넥틴을 구성하는 서열번호 1의 아미노산 서열 중에서 1,497 내지 1,499번 아미노산으로 구성된 서열이 될 수 있다.
본 발명의 용어 "피브로넥틴 유래 헤파린 결합 도메인(heparin-binding domain, HBD)"이란, 상기 피브로넥틴을 구성하는 제3형 피브로넥틴 12 내지 14번 도메인에 의해 형성되는 영역으로서, 헤파린에 대한 결합활성을 나타내는 도메인을 의미한다. 예를 들어, HBD 서열은 피브로넥틴을 구성하는 서열번호 1의 아미노산 서열 중에서 1,693 내지 1,964번 아미노산으로 구성된 서열이 될 수 있다.
본 발명의 용어 "오스테오칼신(osteocalcin, OC)"이란, 감마-카르복실글루타민산(γ-carboxylglutamate: Gla) 잔기를 2-3 개 포함하고, 95개의 아미노산 서열로 구성된, 분자량 약 5.9kDa의 비타민 K 의존성 칼슘 결합 비콜라겐성 단백질을 의미한다. 생리적으로, 상기 오스테오칼신은 골조직의 석회화를 국소적으로 조절하거나 또는 골에 침적되는 칼슘이온의 흡수와 방출을 조절하는 역할을 수행한다. 상기 오스테오칼신의 구체적인 아미노산 서열 또는 그를 코딩하는 유전자의 염기서열 정보는 NCBI의 GenBank 등 공지의 데이터베이스(GenBank Accession No. NM_199173, NM_031368.4, NP_954642, NP_112736.3 등)에서 얻을 수 있는데, 예를 들어, 오스테오칼신은 서열번호 2의 아미노산 서열로 표시될 수 있다.
본 발명에 있어서, 상기 OC의 전체 아미노산 서열 또는 부분 아미노산 서열을 사용하여, 융합단백질을 구성할 수 있다. 이때, OC의 부분 아미노산 서열은 이를 포함하는 융합단백질이 다양한 세포활성을 높은 수준으로 향상시킬 수 있는 효과를 나타내게 하는 한 특별히 이에 제한되지 않으나, 바람직하게는 서열번호 2의 아미노산 서열 중에서, 19 내지 95번 아미노산으로 구성된 서열이 될 수 있다.
본 발명의 용어 "융합단백질"이란, RGD 서열, HBD, 및 OC 도메인을 포함하도록 인위적으로 합성된 단백질을 의미한다.
본 발명에 있어서, 상기 융합단백질에 포함된 RGD 서열, HBD, 및 OC 도메인의 배열 순서는 상기 융합단백질이 다양한 세포활성을 높은 수준으로 향상시킬 수 있는 효과를 나타내게 하는 한 특별히 이에 제한되지 않으나, 바람직하게는 OC 도메인, RGD 서열 및 HBD의 순서로 구성될 수 있고, 바람직하게는 서열번호 3의 아미노산 서열로 구성될 수 있다.
또한, 상기 각 도메인은 상호 직접적으로 연결될 수도 있고, 링커를 통해 연결될 수도 있다. 상기 링커는 상기 융합단백질이 다양한 세포활성을 높은 수준으로 향상시킬 수 있는 효과를 나타내게 하는 한 특별히 이에 제한되지 않으나, 아미노산으로 구성된 펩타이드 링커를 사용할 수 있고, 보다 바람직하게는 잘구부러지는(flexible) 펩타이드 링커를 사용할 수 있으며, 가장 바람직하게는 당업게에서 통상적으로 사용되는 GGSGGT 아미노산 서열(서열번호 4), GGGGS 아미노산 서열(서열번호 5), GGGGSGGGGS 아미노산(서열번호 6) 등의 아미노산 서열을 가지는 펩타이드 링커를 사용할 수 있다. 상기 펩타이드 링커는 상기 링커를 코딩하는 핵산을 각 도메인을 코딩하는 핵산 사이에 인프레임(in frame)으로 연결하여 발현벡터 내에 작동 가능하게 연결하여 발현시킬 수 있다.
아울러, 상기 융합단백질은 이에 포함되는 각 도메인의 야생형의 아미노산 서열과 하나 이상의 아미노산 잔기가 상이한 서열을 가지는 폴리펩티드를 포함할 수 있다. 분자의 활성을 전체적으로 변경시키지 않는 단백질 및 폴리펩티드에서의 아미노산 교환은 당해 분야에 공지되어 있다. 가장 통상적으로 일어나는 교환은 아미노산 잔기 Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Thy/Phe, Ala/Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, Asp/Gly 간의 교환이다. 또한, 아미노산 서열상의 변이 또는 수식에 의해서 단백질의 열, pH등에 대한 구조적 안정성이 증가하거나 단백질 활성이 증가한 단백질을 포함할 수 있다.
끝으로, 상기 융합단백질 또는 상기 융합단백질을 구성하는 각 도메인의 폴리펩티드는 당해 분야에 공지된 화학적 펩티드 합성방법으로 제조하거나, 상기 도메인을 코딩하는 유전자를 PCR (polymerase chain reaction) 에 의해 증폭하거나 공지된 방법으로 합성한 후 발현벡터에 클로닝하여 발현시켜서 제조할 수 있다.
본 발명의 일 실시예에 의하면, 본 발명의 융합단백질(rhOC-FNIII9-14)이 전조골세포(preosteoblastic cell)의 일종인 MC3T3-E1 세포가 나타내는 다양한 세포활성에 미치는 효과를 종래의 융합단백질(rhOC-FNIII9-10)의 효과와 비교하였다. 먼저, 상기 각 융합단백질이 코팅된 배양용기에 MC3T3-E1 세포를 배양하고, 상기 배양된 세포에 대한 결합활성을 비교한 결과, 1㎍/㎖의 농도로 코팅된 웰에서 rhOCFNIII9-14가 rhOCFNIII9-10 보다 유의하게 증가된 수준의 세포결합 활성을 나타냄을 확인하였다(도 3). 또한, 상기 각 융합단백질이 1㎍/㎖의 농도로 코팅된 배양용기에 MC3T3-E1 세포를 5일 동안 배양하고, 상기 배양된 세포의 증식활성을 비교한 결과, rhOCFNIII9-14가 rhOCFNIII9-10 보다 유의하게 증가된 수준의 세포증식 활성을 나타냄을 확인하였다(도 4). 아울러, 골형성 분화활성에 대한 효과를 비교하고자, 상기 각 융합단백질이 1㎍/㎖의 농도로 코팅된 배양용기에 MC3T3-E1 세포를 7일 동안 배양하고, 상기 배양된 세포의 석회화 활성을 비교한 결과, rhOCFNIII9-14가 rhOCFNIII9-10 보다 유의하게 증가된 수준의 석회화 활성을 나타내었고(도 5), 상기 세포에서 발현되는 골형성 분화 관련 유전자인 제1형 콜라겐(Col I), 오스테오칼신(OC), 오스테오폰틴(osteopontin, OPN) 및 Runx2의 발현수준 측면에서도, rhOCFNIII9-14가 rhOCFNIII9-10 보다 유의하게 상기 유전자의 발현수준을 증가시킴을 확인하였다(도 6a 내지 6d).
따라서, 본 발명에서 제공하는 융합단백질은 세포결합 활성, 세포증식 활성 및 골형성 분화활성의 측면에서 종래의 융합단백질보다도 우수한 활성을 나타내는 신규한 단백질임을 알 수 있었다.
상술한 본 발명의 목적을 달성하기 위한 다른 실시양태로서, 본 발명은 상기 융합 단백질을 코딩하는 폴리뉴클레오티드, 상기 폴리뉴클레오티드를 포함하는 융합단백질 발현벡터, 상기 발현벡터가 도입된 형질전환체 및 상기 형질전환체를 이용하여 상기 융합단백질을 생산하는 방법을 제공한다.
본 발명에서 제공하는 폴리뉴클레오티드는 상기 본 발명에서 제공하는 융합단백질을 코딩하는 뉴클레오티드 서열을 포함하고, 바람직하게는 서열번호 7의 뉴클레오티드 서열이 될 수 있다.
상기 폴리뉴클레오티드는 하나 이상의 염기가 치환, 결실, 삽입 또는 이들의 조합에 의해 변이될 수 있다. 뉴클레오타이드 서열을 화학적으로 합성하여 제조하는 경우, 당업계에 널리 공지된 합성법, 예를 들어 문헌(Engels and Uhlmann, Angew Chem IntEd Engl., 37:73-127, 1988)에 기술된 방법을 이용할 수 있으며, 트리에스테르, 포스파이트, 포스포르아미다이트 및 H-포스페이트 방법, PCR 및 기타 오토프라이머 방법, 고체 지지체상의 올리고뉴클레오타이드 합성법 등을 들 수 있다.
본 발명의 용어 "발현벡터"란, 목적하는 숙주세포에서 목적 펩타이드를 발현할 수 있는 재조합 벡터로서, 유전자 삽입물이 발현되도록 작동하게 연결된 필수적인 조절 요소를 포함하는 유전자 제작물을 의미한다. 상기 발현벡터는 개시코돈, 종결코돈, 프로모터, 오퍼레이터 등의 발현조절 요소들을 포함하는데, 상기 개시 코돈 및 종결 코돈은 일반적으로 폴리펩타이드를 암호화하는 뉴클레오티드 서열의 일부로 간주되며, 유전자 제작물이 투여되었을 때 개체에서 반드시 작용을 나타내야 하며 코딩 서열과 인프레임(in frame)에 있어야 한다. 벡터의 프로모터는 구성적 또는 유도성일 수 있다.
본 발명의 용어 "작동가능하게 연결(operably linked)"이란, 일반적 기능을 수행하도록 핵산 발현조절 서열과 목적하는 단백질 또는 RNA를 코딩하는 핵산 서열이 기능적으로 연결(functional linkage)되어 있는 상태를 의미다. 예를 들어 프로모터와 단백질 또는 RNA를 코딩하는 핵산 서열이 작동가능하게 연결되어 코딩서열의 발현에 영향을 미칠 수 있다. 발현 벡터와의 작동적 연결은 당해 기술분야에서 잘 알려진 유전자 재조합 기술을 이용하여 제조할 수 있으며, 부위-특이적 DNA 절단 및 연결은 당해 기술 분야에서 일반적으로 알려진 효소 등을 사용할 수 있다.
또한, 상기 발현벡터는 세포 배양액으로부터 단백질의 분리를 촉진하기 위하여 융합 폴리펩타이드의 배출을 위한 시그널 서열을 포함할 수 있다. 특이적인 개시 시그널은 또한 삽입된 핵산 서열의 효율적인 번역에 필요할 수도 있다. 이들 시그널은 ATG 개시코돈 및 인접한 서열들을 포함한다. 어떤 경우에는, ATG 개시 코돈을 포함할 수 있는 외인성 번역 조절 시그널이 제공되어야 한다. 이들 외인성 번역 조절 시그널들 및 개시 코돈들은 다양한 천연 및 합성 공급원일 수 있다. 발현 효율은 적당한 전사 또는 번역 강화 인자의 도입에 의하여 증가될 수 있다.
아울러, 상기 발현벡터는 융합단백질의 검출을 용이하게 하기 위하여, 임의로 엔도펩티아이제를 사용하여 제거할 수 있는 단백질 태그를 추가로 포함할 수 있다.
본 발명의 용어 "태그(tag)"란, 정량가능한 활성 또는 특성을 나타내는 분자를 의미하며, 플로오레세인과 같은 화학적 형광물질(fluoracer), 형광 단백질(GFP) 또는 관련 단백질과 같은 폴리펩타이드 형광물질을 포함한 형광분자일 수도 있고; Myc 태그, 플래그(Flag) 태그, 히스티딘 태그, 루신 태그, IgG 태그, 스트랩타비딘 태그 등의 에피톱 태그일 수도 있다. 특히, 에피톱 태그를 사용할 경우, 바람직하게는 6개 이상의 아미노산 잔기로 구성되고, 보다 바람직하게는 8개 내지 50개의 아미노산 잔기로 구성된 펩타이드 태그를 사용할 수 있다.
본 발명에 있어서, 상기 발현벡터는 상술한 본 발명에서 제공하는 융합단백질을 코딩하는 뉴클레오티드 서열을 포함할 수 있는데, 이때 사용되는 벡터는 본 발명의 융합단백질을 생산할 수 있는 한, 특별히 이에 제한되지 않으나, 바람직하게는 플라스미드 DNA, 파아지 DNA 등이 될 수 있고, 보다 바람직하게는 상업적으로 개발된 플라스미드(pUC18, pBAD, pIDTSAMRT-AMP 등), 대장균 유래 플라스미드(pYG601BR322, pBR325, pUC118, pUC119 등), 바실러스 서브틸리스 유래 플라스미드(pUB110, pTP5 등), 효모-유래 플라스미드(YEp13, YEp24, YCp50 등), 파아지 DNA(Charon4A, Charon21A, EMBL3, EMBL4, λgt10, λgt11, λZAP 등), 동물 바이러스 벡터(레트로바이러스(retrovirus), 아데노바이러스(adenovirus), 백시니아 바이러스(vaccinia virus) 등), 곤충 바이러스 벡터(배큘로바이러스(baculovirus) 등) 이 될 수 있다. 상기 발현벡터는 숙주 세포에 따라서 단백질의 발현량과 수식 등이 다르게 나타나므로, 목적에 가장 적합한 숙주세포를 선택하여 사용함이 바람직하다. 예를 들어, 본 발명의 실시예에서는 상기 폴리뉴클레오티드를 6개의 히스티딘 태그가 포함된 pBAD 벡터에 도입하여 발현벡터 pBAD-HisB-hOC-FNIII9-14를 제작하였다.
본 발명에서 제공하는 형질전환체는 상기 본 발명에서 제공하는 발현벡터를 숙주에 도입하여 형질전환시켜서 제작되고, 상기 발현벡터에 포함된 폴리뉴클레오티드를 발현시켜서, 본 발명의 융합단백질을 생산하는데 사용될 수 있다. 상기 형질전환은 다양한 방법에 의하여 수행될 수 있는데, 다양한 세포활성을 높은 수준으로 향상시킬 수 있는 효과를 나타내는 본 발명의 융합단백질을 생산할 수 있는 한, 특별히 이에 제한되지 않으나, CaCl2 침전법, CaCl2 침전법에 DMSO(dimethyl sulfoxide)라는 환원물질을 사용함으로써 효율을 높인 Hanahan 방법, 전기천공법(electroporation), 인산칼슘 침전법, 원형질 융합법, 실리콘 카바이드 섬유를 이용한 교반법, 아그로박테리아 매개된 형질전환법, PEG를 이용한 형질전환법, 덱스트란 설페이트, 리포펙타민 및 건조/억제 매개된 형질전환 방법 등이 사용될 수 있다. 또한, 상기 형질전환제의 제작에 사용되는 숙주역시 본 발명의 융합단백질을 생산할 수 있는 한, 특별히 이에 제한되지 않으나, 대장균(E. coli), 스트렙토마이세스, 살모넬라 티피뮤리움 등의 박테리아 세포; 사카로마이세스 세레비지애, 스키조사카로마이세스 폼베 등의 효모 세포; 피치아 파스토리스 등의 균류 세포; 드로조필라, 스포도프테라 Sf9 세포 등의 곤충 세포; CHO, COS, NSO, 293, 보우 멜라노마 세포 등의 동물 세포; 또는 식물 세포가 될 수 있다. 예를 들어, 본 발명에서는 대장균 TOP10 균주를 숙주로서 사용하였다.
상기 형질전환체는 본 발명에서 제공하는 융합단백질을 생산하는 방법에 사용될 수 있다. 구체적으로, 본 발명에서 제공하는 융합단백질을 생산하는 방법은 (a) 상기 형질전환체를 배양하여 배양물을 수득하는 단계; 및, (b) 상기 배양물로부터 본 발명의 융합단백질을 회수하는 단계를 포함한다.
본 발명의 용어 "배양"이란, 미생물을 적당히 인공적으로 조절한 환경조건에서 생육시키는 방법을 의미한다.
본 발명에 있어서, 상기 형질전환체를 배양하는 방법은 당업계에 널리 알려져 있는 방법을 이용하여 수행할 수 있다. 구체적으로 상기 배양은 본 발명의 융합단백질을 발현시켜서 생산할 수 있는 한 특별히 이에 제한되지 않으나, 배치 공정 또는 주입 배치 또는 반복 주입 배치 공정(fed batch or repeated fed batch process)에서 연속식으로 배양할 수 있다.
배양에 사용되는 배지는 적당한 탄소원, 질소원, 아미노산, 비타민 등을 함유한 통상의 배지 내에서 호기성 조건 하에서 온도, pH 등을 조절하면서 적절한 방식으로 특정 균주의 요건을 충족해야 한다. 사용될 수 있는 탄소원으로는 글루코즈 및 자일로즈의 혼합당을 주 탄소원으로 사용하며 이외에 수크로즈, 락토즈, 프락토즈, 말토즈, 전분, 셀룰로즈와 같은 당 및 탄수화물, 대두유, 해바라기유, 피마자유, 코코넛유 등과 같은 오일 및 지방, 팔미트산, 스테아린산, 리놀레산과 같은 지방산, 글리세롤, 에탄올과 같은 알코올, 아세트산과 같은 유기산이 포함된다. 이들 물질은 개별적으로 또는 혼합물로서 사용될 수 있다. 사용될 수 있는 질소원으로는 암모니아, 황산암모늄, 염화암모늄, 초산암모늄, 인산암모늄, 탄산안모늄, 및 질산암모늄과 같은 무기질소원; 글루탐산, 메티오닌, 글루타민과 같은 아미노산 및 펩톤, NZ-아민, 육류 추출물, 효모 추출물, 맥아 추출물, 옥수수 침지액, 카세인 가수분해물, 어류 또는 그의 분해생성물, 탈지 대두 케이크 또는 그의 분해생성물 등 유기질소원이 사용될 수 있다. 이들 질소원은 단독 또는 조합되어 사용될 수 있다. 상기 배지에는 인원으로서 인산 제1칼륨, 인산 제2칼륨 및 대응되는 소듐-함유 염이 포함될 수 있다. 사용될 수 있는 인원으로는 인산이수소칼륨 또는 인산수소이칼륨 또는 상응하는 나트륨-함유 염이 포함된다. 또한, 무기화합물로는 염화나트륨, 염화칼슘, 염화철, 황산마그네슘, 황산철, 황산망간 및 탄산칼슘 등이 사용될 수 있다. 마지막으로, 상기 물질에 더하여 아미노산 및 비타민과 같은 필수 성장 물질이 사용될 수 있다.
또한, 배양 배지에 적절한 전구체들이 사용될 수 있다. 상기된 원료들은 배양과정에서 배양물에 적절한 방식에 의해 회분식, 유가식 또는 연속식으로 첨가될 수 있으나, 특별히 이에 제한되지는 않는다. 수산화나트륨, 수산화칼륨, 암모니아와 같은 기초 화합물 또는 인산 또는 황산과 같은 산 화합물을 적절한 방식으로 사용하여 배양물의 pH를 조절할 수 있다.
또한, 지방산 폴리글리콜 에스테르와 같은 소포제를 사용하여 기포 생성을 억제할 수 있다. 호기 상태를 유지하기 위해 배양물 내로 산소 또는 산소-함유 기체(예, 공기)를 주입한다. 배양물의 온도는 보통 27℃ 내지 37℃, 바람직하게는 30℃ 내지 35℃이다. 배양은 D형 젖산의 생성량이 최대로 얻어질 때까지 계속한다. 이러한 목적으로 보통 10 내지 100 시간에서 달성된다. 대체로 D형 젖산은 배양 배지 중으로 배출되지만, 경우에 따라서는 세포 중에 포함되어 있을 수 있다.
아울러, 배양물로부터 상기 융합단백질을 회수하는 단계는 당업계에 공지된 방법에 의해 수행될 수 있다. 구체적으로, 상기 회수 방법은 생산된 본 발명의 융합단백질을 회수할 수 있는 한, 특별히 이에 제한되지 않으나, 바람직하게는 원심분리, 여과, 추출, 분무, 건조, 증방, 침전, 결정화, 전기영동, 분별용해(예를 들면 암모늄 설페이트 침전), 크로마토그래피(예를 들면 이온 교환, 친화성, 소수성 및 크기배제) 등의 방법을 사용할 수 있다.
본 발명의 일 실시예에 의하면, PCR을 수행하여 인간의 오스테오칼신을 코딩하는 유전자인 hOC의 뉴클레오티드 서열을 증폭시키고, 상기 증폭된 hOC의 뉴클레오티드 서열에 제한효소 절단부위(KpnI/HindIII)를 삽입시켰으며, FNIII9-14 서열을 증폭시켰다. 상기 제한효소 절단부위가 삽입된 hOC의 뉴클레오티드 서열과 상기 증폭된 FNIII9-14 서열을 결합시켜서, rhOC-FNIII9-14를 코딩하는 폴리뉴클레오티드 서열을 제작하였다. 상기 제작된 폴리뉴클레오티드 서열을 6개의 히스티딘 태그를 코딩하는 뉴클레오티드 서열이 포함된 pBAD 벡터에 도입하여 발현벡터 pBAD-HisB-hOC-FNIII9-14를 제작하였다(실시예 1-2). 상기 제작된 발현벡터 pBAD-HisB-hOC-FNIII9-14를 대장균 TOP10에 도입하여 형질전환시킴으로써, HisB-hOC-FNIII9-14를 발현시켜서 생산할 수 있는 형질전환체를 제작하고, 상기 제작된 형질전환체를 배양하였으며, 이로부터 융합단백질인 HisB-hOC-FNIII9-14를 생산하고, 상기 생산된 융합단백질을 Ni-NTA 컬럼 크로마토 그래피에 적용하여 정제함으로써, 목적하는 융합단백질 hOC-FNIII9-14를 수득하였다(실시예 1-3). 상기 수득한 융합단백질을 대상으로, 전기영동 분석 및 웨스턴 블럿 분석을 수행한 결과, 상기 융합단백질은 약 70 kDa의 크기를 갖는 단백질임을 확인하였다(도 2).
상술한 본 발명의 목적을 달성하기 위한 또 다른 실시양태로서, 본 발명은 상기 융합 단백질을 유효성분으로 포함하는 골질환 예방 또는 치료용 약학 조성물 또는 골 또는 치아 재생용 약학 조성물을 제공한다.
상술한 바와 같이, 본 발명에서 제공하는 융합단백질은 세포결합 활성, 세포증식 활성 및 골형성 분화활성의 측면에서 종래의 융합단백질보다도 우수한 활성을 나타내는 신규한 단백질임을 확인하였으므로, 상기 융합단백질을 골조직의 퇴화, 손실, 붕괴 등의 증상이 수반되는 다양한 골질환의 예방 또는 치료용 약학 조성물 또는 손상된 골 또는 치아를 재생시키기 위한 약학 조성물의 유효성분으로 사용할 수 있음을 알 수 있었다.
본 발명의 용어 "골질환"이란, 조골세포 및 파골세포의 불균형으로 인해 유발되어 골조직의 장애를 초래하거나 또는 골조직을 파괴하는 질환을 의미하는데, 상기 골 관련 질환은 본 발명에서 제공하는 융합단백질에 의하여 증상이 예방, 개선, 경감 또는 치료될 수 있는 한 특별히 이에 제한되지 않으나, 바람직하게는 성장기 발육부진, 골절, 구루병(rickets), 골연화증(osteomalacia), 척추측만증(scoliosis), 골반변형(pelvic deformity), 골다공증(osteoprosis), 류마티스성 관절염(rheumatoid arthritis), 치주질환(periodontal disease), 갑상선기능항진증(hyperparathyroidism), 파제트병(Paget disease), 전이성 골암(metastatic bone cancers) 등이 될 수 있다.
본 발명의 용어 "골질환의 예방 또는 치료"란 상기 골 관련 질환의 발병을 예방하거나 또는 상기 질환의 발병에 의한 증세를 호전하거나 이롭게 변경하는 모든 행위를 의미하는데, 골질환 증상의 예방, 감소, 개선, 그 증상의 고통 경감, 골질환 발생율 감소 또는 치료결과를 증가시키는 환자의 어떠한 다른 변화를 모두 포함한다.
한편, 본 발명의 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 추가로 포함할 수 있다. 구체적으로, 상기 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명에서, 상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 융합단백질에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.
본 발명의 약학 조성물에 포함된 상기 융합단백질의 함량은 특별히 이에 제한되지 않으나, 최종 조성물 총중량을 기준으로 0.0001 내지 50 중량%, 보다 바람직하게는 0.01 내지 5 중량%의 함량으로 포함될 수 있다.
상기 본 발명의 약학 조성물은 약제학적으로 유효한 양으로 투여될 수 있는데, 본 발명의 용어 "약제학적으로 유효한 양"이란 의학적 치료 또는 예방에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료 또는 예방하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하다.
본 발명의 약학조성물의 투여량은 예를 들어, 본 발명의 약학 조성물을 사람을 포함하는 포유동물에 하루 동안 0.01 내지 1 ㎎/㎏, 보다 바람직하게는 0.1 내지 0.1 ㎎/㎏으로 투여할 수 있고, 본 발명의 조성물의 투여빈도는 특별히 이에 제한되지 않으나, 1일 1회 투여하거나 또는 용량을 분할하여 수회 투여할 수 있다.
상기 목적을 달성하기 위한 또 다른 실시양태로서, 본 발명은 상기 약학 조성물을 약제학적으로 유효한 양으로 골질환이 발병될 가능성이 있거나 또는 발병된 개체에 투여하는 단계를 포함하는 골질환을 예방 또는 치료하는 방법을 제공한다.
상술한 바와 같이, 본 발명에서 제공하는 융합단백질은 골질환 예방 또는 치료용 약학 조성물의 유효성분으로서 사용할 수 있으므로, 상기 조성물은 골질환을 예방 또는 치료하거나, 또는 손상된 골 또는 치아를 재생하는데 사용될 수 있다.
본 발명에서 용어 "개체"란 골질환이 발병될 가능성이 있거나 또는 발병된 쥐, 가축, 인간 등을 포함하는 포유동물을 제한 없이 포함한다.
본 발명의 골질환을 치료하는 방법에 있어서, 상기 약학 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여도 투여될 수 있다. 본 발명의 약학 조성물은 특별히 이에 제한되지 않으나, 목적하는 바에 따라 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 비내 투여, 폐내 투여, 직장내 투여될 수 있다. 다만, 경구 투여시에는 위산에 의하여 상기 융합단백질이 변성될 수 있기 때문에 경구용 조성물은 활성 약제를 코팅하거나 위에서의 분해로부터 보호되도록 제형화 되어야 한다. 또한, 상기 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.
본 발명의 융합단백질은 RGD 서열 뿐만 아니라 헤파린 결합 도메인을 포함하여, RGD 서열만을 포함하는 종래의 융합단백질에 비하여, 세포결합, 세포증식 및 골형성 분화와 같은 다양한 세포활성을 더욱 활성화시킬 수 있음을 확인하였으므로, 골질환의 예방 또는 치료 뿐만 아니라, 손상된 골 또는 치아를 재생하는데에도 널리 활용될 수 있을 것이다.
도 1은 피브로넥틴을 코딩하는 유전자의 구조를 도식화하여 나타내는 개략도이다.
도 2는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14를 전기영동 분석 및 웨스턴 블럿분석을 수행한 결과를 나타내는 사진으로서, M은 크기 마커를 나타내고, 1번 레인은 rhOC-FNIII9-10을 나타내며, 2번 레인은 rhOC-FNIII9-14을 나타낸다.
도 3은 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14의 농도에 따른, 세포 결합수준의 변화를 나타내는 그래프이다.
도 4는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 세포증식에 미치는 효과를 나타내는 그래프이다.
도 5는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 골형성 분화에 미치는 효과를 나타내는 사진 및 그래프이다.
도 6a는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 골형성 분화 관련 유전자인 Col I의 발현에 미치는 효과를 분석한 결과를 나타내는 그래프이다.
도 6b는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 골형성 분화 관련 유전자인 OC의 발현에 미치는 효과를 분석한 결과를 나타내는 그래프이다.
도 6c는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 골형성 분화 관련 유전자인 OPN의 발현에 미치는 효과를 분석한 결과를 나타내는 그래프이다.
도 6d는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 골형성 분화 관련 유전자인 Runx2의 발현에 미치는 효과를 분석한 결과를 나타내는 그래프이다.
도 2는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14를 전기영동 분석 및 웨스턴 블럿분석을 수행한 결과를 나타내는 사진으로서, M은 크기 마커를 나타내고, 1번 레인은 rhOC-FNIII9-10을 나타내며, 2번 레인은 rhOC-FNIII9-14을 나타낸다.
도 3은 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14의 농도에 따른, 세포 결합수준의 변화를 나타내는 그래프이다.
도 4는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 세포증식에 미치는 효과를 나타내는 그래프이다.
도 5는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 골형성 분화에 미치는 효과를 나타내는 사진 및 그래프이다.
도 6a는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 골형성 분화 관련 유전자인 Col I의 발현에 미치는 효과를 분석한 결과를 나타내는 그래프이다.
도 6b는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 골형성 분화 관련 유전자인 OC의 발현에 미치는 효과를 분석한 결과를 나타내는 그래프이다.
도 6c는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 골형성 분화 관련 유전자인 OPN의 발현에 미치는 효과를 분석한 결과를 나타내는 그래프이다.
도 6d는 본 발명에서 제공하는 rhOC-FNIII9-10 또는 rhOC-FNIII9-14가 골형성 분화 관련 유전자인 Runx2의 발현에 미치는 효과를 분석한 결과를 나타내는 그래프이다.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.
실시예 1: 재조합 융합단백질(rhOC-FNIII9-10 또는 rhOC-FNIII9-14)의 제조
실시예
1-1:
rhOC
-
FNIII9
-10 생산용 발현벡터의 제작
rhOC-FNIII9-10을 제작하기 위하여, 먼저 하기 프라이머를 사용한 PCR을 수행하여 인간의 오스테오칼신을 코딩하는 유전자인 hOC의 뉴클레오티드 서열을 증폭시켰다. 이때, PCR 조건은 55℃ 1분, 72℃ 1분 및 94℃ 1분의 주기를 30회 반복하도록 설정하였다.
hOC forward primer, 5'-TAGGAGCCCTCACACTCCTC-3'(서열번호 8)
hOC reverse primer, 5'-CTGGAGAGGAGCAGAACTGG-3'(서열번호 9)
이어, 상기 증폭된 hOC의 뉴클레오티드 서열을 주형으로 하고, 하기의 프라이머를 이용한 PCR을 수행하여 상기 hOC 뉴클레오티드 서열에 제한효소 절단부위(BglII/KpnI)를 삽입하여, hOC의 변형된 폴리뉴클레오티드를 수득하였다. 이때, PCR 조건은 상술한 바와 동일하게 설정하였다.
forward primer(for the BglII site)
5'-AACAGATCTTACCTGTATCAATGGCTGGGA-3'(서열번호 10)
reverse primer(for the KpnI site)
5'-AATGGTACCGACCGGGCCGTAGAAGCGCCG-3'(서열번호 11)
한편, rhOC-FNIII9-10을 제작하기 위하여, 인간의 피브로넥틴 유전자를 주형으로 하고, 하기의 프라이머를 이용한 PCR을 수행하여 인간의 피브로넥틴의 III 도메인의 9-10(FNIII9-10)을 코딩하는 폴리뉴클레오티드를 수득하였다. 이때, PCR 조건은 상술한 바와 동일하게 설정하였다.
forward primer(for the SacI site)
5'-CTCGAGCAACAATCAACAGTTTC-3'(서열번호 12)
reverse primer(for the SacI site)
5'-CTCGAGTGGTTTGTCAATTTC-3'(서열번호 13)
상기 수득한 FNIII9-10을 코딩하는 폴리뉴클레오티드를 제한효소 SacI으로 절단하고, pBAD/His-OC 벡터의 멀티클로닝 부위에 도입하여 pBAD/His-FNIII9-10/OC를 제작하였다.
상기 제작된 pBAD/His-FNRGD/OC에 상기 수득한 hOC의 변형된 폴리뉴클레오티드를 도입하여 rhOC-FNIII9-10를 발현시키는 발현벡터를 수득하고, 이로부터 rhOC-FNIII9-10를 코딩하는 폴리뉴클레오티드를 수득하였다. 상기 수득한 rhOC-FNIII9-10를 코딩하는 폴리뉴클레오티드를 BglII/KpnI으로 절단하고, 이를 pBAD 벡터에 도입하여, rhOC-FNIII9-10 생산용 발현벡터(pBAD-HisB-hOC-FNIII9-10)를 제작하였다.
실시예
1-2:
rhOC
-
FNIII9
-14 생산용 발현벡터의 제작
먼저, 상기 실시예 1-1의 방법으로 hOC 서열을 수득하고, 상기 hOC 서열에 제한효소 절단부위(KpnI/HindIII)를 삽입하여, hOC의 변형된 폴리뉴클레오티드를 수득하였다. 이때, PCR 조건은 상기 실시예 1-1과 동일하게 설정하였다.
한편, rhOC-FNIII9-14를 제작하기 위하여, 인간의 피브로넥틴 유전자를 주형으로 하고, 하기의 프라이머를 이용한 PCR을 수행하여 인간의 피브로넥틴의 III 도메인의 9-14(FNIII9-14)를 코딩하는 폴리뉴클레오티드를 수득하였다. 이때, PCR 조건은 상기 실시예 1-1과 동일하게 설정하였다.
forward primer, 5'-ATTGATTATTTGCACGGCGT-3'(서열번호 14)
reverse primer, 5'-ACGGCGTTTCACTTCTGAGT-3'(서열번호 15)
상기 수득한 FNIII9-14를 코딩하는 폴리뉴클레오티드를 pBAD/His-OC 벡터의 멀티클로닝 부위에 도입하여 pBAD/His-FNIII9-14/OC를 제작하였다.
상기 제작된 pBAD/His-FNIII9-14/OC에 상기 수득한 hOC의 변형된 폴리뉴클레오티드를 도입하여 rhOC-FNIII9-14를 발현시키는 발현벡터를 수득하고, 이로부터 rhOC-FNIII9-14를 코딩하는 폴리뉴클레오티드를 수득하였다. 상기 수득한 rhOC-FNIII9-14를 코딩하는 폴리뉴클레오티드를 KpnI/HindIII으로 절단하고, 이를 pBAD 벡터에 도입하여, rhOC-FNIII9-14 생산용 발현벡터(pBAD-HisB-hOC-FNIII9-14)를 제작하였다.
실시예 1-3: 재조합 융합단백질의 제조
상기 실시예 1-1 및 1-2에서 제작한 각각의 발현벡터를 대장균 TOP10에 도입하여 각각의 형질전환체를 제조하였다.
상기 제조된 각 형질전환체를 앰피실린을 포함하는 LB 배지에 접종하고, 37℃에서 하룻밤 동안 배양하였다. 배양물의 OD600 값이 0.6이 될 때, 0.1 % (w/v) L-아라비노스를 가하고 20℃에서 6시간 동안 배양하였다. 배양이 종료된 후, 상기 배양물을 6,000Xg 에서 10분동안 원심분리하여 균체를 수득하고, 상기 수득한 균체를 용해시킨 후, 초음파를 처리하여 각각의 세포파쇄물을 수득하였다. 상기 수득한 각 세포파쇄물을 14,000Xg 에서 30분동안 원심분리하여 액상성분을 수득하고, 이를 Ni-NTA(nickel-nitrilotriacetic acid) 친화성 컬럼 크로마토그래피에 적용하여 재조합 융합단백질인 rhOC-FNIII9-10과 rhOC-FNIII9-14를 각각 정제하였다.
상기 정제된 rhOC-FNIII9-10과 rhOC-FNIII9-14를 12%(v/v) SDS-PAGE에 적용하고, 그 결과물을 코마지 브릴리언트 블루 염색제로 염색하여 확인하였다. 아울러, 상기 전기영동된 각 단백질을 대상으로 페록시다제가 결합된 항-폴리히스티딘 단클론 항체(sc-8036 HRP, Santa Cruz Biotechnology, Santa Cruz, CA, USA)를 사용한 웨스턴 블럿분석을 수행하여, 상기 정제된 각 재조합 융합 단백질의 크기를 확인하였다(도 2). 도 2에서 보듯이, rhOC-FNIII9-10의 분자량은 약 45kDa이고, rhOC-FNIII9-14의 분자량은 약 70 kDa임을 확인하였다.
실시예 2: 재조합 융합단백질(rhOC-FNIII9-10 또는 rhOC-FNIII9-14)을 이용한 세포활성 분석
실시예
2-1:
MC3T3
-
E1
세포 배양
MC3T3-E1 세포는 신생 마우스의 골로부터 수득한 전조골세포(preosteoblastic cell)이다. 상기 MC3T3-E1 세포를 10%(v/v) FBS, 100U/㎖의 페니실린 G, 100㎍/㎖의 스트렙토마이신 설페이트 및 0.25㎍/㎖의 암포테리신 B를 포함하는 최소배지(a-MEM, Invitrogen)에 접종하고, 37℃ 및 5% CO2 환경에서 배양하였다. 배양용기에 0.25% 트립신/EDTA을 5분간 처리하여 포화배양된 세포를 수득하고, 일부를 계대배양하였다. 3회 계대배양된 MC3T3-E1 세포를 이후의 세포활성 분석에 사용하였다.
실시예
2-2: 세포결합활성 분석
상기 실시예 1에서 제조한 rhOC-FNIII9-10 또는 rhOC-FNIII9-14를 24웰 플레이트의 각 웰에 0, 0.5, 및 1㎍/㎖의 농도로 코팅하고 4℃에서 하룻밤 동안 방치하였다. 이어, 각 웰을 DPBS(Dulbecco’s phosphate buffered saline)로 세척하였다. 그런 다음, 각 웰에 1%(w/v) BSA를 30분동안 처리하여 블로킹 시켰다.
한편, 상기 각 웰에 상기 실시예 2-1에서 배양한 MC3T3-E1 세포를 웰당 105 세포수가 되도록 접종하여 30분 동안 반응시켰다. 반응이 종료된 후, 상기 세포를 DPBS로 2회 세척하고, 3.7%(w/v) 포르말린 용액을 상온에서 15분 동안 처리하여 고정시켰다. 상기 고정된 세포에 0.25%(w/v) Crystal Violet을 포함하는 2%(v/v) 에탄올을 가하고 37℃에서 1시간 동안 염색하였다. 염색이 종료된 후, 상기 세포를 DPBS로 조심스럽게 3회 세척하고, 상기 세척된 세포에 2% SDS 용액을 가하여 세포를 파쇄하였으며, 상기 세포파쇄물을 96웰 플레이트로 옮기고, 570 nm에서 흡광도를 측정하였다(도 3). 도 3에서 보듯이, 각 웰에 코팅된 rhOC-FNIII9-10 또는 rhOC-FNIII9-14의 처리양이 증가할 수록 세포 결합수준이 증가하였고, 특히 1㎍/㎖의 농도로 코팅된 웰에서는 rhOCFNIII9-14가 rhOCFNIII9-10 보다 유의하게 증가된 수준의 세포결합 활성을 나타냄을 확인하였다.
따라서, 이하의 실시예에서는 상기 각 융합단백질을 1㎍/㎖의 농도로 사용하였다.
실시예
2-3: 세포증식활성 분석
상기 실시예 1에서 제조한 rhOC-FNIII9-10 또는 rhOC-FNIII9-14를 1㎍/㎖의 농도로 코팅하는 것을 제외하고는, 상기 실시예 2-2의 방법과 동일한 방법을 수행하여 단백질이 코팅된 24웰 플레이트를 준비하였다. 상기 준비된 24웰 플레이트의 각 웰에 상기 실시예 2-1에서 배양한 MC3T3-E1 세포를 웰당 103 세포수가 되도록 접종하고, 37℃에서 3일 또는 5일 동안 배양하였다. 배양이 종료된 후, 배양된 세포를 DPBS로 3회 세척하고, 각 웰에 500㎕ MTT 용액(5 mg/㎖ in PBS)을 가하여 4시간 동안 반응시켰다. 반응이 종료된 후, 각 웰로부터 배지를 제거하고, formazan crystal이 용해된 DMSO 200㎕를 상기 세포에 가한 다음, 540 nm에서 흡광도를 측정하였다(도 4). 도 4에서 보듯이, 3일 동안 배양한 경우에는 코팅된 단백질에 따른 증식수준의 변화가 검출되지 않았으나, 5일 동안 배양한 후에는 rhOC-FNIII9-14 단백질이 코팅된 조건에서 배양된 MC3T3-E1 세포가 rhOC-FNIII9-10 단백질이 코팅된 조건에서 배양된 MC3T3-E1 세포보다도 증식수준이 유의하게 증가함을 확인하였다.
따라서, rhOC-FNIII9-14는 세포증식을 촉진하는 효과를 나타냄을 알 수 있었다.
실시예
2-4:
골형성
분화에 미치는 효과분석
생체내에서 골형성 분화가 진행되면, 골조직이 석회화 되는 과정이 수반되므로, 본 발명에서 제공하는 단백질이 골형성 분화에 미치는 효과를 분석하기 위하여, Alizarin Red S 염색을 수행하여 석회화 활성을 측정하고, 이를 비교하였다.
구체적으로, 상기 실시예 1에서 제조한 rhOC-FNIII9-10 또는 rhOC-FNIII9-14를 1㎍/㎖의 농도로 코팅하는 것을 제외하고는, 상기 실시예 2-2의 방법과 동일한 방법을 수행하여 단백질이 코팅된 24웰 플레이트를 준비하였다. 상기 준비된 24웰 플레이트의 각 웰에 상기 실시예 2-1에서 배양한 MC3T3-E1 세포를 웰당 103 세포수가 되도록 접종하고, 37℃에서 7일 동안 배양하였다. 배양된 세포를 PBS로 세척하고, 95%(v/v) 메탄올을 30분 동안 가하여 고정시킨 다음, 알리자린 레드 S(Alizarin Red S) 용액을 가하여 하룻밤 동안 염색하고, 상기 염색약을 제거하였으며, 이를 PBS로 세척한 후, 상기 염색된 세포를 촬영하였다. 다음으로, 상기 염색된 세포에 10%(w/v) CPC(cetylpyridinium chloride)를 포함하는 10 mmol 인산나트륨 완충액(pH 7.0)을 처리하고 상온에서 30분 동안 반응시켜서, 세포를 탈색시켜서, 세포에 흡착되었던 알리자린 레드 S를 완충액으로 방출시켰다. 이어, 상기 시료를 450 nm에서 흡광도를 측정하여, 완충액으로 방출된 알리자린 레드 S의 수준을 측정하여, 이를 이용하여 알리자린 레드 S의 농도를 산출하였다(도 5). 도 5에서 보듯이, rhOC-FNIII9-14 단백질이 코팅된 조건에서 배양된 MC3T3-E1 세포는 rhOC-FNIII9-10 단백질이 코팅된 조건에서 배양된 MC3T3-E1 세포보다도 알리자린 레드 S의 염색수준이 유의하게 증가함을 확인하였다.
따라서, rhOC-FNIII9-14는 rhOC-FNIII9-10 보다도 석회화를 촉진시키므로, 골형성 분화를 상대적으로 높은 수준으로 촉진시킬 수 있음을 알 수 있었다.
실시예
2-5:
골형성
분화 관련 유전자 발현에 미치는 효과분석
상기 실시예 2-4와 동일한 방법으로 각각의 배양된 세포를 수득하였다. 상기 수득한 세포를 대상으로, RNA 추출키트(Easy-spin RNA extraction kit, iNtRON, Seoul, Korea)를 이용하여 총 RNA를 추출하고, 이로부터 cDNA를 합성하였다. 상기 합성된 cDNA를 주형으로 사용하고, 하기의 프라이머를 사용한 정량적 실시간 PCR 분석(Quantitative real-time PCR analysis)을 수행하여, rhOC-FNIII9-10 또는 rhOC-FNIII9-14이 골형성 분화 관련 유전자인 제1형 콜라겐(Col I), 오스테오칼신(OC), 오스테오폰틴(osteopontin, OPN) 및 Runx2의 발현수준에 미치는 효과를 분석하였다(도 6a 내지 6d). 이때, 상기 PCR 분석반응은 각 프라이머 0.1μM, 2 X SYBR Green PCR master mix(Applied Biosystems, AmpliTaq Gold DNA polymerase, a dNTP mix, SYBR Green I dye, Rox dye, 및 10 mM MgCl2) 10㎕ 및 주형 cDNA 1㎕를 포함하는 반응액 20㎕에서 수행하였고, 각 유전자의 CT(cycle threshold) 값은 ABI 장치의 자동화 역치 분석기능을 사용하여 결정하고, CT(GAPDH) 값을 정상화하여, dCT(=CT(GAPDH)-CT(specific gene)) 값을 수득하였다.
GAPDH F: 5'-TCCACTCACGGCAAATTCAAC-3'(서열번호 16)
GAPDH R: 5'-AGCCCAAGATGCCCTTCAGT-3'(서열번호 17)
ColI F: 5'-GCATGGCCAAGAAGACATCC-3'(서열번호 18)
ColI R: 5'-CCTCGGGTTTCCACGTCTC-3'(서열번호 19)
OC F: 5'-CATCACTGCCACCCAGAAGAC-3'(서열번호 20)
OC R: 5'-CAGTGGATGCAGGGATGATGT-3'(서열번호 21)
OPN F: 5'-CCAATGAAAGCCATGACCAC-3'(서열번호 22)
OPN R: 5'-CGACTGTAGGGACGATTGGA-3'(서열번호 23)
Runx 2 F: 5'-GGCCGGGAATGATGAGAACTA-3'(서열번호 24)
Runx 2 R: 5'-GGCCCACAAATCTCAGATCGT-3'(서열번호 25)
도 6a 내지 6d에서 보듯이, rhOC-FNIII9-14 단백질이 코팅된 조건에서 배양된 MC3T3-E1 세포는 rhOC-FNIII9-10 단백질이 코팅된 조건에서 배양된 MC3T3-E1 세포보다도 골형성 분화 관련 유전자인 Col I, OC, OPN 및 Runx2이 모두 상대적으로 유의하게 높은 수준으로 발현됨을 확인하였다.
따라서, rhOC-FNIII9-14 단백질의 골형성 분화를 촉진하는 효과는 골형성 분화 관련 유전자의 발현수준을 증가시켜서 유도하는 것임을 알 수 있었다.
상술한 바를 종합하면, 본 발명에서 제공하는 RGD 서열 및 HBD를 포함하는 rhOC-FNIII9-14 단백질은 이에 포함된 HBD로 인하여, RGD 서열만을 포함하는 rhOC-FNIII9-10 단백질에 비하여 세포 결합수준, 세포증식 및 골형성 분화를 상대적으로 높은 수준으로 촉진하는 효과를 나타냄을 알 수 있었다.
<110> Industry-Academic Cooperation Foundation, Dankook University
INHA-INDUSTRY PARTNERSHIP INSTITUTE
<120> Fusion protein comprising cell-binding sequence, heparin-binding
domain and osteocalcin domain, and pharmaceutical composition
comprising the same
<130> PA131391/KR
<160> 25
<170> KopatentIn 2.0
<210> 1
<211> 2328
<212> PRT
<213> Homo sapiens
<400> 1
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Gln Ile Asn Gln Gln Trp Glu Arg Thr Tyr Leu Gly Asn Val Leu Val
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Cys Thr Cys Tyr Gly Gly Ser Arg Gly Phe Asn Cys Glu Ser Lys Pro
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Glu Ala Glu Glu Thr Cys Phe Asp Lys Tyr Thr Gly Asn Thr Tyr Arg
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Val Gly Asp Thr Tyr Glu Arg Pro Lys Asp Ser Met Ile Trp Asp Cys
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Thr Cys Ile Gly Ala Gly Arg Gly Arg Ile Ser Cys Thr Ile Ala Asn
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Arg Cys His Glu Gly Gly Gln Ser Tyr Lys Ile Gly Asp Thr Trp Arg
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Arg Pro His Glu Thr Gly Gly Tyr Met Leu Glu Cys Val Cys Leu Gly
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Asn Gly Lys Gly Glu Trp Thr Cys Lys Pro Ile Ala Glu Lys Cys Phe
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Asp His Ala Ala Gly Thr Ser Tyr Val Val Gly Glu Thr Trp Glu Lys
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Pro Tyr Gln Gly Trp Met Met Val Asp Cys Thr Cys Leu Gly Glu Gly
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Ser Gly Arg Ile Thr Cys Thr Ser Arg Asn Arg Cys Asn Asp Gln Asp
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Thr Arg Thr Ser Tyr Arg Ile Gly Asp Thr Trp Ser Lys Lys Asp Asn
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Arg Gly Asn Leu Leu Gln Cys Ile Cys Thr Gly Asn Gly Arg Gly Glu
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Trp Lys Cys Glu Arg His Thr Ser Val Gln Thr Thr Ser Ser Gly Ser
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Gly Pro Phe Thr Asp Val Arg Ala Ala Val Tyr Gln Pro Gln Pro His
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Pro Gln Pro Pro Pro Tyr Gly His Cys Val Thr Asp Ser Gly Val Val
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Tyr Ser Val Gly Met Gln Trp Leu Lys Thr Gln Gly Asn Lys Gln Met
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Leu Cys Thr Cys Leu Gly Asn Gly Val Ser Cys Gln Glu Thr Ala Val
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Thr Gln Thr Tyr Gly Gly Asn Leu Asn Gly Glu Pro Cys Val Leu Pro
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Phe Thr Tyr Asn Gly Arg Thr Phe Tyr Ser Cys Thr Thr Glu Gly Arg
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Gln Asp Gly His Leu Trp Cys Ser Thr Thr Ser Asn Tyr Glu Gln Asp
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Gln Lys Tyr Ser Phe Cys Thr Asp His Thr Val Leu Val Gln Thr Gln
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Gly Gly Asn Ser Asn Gly Ala Leu Cys His Phe Pro Phe Leu Tyr Asn
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Asn His Asn Tyr Thr Asp Cys Thr Ser Glu Gly Arg Arg Asp Asn Met
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Lys Trp Cys Gly Thr Thr Gln Asn Tyr Asp Ala Asp Gln Lys Phe Gly
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Phe Cys Pro Met Ala Ala His Glu Glu Ile Cys Thr Thr Asn Glu Gly
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His Met Met Arg Cys Thr Cys Val Gly Asn Gly Arg Gly Glu Trp Thr
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Thr Tyr Asn Val Asn Asp Thr Phe His Lys Arg His Glu Glu Gly His
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Met Leu Asn Cys Thr Cys Phe Gly Gln Gly Arg Gly Arg Trp Lys Cys
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Asp Pro Val Asp Gln Cys Gln Asp Ser Glu Thr Gly Thr Phe Tyr Gln
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Ile Gly Asp Ser Trp Glu Lys Tyr Val His Gly Val Arg Tyr Gln Cys
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Tyr Cys Tyr Gly Arg Gly Ile Gly Glu Trp His Cys Gln Pro Leu Gln
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Thr Tyr Pro Ser Ser Ser Gly Pro Val Glu Val Phe Ile Thr Glu Thr
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Pro Ser Gln Pro Asn Ser His Pro Ile Gln Trp Asn Ala Pro Gln Pro
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Ser His Ile Ser Lys Tyr Ile Leu Arg Trp Arg Pro Lys Asn Ser Val
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Gly Arg Trp Lys Glu Ala Thr Ile Pro Gly His Leu Asn Ser Tyr Thr
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Ile Lys Gly Leu Lys Pro Gly Val Val Tyr Glu Gly Gln Leu Ile Ser
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Ile Gln Gln Tyr Gly His Gln Glu Val Thr Arg Phe Asp Phe Thr Thr
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Thr Ser Thr Ser Thr Pro Val Thr Ser Asn Thr Val Thr Gly Glu Thr
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Thr Pro Phe Ser Pro Leu Val Ala Thr Ser Glu Ser Val Thr Glu Ile
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Thr Ala Ser Ser Phe Val Val Ser Trp Val Ser Ala Ser Asp Thr Val
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Ser Gly Phe Arg Val Glu Tyr Glu Leu Ser Glu Glu Gly Asp Glu Pro
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Gln Tyr Leu Asp Leu Pro Ser Thr Ala Thr Ser Val Asn Ile Pro Asp
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Leu Leu Pro Gly Arg Lys Tyr Ile Val Asn Val Tyr Gln Ile Ser Glu
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Asp Gly Glu Gln Ser Leu Ile Leu Ser Thr Ser Gln Thr Thr Ala Pro
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Asp Ala Pro Pro Asp Pro Thr Val Asp Gln Val Asp Asp Thr Ser Ile
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Val Val Arg Trp Ser Arg Pro Gln Ala Pro Ile Thr Gly Tyr Arg Ile
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Val Tyr Ser Pro Ser Val Glu Gly Ser Ser Thr Glu Leu Asn Leu Pro
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Glu Thr Ala Asn Ser Val Thr Leu Ser Asp Leu Gln Pro Gly Val Gln
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Tyr Asn Ile Thr Ile Tyr Ala Val Glu Glu Asn Gln Glu Ser Thr Pro
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Val Val Ile Gln Gln Glu Thr Thr Gly Thr Pro Arg Ser Asp Thr Val
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Pro Ser Pro Arg Asp Leu Gln Phe Val Glu Val Thr Asp Val Lys Val
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Thr Ile Met Trp Thr Pro Pro Glu Ser Ala Val Thr Gly Tyr Arg Val
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Asp Val Ile Pro Val Asn Leu Pro Gly Glu His Gly Gln Arg Leu Pro
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Ile Ser Arg Asn Thr Phe Ala Glu Val Thr Gly Leu Ser Pro Gly Val
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Thr Tyr Tyr Phe Lys Val Phe Ala Val Ser His Gly Arg Glu Ser Lys
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Pro Leu Thr Ala Gln Gln Thr Thr Lys Leu Asp Ala Pro Thr Asn Leu
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Gln Phe Val Asn Glu Thr Asp Ser Thr Val Leu Val Arg Trp Thr Pro
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Pro Arg Ala Gln Ile Thr Gly Tyr Arg Leu Thr Val Gly Leu Thr Arg
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Arg Gly Gln Pro Arg Gln Tyr Asn Val Gly Pro Ser Val Ser Lys Tyr
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Pro Leu Arg Asn Leu Gln Pro Ala Ser Glu Tyr Thr Val Ser Leu Val
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Ala Ile Lys Gly Asn Gln Glu Ser Pro Lys Ala Thr Gly Val Phe Thr
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Thr Leu Gln Pro Gly Ser Ser Ile Pro Pro Tyr Asn Thr Glu Val Thr
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Glu Thr Thr Ile Val Ile Thr Trp Thr Pro Ala Pro Arg Ile Gly Phe
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Lys Leu Gly Val Arg Pro Ser Gln Gly Gly Glu Ala Pro Arg Glu Val
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Thr Ser Asp Ser Gly Ser Ile Val Val Ser Gly Leu Thr Pro Gly Val
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Ala Pro Ile Val Asn Lys Val Val Thr Pro Leu Ser Pro Pro Thr Asn
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Leu His Leu Glu Ala Asn Pro Asp Thr Gly Val Leu Thr Val Ser Trp
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Glu Arg Ser Thr Thr Pro Asp Ile Thr Gly Tyr Arg Ile Thr Thr Thr
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Pro Thr Asn Gly Gln Gln Gly Asn Ser Leu Glu Glu Val Val His Ala
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Asp Gln Ser Ser Cys Thr Phe Asp Asn Leu Ser Pro Gly Leu Glu Tyr
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Asn Val Ser Val Tyr Thr Val Lys Asp Asp Lys Glu Ser Val Pro Ile
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Ser Asp Thr Ile Ile Pro Ala Val Pro Pro Pro Thr Asp Leu Arg Phe
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Thr Asn Ile Gly Pro Asp Thr Met Arg Val Thr Trp Ala Pro Pro Pro
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Ser Ile Asp Leu Thr Asn Phe Leu Val Arg Tyr Ser Pro Val Lys Asn
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Glu Glu Asp Val Ala Glu Leu Ser Ile Ser Pro Ser Asp Asn Ala Val
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Val Leu Thr Asn Leu Leu Pro Gly Thr Glu Tyr Val Val Ser Val Ser
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Ser Val Tyr Glu Gln His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys
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Thr Gly Leu Asp Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala
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Asn Ser Phe Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly
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Tyr Arg Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu
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Asp Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr
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Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg Glu
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Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp Val Pro
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Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu Leu Ile Ser
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Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg Ile Thr Tyr Gly
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Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe Thr Val Pro Gly Ser
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Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys Pro Gly Val Asp Tyr Thr
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Ile Thr Val Tyr Ala Val Thr Gly Arg Gly Asp Ser Pro Ala Ser Ser
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Lys Pro Ile Ser Ile Asn Tyr Arg Thr Glu Ile Asp Lys Pro Ser Gln
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Met Gln Val Thr Asp Val Gln Asp Asn Ser Ile Ser Val Lys Trp Leu
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Pro Ser Ser Ser Pro Val Thr Gly Tyr Arg Val Thr Thr Thr Pro Lys
1540 1545 1550
Asn Gly Pro Gly Pro Thr Lys Thr Lys Thr Ala Gly Pro Asp Gln Thr
1555 1560 1565
Glu Met Thr Ile Glu Gly Leu Gln Pro Thr Val Glu Tyr Val Val Ser
1570 1575 1580
Val Tyr Ala Gln Asn Pro Ser Gly Glu Ser Gln Pro Leu Val Gln Thr
1585 1590 1595 1600
Ala Val Thr Asn Ile Asp Arg Pro Lys Gly Leu Ala Phe Thr Asp Val
1605 1610 1615
Asp Val Asp Ser Ile Lys Ile Ala Trp Glu Ser Pro Gln Gly Gln Val
1620 1625 1630
Ser Arg Tyr Arg Val Thr Tyr Ser Ser Pro Glu Asp Gly Ile His Glu
1635 1640 1645
Leu Phe Pro Ala Pro Asp Gly Glu Glu Asp Thr Ala Glu Leu Gln Gly
1650 1655 1660
Leu Arg Pro Gly Ser Glu Tyr Thr Val Ser Val Val Ala Leu His Asp
1665 1670 1675 1680
Asp Met Glu Ser Gln Pro Leu Ile Gly Thr Gln Ser Thr Ala Ile Pro
1685 1690 1695
Ala Pro Thr Asp Leu Lys Phe Thr Gln Val Thr Pro Thr Ser Leu Ser
1700 1705 1710
Ala Gln Trp Thr Pro Pro Asn Val Gln Leu Thr Gly Tyr Arg Val Arg
1715 1720 1725
Val Thr Pro Lys Glu Lys Thr Gly Pro Met Lys Glu Ile Asn Leu Ala
1730 1735 1740
Pro Asp Ser Ser Ser Val Val Val Ser Gly Leu Met Val Ala Thr Lys
1745 1750 1755 1760
Tyr Glu Val Ser Val Tyr Ala Leu Lys Asp Thr Leu Thr Ser Arg Pro
1765 1770 1775
Ala Gln Gly Val Val Thr Thr Leu Glu Asn Val Ser Pro Pro Arg Arg
1780 1785 1790
Ala Arg Val Thr Asp Ala Thr Glu Thr Thr Ile Thr Ile Ser Trp Arg
1795 1800 1805
Thr Lys Thr Glu Thr Ile Thr Gly Phe Gln Val Asp Ala Val Pro Ala
1810 1815 1820
Asn Gly Gln Thr Pro Ile Gln Arg Thr Ile Lys Pro Asp Val Arg Ser
1825 1830 1835 1840
Tyr Thr Ile Thr Gly Leu Gln Pro Gly Thr Asp Tyr Lys Ile Tyr Leu
1845 1850 1855
Tyr Thr Leu Asn Asp Asn Ala Arg Ser Ser Pro Val Val Ile Asp Ala
1860 1865 1870
Ser Thr Ala Ile Asp Ala Pro Ser Asn Leu Arg Phe Leu Ala Thr Thr
1875 1880 1885
Pro Asn Ser Leu Leu Val Ser Trp Gln Pro Pro Arg Ala Arg Ile Thr
1890 1895 1900
Gly Tyr Ile Ile Lys Tyr Glu Lys Pro Gly Ser Pro Pro Arg Glu Val
1905 1910 1915 1920
Val Pro Arg Pro Arg Pro Gly Val Thr Glu Ala Thr Ile Thr Gly Leu
1925 1930 1935
Glu Pro Gly Thr Glu Tyr Thr Ile Tyr Val Ile Ala Leu Lys Asn Asn
1940 1945 1950
Gln Lys Ser Glu Pro Leu Ile Gly Arg Lys Lys Thr Asp Glu Leu Pro
1955 1960 1965
Gln Leu Val Thr Leu Pro His Pro Asn Leu His Gly Pro Glu Ile Leu
1970 1975 1980
Asp Val Pro Ser Thr Val Gln Lys Thr Pro Phe Val Thr His Pro Gly
1985 1990 1995 2000
Tyr Asp Thr Gly Asn Gly Ile Gln Leu Pro Gly Thr Ser Gly Gln Gln
2005 2010 2015
Pro Ser Val Gly Gln Gln Met Ile Phe Glu Glu His Gly Phe Arg Arg
2020 2025 2030
Thr Thr Pro Pro Thr Thr Ala Thr Pro Ile Arg His Arg Pro Arg Pro
2035 2040 2045
Tyr Pro Pro Asn Val Gly Gln Glu Ala Leu Ser Gln Thr Thr Ile Ser
2050 2055 2060
Trp Ala Pro Phe Gln Asp Thr Ser Glu Tyr Ile Ile Ser Cys His Pro
2065 2070 2075 2080
Val Gly Thr Asp Glu Glu Pro Leu Gln Phe Arg Val Pro Gly Thr Ser
2085 2090 2095
Thr Ser Ala Thr Leu Thr Gly Leu Thr Arg Gly Ala Thr Tyr Asn Ile
2100 2105 2110
Ile Val Glu Ala Leu Lys Asp Gln Gln Arg His Lys Val Arg Glu Glu
2115 2120 2125
Val Val Thr Val Gly Asn Ser Val Asn Glu Gly Leu Asn Gln Pro Thr
2130 2135 2140
Asp Asp Ser Cys Phe Asp Pro Tyr Thr Val Ser His Tyr Ala Val Gly
2145 2150 2155 2160
Asp Glu Trp Glu Arg Met Ser Glu Ser Gly Phe Lys Leu Leu Cys Gln
2165 2170 2175
Cys Leu Gly Phe Gly Ser Gly His Phe Arg Cys Asp Ser Ser Arg Trp
2180 2185 2190
Cys His Asp Asn Gly Val Asn Tyr Lys Ile Gly Glu Lys Trp Asp Arg
2195 2200 2205
Gln Gly Glu Asn Gly Gln Met Met Ser Cys Thr Cys Leu Gly Asn Gly
2210 2215 2220
Lys Gly Glu Phe Lys Cys Asp Pro His Glu Ala Thr Cys Tyr Asp Asp
2225 2230 2235 2240
Gly Lys Thr Tyr His Val Gly Glu Gln Trp Gln Lys Glu Tyr Leu Gly
2245 2250 2255
Ala Ile Cys Ser Cys Thr Cys Phe Gly Gly Gln Arg Gly Trp Arg Cys
2260 2265 2270
Asp Asn Cys Arg Arg Pro Gly Gly Glu Pro Ser Pro Glu Gly Thr Thr
2275 2280 2285
Gly Gln Ser Tyr Asn Gln Tyr Ser Gln Arg Tyr His Gln Arg Thr Asn
2290 2295 2300
Thr Asn Val Asn Cys Pro Ile Glu Cys Phe Met Pro Leu Asp Val Gln
2305 2310 2315 2320
Ala Asp Arg Glu Asp Ser Arg Glu
2325
<210> 2
<211> 95
<212> PRT
<213> Homo sapiens
<400> 2
Met Arg Thr Leu Ser Leu Leu Thr Leu Leu Ala Leu Ala Ala Leu Cys
1 5 10 15
Leu Ser Asp Leu Thr Asp Ala Lys Pro Ser Gly Pro Glu Ser Asp Lys
20 25 30
Ala Phe Met Ser Lys Gln Glu Gly Asn Lys Val Val Asn Arg Leu Arg
35 40 45
Arg Tyr Leu Gly Ala Ser Val Pro Ser Pro Asp Pro Leu Glu Pro Thr
50 55 60
Arg Glu Gln Cys Glu Leu Asn Pro Ala Cys Asp Glu Leu Ser Asp Gln
65 70 75 80
Tyr Gly Leu Lys Thr Ala Tyr Lys Arg Ile Tyr Gly Ile Thr Ile
85 90 95
<210> 3
<211> 685
<212> PRT
<213> Artificial Sequence
<220>
<223> rhOC-FNIII9-14
<400> 3
Tyr Leu Tyr Gln Trp Leu Gly Ala Pro Val Pro Tyr Pro Asp Pro Leu
1 5 10 15
Glu Pro Arg Arg Glu Val Cys Glu Leu Asn Pro Asp Cys Asp Glu Leu
20 25 30
Ala Asp His Ile Gly Phe Gln Glu Ala Tyr Arg Arg Phe Tyr Gly Pro
35 40 45
Val Gly Thr Gly Leu Asp Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile
50 55 60
Thr Ala Asn Ser Phe Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile
65 70 75 80
Thr Gly Tyr Arg Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro
85 90 95
Arg Glu Asp Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn
100 105 110
Leu Thr Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly
115 120 125
Arg Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp
130 135 140
Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu Leu
145 150 155 160
Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg Ile Thr
165 170 175
Tyr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe Thr Val Pro
180 185 190
Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys Pro Gly Val Asp
195 200 205
Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg Gly Asp Ser Pro Ala
210 215 220
Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg Thr Glu Ile Asp Lys Pro
225 230 235 240
Ser Gln Met Gln Val Thr Asp Val Gln Asp Asn Ser Ile Ser Val Lys
245 250 255
Trp Leu Pro Ser Ser Ser Pro Val Thr Gly Tyr Arg Val Thr Thr Thr
260 265 270
Pro Lys Asn Gly Pro Gly Pro Thr Lys Thr Lys Thr Ala Gly Pro Asp
275 280 285
Gln Thr Glu Met Thr Ile Glu Gly Leu Gln Pro Thr Val Glu Tyr Val
290 295 300
Val Ser Val Tyr Ala Gln Asn Pro Ser Gly Glu Ser Gln Pro Leu Val
305 310 315 320
Gln Thr Ala Val Thr Asn Ile Asp Arg Pro Lys Gly Leu Ala Phe Thr
325 330 335
Asp Val Asp Val Asp Ser Ile Lys Ile Ala Trp Glu Ser Pro Gln Gly
340 345 350
Gln Val Ser Arg Tyr Arg Val Thr Tyr Ser Ser Pro Glu Asp Gly Ile
355 360 365
His Glu Leu Phe Pro Ala Pro Asp Gly Glu Glu Asp Thr Ala Glu Leu
370 375 380
Gln Gly Leu Arg Pro Gly Glu Tyr Thr Val Ser Val Val Ala Leu His
385 390 395 400
Asp Asp Met Glu Ser Gln Pro Leu Ile Gly Thr Gln Ser Thr Ala Ile
405 410 415
Pro Ala Pro Thr Asp Leu Lys Phe Thr Gln Val Thr Pro Thr Ser Leu
420 425 430
Ser Ala Gln Trp Thr Pro Pro Asn Val Gln Leu Thr Gly Tyr Arg Val
435 440 445
Arg Val Thr Pro Lys Glu Lys Thr Gly Pro Met Lys Glu Ile Asn Leu
450 455 460
Ala Pro Asp Ser Ser Ser Val Val Val Ser Gly Leu Met Val Ala Thr
465 470 475 480
Lys Tyr Glu Val Ser Val Tyr Ala Leu Lys Asp Thr Leu Thr Ser Arg
485 490 495
Pro Ala Gln Gly Val Val Thr Thr Leu Glu Asn Val Ser Pro Pro Arg
500 505 510
Arg Ala Arg Val Thr Asp Ala Thr Glu Thr Thr Ile Thr Ile Ser Trp
515 520 525
Arg Thr Lys Thr Glu Thr Ile Thr Gly Phe Gln Val Asp Ala Val Pro
530 535 540
Ala Asn Gly Gln Thr Pro Ile Gln Arg Thr Ile Lys Pro Asp Val Arg
545 550 555 560
Ser Tyr Thr Ile Thr Gly Leu Gln Pro Gly Thr Asp Tyr Lys Ile Tyr
565 570 575
Leu Tyr Thr Leu Asn Asp Asn Ala Arg Ser Ser Pro Val Val Ile Asp
580 585 590
Ala Ser Thr Ala Ile Asp Ala Pro Ser Asn Leu Arg Phe Leu Ala Thr
595 600 605
Thr Pro Asn Ser Leu Leu Val Ser Trp Gln Pro Pro Arg Ala Arg Ile
610 615 620
Thr Gly Tyr Ile Ile Lys Tyr Glu Lys Pro Gly Ser Pro Pro Arg Glu
625 630 635 640
Val Val Pro Arg Pro Arg Pro Gly Val Thr Glu Ala Thr Ile Thr Gly
645 650 655
Leu Glu Pro Gly Thr Glu Tyr Thr Ile Tyr Val Ile Ala Leu Lys Asn
660 665 670
Asn Gln Lys Ser Glu Pro Leu Ile Gly Arg Lys Lys Thr
675 680 685
<210> 4
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> peptide linker
<400> 4
Gly Gly Ser Gly Gly Thr
1 5
<210> 5
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> peptide linker
<400> 5
Gly Gly Gly Gly Ser
1 5
<210> 6
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> peptide linker
<400> 6
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 7
<211> 2058
<212> DNA
<213> Artificial Sequence
<220>
<223> rhOC-FNIII9-14
<400> 7
tacctgtatc aatggctggg agccccagtc ccctacccgg atcccctgga gcccaggagg 60
gaggtgtgtg agctcaatcc ggactgtgac gagttggctg accacatcgg ctttcaggag 120
gcctatcggc gcttctacgg cccggtcgga tccggtcttg attccccaac tggcattgac 180
ttttctgata ttactgccaa ctcttttact gtgcactgga ttgctcctcg agccaccatc 240
actggctaca ggatccgcca tcatcccgag cacttcagtg ggagacctcg agaagatcgg 300
gtgccccact ctcggaattc catcaccctc accaacctca ctccaggcac agagtatgtg 360
gtcagcatcg ttgctcttaa tggcagagag gaaagtccct tattgattgg ccaacaatca 420
acagtttctg atgttccgag ggacctggaa gttgttgctg cgacccccac cagcctactg 480
atcagctggg atgctcctgc tgtcacagtg agatattaca ggatcactta cggagaaaca 540
ggaggaaata gccctgtcca ggagttcact gtgcctggga gcaagtctac agctaccatc 600
agcggcctta aacctggagt tgattatacc atcactgtgt atgctgtcac tggccgtgga 660
gacagccccg caagcagcaa gccaatttcc attaattacc gaacagaaat tgacaaacca 720
tcccagatgc aagtgaccga tgttcaggac aacagcatta gtgtcaagtg gctgccttca 780
agttcccctg ttactggtta cagagtaacc accactccca aaaatggacc aggaccaaca 840
aaaactaaaa ctgcaggtcc agatcaaaca gaaatgacta ttgaaggctt gcagcccaca 900
gtggagtatg tggttagtgt ctatgctcag aatccaagcg gagagagtca gcctctggtt 960
cagactgcag taaccaacat tgatcgccct aaaggactgg cattcactga tgtggatgtc 1020
gattccatca aaattgcttg ggaaagccca caggggcaag tttccaggta cagggtgacc 1080
tactcgagcc ctgaggatgg aatccatgag ctattccctg cacctgatgg tgaagaagac 1140
actgcagagc tgcaaggcct cagaccgggt tctgagtaca cagtcagtgt ggttgccttg 1200
cacgatgata tggagagcca gcccctgatt ggaacccagt ccacagctat tcctgcacca 1260
actgacctga agttcactca ggtcacaccc acaagcctga gcgcccagtg gacaccaccc 1320
aatgttcagc tcactggata tcgagtgcgg gtgaccccca aggagaagac cggaccaatg 1380
aaagaaatca accttgctcc tgacagctca tccgtggttg tatcaggact tatggtggcc 1440
accaaatatg aagtgagtgt ctatgctctt aaggacactt tgacaagcag accagctcag 1500
ggtgttgtca ccactctgga gaatgtcagc ccaccaagaa gggctcgtgt gacagatgct 1560
actgagacca ccatcaccat tagctggaga accaagactg agacgatcac tggcttccaa 1620
gttgatgccg ttccagccaa tggccagact ccaatccaga gaaccatcaa gccagatgtc 1680
agaagctaca ccatcacagg tttacaacca ggcactgact acaagatcta cctgtacacc 1740
ttgaatgaca atgctcggag ctcccctgtg gtcatcgacg cctccactgc cattgatgca 1800
ccatccaacc tgcgtttcct ggccaccaca cccaattcct tgctggtatc atggcagccg 1860
ccacgtgcca ggattaccgg ctacatcatc aagtatgaga agcctgggtc tcctcccaga 1920
gaagtggtcc ctcggccccg ccctggtgtc acagaggcta ctattactgg cctggaaccg 1980
ggaaccgaat atacaattta tgtcattgcc ctgaagaata atcagaagag cgagcccctg 2040
attggaagga aaaagaca 2058
<210> 8
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> hOC forward primer
<400> 8
taggagccct cacactcctc 20
<210> 9
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> hOC reverse primer
<400> 9
ctggagagga gcagaactgg 20
<210> 10
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> forward primer for the BglII site
<400> 10
aacagatctt acctgtatca atggctggga 30
<210> 11
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> reverse primer for the KpnI site
<400> 11
aatggtaccg accgggccgt agaagcgccg 30
<210> 12
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> forward primer for the SacI site
<400> 12
ctcgagcaac aatcaacagt ttc 23
<210> 13
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> reverse primer for the SacI site
<400> 13
ctcgagtggt ttgtcaattt c 21
<210> 14
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> forward primer
<400> 14
attgattatt tgcacggcgt 20
<210> 15
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> reverse primer
<400> 15
acggcgtttc acttctgagt 20
<210> 16
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> GAPDH F primer
<400> 16
tccactcacg gcaaattcaa c 21
<210> 17
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> GAPDH R primer
<400> 17
agcccaagat gcccttcagt 20
<210> 18
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> ColI F primer
<400> 18
gcatggccaa gaagacatcc 20
<210> 19
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> ColI R primer
<400> 19
cctcgggttt ccacgtctc 19
<210> 20
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> OC F primer
<400> 20
catcactgcc acccagaaga c 21
<210> 21
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> OC R primer
<400> 21
cagtggatgc agggatgatg t 21
<210> 22
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> OPN F primer
<400> 22
ccaatgaaag ccatgaccac 20
<210> 23
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> OPN R primer
<400> 23
cgactgtagg gacgattgga 20
<210> 24
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Runx 2 F primer
<400> 24
ggccgggaat gatgagaact a 21
<210> 25
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Runx 2 R primer
<400> 25
ggcccacaaa tctcagatcg t 21
Claims (13)
- 삭제
- 삭제
- 삭제
- 피브로넥틴 유래 RGD(Arg-Gly-Asp) 서열과 헤파린 결합 도메인(heparin-binding domain, HBD), 및 오스테오칼신 도메인을 포함하는, 서열번호 3의 아미노산 서열로 구성되는 융합단백질
- 삭제
- 제4항에 있어서,
상기 융합단백질은 세포결합 활성, 세포증식 활성 및 골형성 분화활성을 나타내는 것인 융합단백질.
- 제4항의 융합단백질을 코딩하는 뉴클레오티드 서열을 포함하는 폴리뉴클레오티드.
- 제7항에 있어서,
서열번호 7의 뉴클레오티드 서열을 포함하는 폴리뉴클레오티드.
- 제7항의 폴리뉴클레오티드를 포함하는 발현벡터.
- 제9항의 발현벡터가 도입되어 형질전환된 형질전환체.
- (a) 제10항의 형질전환체를 형질전환체를 배양하여 배양물을 수득하는 단계; 및,
(b) 상기 배양물로부터 제4항의 융합단백질을 회수하는 단계를 포함하는, 제4항의 융합단백질의 생산방법.
- 제4항 또는 제6항 중 어느 한 항의 융합단백질을 유효성분으로 포함하는, 성장기 발육부진, 골절, 구루병(rickets), 골연화증(osteomalacia), 척추측만증(scoliosis), 골반변형(pelvic deformity), 골다공증(osteoprosis), 류마티스성 관절염(rheumatoid arthritis), 치주질환(periodontal disease), 갑상선기능항진증(hyperparathyroidism), 파제트병(Paget disease), 전이성 골암(metastatic bone cancers)으로 이루어진 군에서 선택되는 1 이상의 골질환 예방 또는 치료용 약학 조성물.
- 제4항 또는 제6항 중 어느 한 항의 융합단백질을 유효성분으로 포함하는 골 또는 치아 재생용 약학 조성물.
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agnella, S. et al., Tissue Eng. 11(1-2):pp.226-236 (2005. 9.29.)* |
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