KR101234361B1 - 치아 및 뼈 재생을 위한 융합 단백질 - Google Patents
치아 및 뼈 재생을 위한 융합 단백질 Download PDFInfo
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- KR101234361B1 KR101234361B1 KR1020100119152A KR20100119152A KR101234361B1 KR 101234361 B1 KR101234361 B1 KR 101234361B1 KR 1020100119152 A KR1020100119152 A KR 1020100119152A KR 20100119152 A KR20100119152 A KR 20100119152A KR 101234361 B1 KR101234361 B1 KR 101234361B1
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Abstract
본 발명은 피브로넥틴 도메인 및 오스테오칼신 도메인을 포함하는 융합 단백질, 및 상기 단백질을 포함하는 뼈 또는 치아 재생용 조성물 및 뼈 질환 예방 또는 치료용 조성물에 관한 것이다. 또한, 본 발명은 상기 단백질을 히드록시아파타이트(HA) 로 구성된 구조물에 코팅하는 단계; 및 상기 코팅된 구조물에 조골세포를 부착시키는 단계를 포함하는 뼈 또는 치아 재생 방법에 관한 것이다. 본 발명의 융합 단백질은 히드록시아파타이트에 대한 결합 친화도가 높을 뿐만 아니라 조골세포의 부착 및 유지를 촉진시키고, 조골세포의 분화를 향상시켜 뼈 및 치아 재생용 조성물, 나아가 뼈 질환 예방 또는 치료용 조성물로 사용할 수 있다. 또한, 상기 단백질을 히드록시아파타이트(HA) 등으로 구성된 구조물에 코팅함으로써, 뼈 조직 공학 및 생의학에 적용할 수 있다.
Description
본 발명은 피브로넥틴 도메인 및 오스테오칼신 도메인을 포함하는 융합 단백질, 및 상기 단백질을 포함하는 뼈 또는 치아 재생용 조성물 및 뼈 질환 예방 또는 치료용 조성물에 관한 것이다. 또한, 본 발명은 상기 단백질을 히드록시아파타이트(HA) 로 구성된 구조물에 코팅하는 단계; 및 상기 코팅된 구조물에 조골세포를 부착시키는 단계를 포함하는 뼈 또는 치아 재생 방법에 관한 것이다.
조직의 발생, 조직화 그리고 유지를 포함한 다양한 생리적 기능을 수행하기 위해서는 세포가 미세환경의 세포외 기질(extracellular matrix, ECM) 단백질에 특이적으로 부착되는 것이 필요하다. 따라서, ECM 리간드에 세포가 부착되는 것이 생체적합물질, 인공장기, 조직공학, 시험관내 세포 배양을 위한 지지체 등 생명공학적 응용에 필수적이다.
세포의 부착에는 인테그린(integrin)이라 불리는 세포 표면 부착 수용체가 중요한 역할을 하는데, 인테그린과 세포외 기질과의 상호작용을 통해 세포의 성장, 분화, 사멸 및 발생과정이 조절된다. 인테그린과 작용하여 세포의 기능을 조절하는 중요한 세포외 기질 중 가장 잘 알려진 것 중 하나가 피브로넥틴(fibronectin)이다. 피브로넥틴은 분자량이 약 220 kDa의 비교적 큰 단백질로서 RGD 모티프를 비롯한 몇 개의 모티프들을 포함하여 다양한 인테그린과 작용하여 세포의 기능을 조절한다.
뼈 γ-카르복시글루탐산(Gla)-단백질(BGP)로 불리우는 오스테오칼신 (Osteocalcin) 은 세포외 기질에 풍부한 비콜라겐성 단백질이다. 성숙된 단백질은 49 개의 아미노산 잔기로 구성되어 있고 5700Da의 분자량을 가진다. 상기 오스테오칼신은 뼈 성숙의 후기 단계에서 조골세포에 의해 생성되고 분리되며, 오스테오칼신은 히드록시아파타이트에 대한 높은 친화도를 가져, 무기질화에 중요한 역할을 한다.
히드록시아파타이트(hydroxyapatite, HA)는 천연 뼈 또는 치아 무기질 부분과 유사한 화학적 구성 때문에, 뼈 이식이나 재생의 뼈 대체 물질로 널리 사용되는 것 중에 하나이다. 또한, 히드록시아파타이트는 뼈 조직공학 분야에서 뼈-관련 세포 유인을 위한 스캐폴드 물질로 개발되어왔다.
본 발명은 Arg-Gly-Asp(RGD) 서열을 포함하는 피브로넥틴 도메인 및 오스테오칼신 도메인을 포함하는 융합 단백질, 및 상기 단백질을 코딩하는 뉴클레오타이드 서열을 가지는 핵산을 제공하고자 한다.
또한, 본 발명은 상기 단백질을 포함하는 뼈 또는 치아 재생용 조성물 및 뼈 질환 예방 또는 치료용 조성물을 제공하고자 한다.
또한, 본 발명은 상기 단백질을 히드록시아파타이트(HA) 로 구성된 구조물에 코팅하는 단계; 및 상기 코팅된 구조물에 조골세포를 부착시키는 단계를 포함하는 뼈 또는 치아 재생 방법을 제공하고자 한다.
또한, 본 발명은 히드록시아파타이트(HA) 로 구성된 구조물로서, 상기 단백질로 코팅된 것을 특징으로 하는 구조물을 제공하고자 한다.
종래의 피브로넥틴 단백질은 뼈 조직에 특이적이지 못한 점, 생체 내에서 확산되어 그 효과를 장기간 지속할 수 없다는 점, 및 반감기가 짧은 점 때문에 치료로 응용하기 위해서는 농도를 유지하는데 그 어려움이 있었다.
이에 본 발명자는 RGD 서열을 포함하는 피브로넥틴 도메인 및 오스테오칼신 도메인을 포함한 융합 단백질을 제조하였고, 이러한 융합 단백질이 히드록시아파타이트에 대한 결합 친화도가 높을 뿐만 아니라 조골세포의 부착 및 유지를 촉진시키고, 조골세포의 분화를 향상시켜 뼈 및 치아 재생용 조성물, 나아가 뼈 질환 예방 또는 치료용 조성물로 사용할 수 있다는 것을 확인하여 이를 토대로 본 발명을 완성하였다.
하나의 양태로서, 본 발명은 Arg-Gly-Asp(RGD) 서열을 포함하는 피브로넥틴 도메인 및 오스테오칼신 도메인을 포함하는 융합 단백질을 제공한다. 본 발명에서 "피브로넥틴(fibronectin)"은 분자량이 약 220 kDa의 단백질로서 서열번호 7의 아미노산 서열을 가지고, RGD모티프를 비롯한 몇 개의 모티프들을 포함하며 다양한 인테그린과 작용하여 세포의 기능을 조절한다. 세포 표면 부착 수용체인 인테그린과 작용하는 피브로넥틴의 여러 가지 모티프 중 RGD는 세포 부착 모티프로서 10번째 타입Ⅲ 반복 단위에 존재한다. 본 발명의 피브로넥틴 도메인은 피브로넥틴의 10번째 타입Ⅲ 반복 단위이고 RGD 서열을 포함한다. 바람직하게는, 상기 피브로넥틴 도메인은 서열번호 1의 아미노산 서열을 가질 수 있다.
본 발명에서 "오스테오칼신(osteocalcin)"은 감마-카르복실글루타민산(γ-carboxylglutamate: Gla) 잔기를 2-3 개 포함하며 분자량 약 5,900 Da의 비타민 K 의존성 칼슘 결합 비콜라겐성 단백질로서, 서열번호 8의 아미노산 서열을 가진다. 뼈 속의 오스테오칼신은 국소 무기질화 조절을 하거나 뼈와 체액간의 Ca2+의 움직임을 제어하는 등 뼈의 대사에 있어서 중요한 생리적 역할을 한다. 오스테오칼신은 조골세포에서 합성된 후 세포 내에서 비타민 K 의존성 탈탄산효소(carboxylase)에 의해 Gla화된다. Gla화된 오스테오칼신(Gla-OC)은 뼈 속의 히드록시아파타이트(hydroxyapatite,HA)와 결합하여 뼈 기질에 축적되어 뼈 형성에 관여하고 Gla화되지 않은 오스테오칼신(Glu-OC)은 뼈 기질과의 친화성이 약하여 혈액으로 방출되어 뼈흡수의 지표가 된다. 오스테오칼신은 히드록시아파타이트에 대한 높은 친화도를 가지며, 본 발명의 오스테오칼신 도메인은 히드록시아파타이트(HA)에 결합하는 18-95 아미노산 부위를 포함할 수 있다. 바람직하게는 상기 오스테오칼신 도메인은 서열번호 2의 아미노산 서열을 가질 수 있다.
또한, 상기 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.
상기 피브로넥틴 도메인 또는 오스테오칼신 도메인 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 발현시킬 수 있다. 상기 유전자는 서열번호 3 및 4의 염기서열을 가지는 것일 수 있다. 상기 유전자 서열은 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 발명에서 "피브로넥틴 도메인 및 오스테오칼신 도메인을 포함하는 융합 단백질"은 피브로넥틴 도메인 및 오스테오칼신 도메인을 모두 포함하도록 재조합한 단백질로서, 본 발명에서 "FNRGD/OC"도 동일한 의미를 가진다.
본 발명의 융합 단백질은 히드록시아파타이트(HA)에 결합하여 인테그린 매개 세포 부착을 촉진하는 기능을 하고, 더욱 상세하게는 치아 및 뼈 무기질 성분에 조골세포 부착 및 유지를 촉진시키고, 조골세포의 분화를 증진시킨다. 본 발명의 융합 단백질은 피브로넥틴 도메인의 C 말단에 오스테오칼신 도메인이 연결된 구조 또는 피브로넥틴 도메인의 N 말단에 오스테오칼신 도메인이 연결된 구조일 수 있다. 바람직하게는, 서열번호 5의 아미노산 서열을 가진다.
상기 피브로넥틴 도메인 및 오스테오칼신 도메인을 포함하는 융합 단백질은 당해 분야에 공지된 화학적 펩티드 합성방법으로 제조하거나, 상기 각 도메인을 코딩하는 유전자를 PCR (polymerase chain reaction) 에 의해 증폭하거나 공지된 방법으로 합성한 후 인프레임(in frame)으로 연결하여 발현벡터 내에 작동 가능하게 연결하여 클로닝하여 발현시킬 수 있다. 구체적으로는 서열번호 6의 염기서열을 가지는 핵산을 발현벡터 내에 작동 가능하게 연결하여 발현시킬 수 있다. 본 발명에서 "작동가능하게 연결(operably linked)"은 일반적 기능을 수행하도록 핵산 발현조절 서열과 목적하는 단백질 또는 RNA를 코딩하는 핵산 서열이 기능적으로 연결(functional linkage)되어 있는 것을 말한다. 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 사용한다.
본 발명에서 "발현벡터"란 적당한 숙주세포에서 목적 단백질을 발현할 수 있는 재조합 벡터로서, 유전자 삽입물이 발현되도록 작동하게 연결된 필수적인 조절 요소를 포함하는 유전자 제작물을 말한다. 본 발명의 발현벡터는 적합한 발현벡터가 일반적으로 가지고 있는 요소로서 프로모터, 오퍼레이터, 개시코돈, 폴리아데닐화 시그널 및 인헨서 같은 발현 조절 요소들을 포함한다. 개시 코돈 및 종결 코돈은 일반적으로 면역원성 표적 단백질을 코딩하는 뉴클레오 타이드 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.
발현벡터는 통상의 모든 발현 벡터를 다 사용할 수 있다. 숙주 세포에 따라서 단백질의 발현량과 수식 등이 다르게 나타나므로, 목적에 가장 적합한 숙주세포를 선택하여 사용하면 된다. 본 발명의 구체예에서, 본 발명의 융합단백질을 코딩하는 유전자를 포함한 발현 벡터로서 pBAC/His-FNRGD/OC를 제조하였다.
본 발명의 융합 단백질에서, 피브로넥틴 도메인 및 오스테오칼신 도메인 사이에 링커 펩타이드를 포함할 수 있다. 링커 펩타이드로는 통상적으로 사용되는 잘 구부러지는(flexible) 링커 펩타이드를 사용할 수 있고, GGSGGT 아미노산 서열, GGGGS 아미노산 서열, GGGGSGGGGS 아미노산 서열을 가지는 링커 펩타이드를 사용할 수 있으나, 이에 제한되지는 않는다. 링커 펩타이드는 상기 링커 펩타이드를 코딩하는 핵산을 각 도메인을 코딩하는 핵산 사이에 인프레임(in frame)으로 연결하여 발현벡터 내에 작동 가능하게 연결하여 발현시킬 수 있다.
본 발명의 벡터는 융합단백질의 검출을 용이하게 하기 위하여, 임의로 엔도펩티아이제를 사용하여 제거할 수 있는 단백질 태그를 추가로 포함할 수 있다. 본 발명에서 용어, "태그(tag)"란 정량가능한 활성 또는 특성을 나타내는 분자를 말하며, 플로오레세인과 같은 화학적 형광물질(fluoracer), 형광 단백질(GFP) 또는 관련 단백질과 같은 폴리펩타이드 형광물질을 포함한 형광분자일 수 있고, Myc 태그, 플래그(Flag) 태그, 히스티딘 태그, 루신 태그, IgG 태그 및 스트랩타비딘 태그 등 에피톱 태그일 수도 있다. 적합한 태그 폴리펩티드는 일반적으로 6개 이상의 아미노산 잔기를 가지며, 통상적으로 약 8개 내지 50개의 아미노산 잔기를 가지는데, 본 발명에서는 6개의 히스티딘 태그를 사용하였다.
상기 벡터가 발현되는 형질전환체를 영양배지에서 배양하면 유용한 단백질을 대량으로 제조, 분리 가능하다. 배지와 배양조건은 숙주 세포에 따라 관용되는 것을 적당히 선택하여 이용할 수 있다. 배양시 세포의 생육과 단백질의 대량 생산에 적합하도록 온도, 배지의 pH 및 배양시간 등의 조건들을 적절하게 조절하여야 한다. 본 발명에 따른 발현 벡터로 형질전환될 수 있는 숙주 세포는 원핵 세포를 포함하며, DNA의 도입효율이 높고, 도입된 DNA의 발현효율이 높은 숙주가 통상 사용된다. 세균, 예를 들어 에쉐리키아, 슈도모나스, 바실러스, 스트렙토마이세스와 같은 주지의 원핵 숙주들이 사용될 수 있는 숙주 세포의 예이다. 바람직하게는 대장균이 사용될 수 있다. 펩티드의 발현은 유도인자 IPTG를 사용하여 발현을 유도할 수 있고, 유도시간은 단백질의 양을 최대화되게 조절할 수 있다. 본 발명에서, 재조합적으로 생산된 펩티드는 배지 또는 세포 분해물로부터 회수될 수 있다. 막 결합형인 경우, 적합한 계면활성제 용액(예, 트리톤-X 100)을 사용하거나 또는 효소적 절단에 의해 막으로부터 유리될 수 있다. 펩티드 발현에 사용된 세포는 동결-해동 반복, 음파처리, 기계적 파괴 또는 세포 분해제와 같은 다양한 물질적 또는 화학적 수단에 의해 파괴될 수 있으며, 통상적인 생화학 분리 기술에 의해서 분리. 정제 가능하다(Sambrook et al., Molecular Cloning: A laborarory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, 1989; Deuscher, M., Guide to Protein Purification Methods Enzymology, Vol. 182. Academic Press. Inc., San Diego, CA, 1990). 전기영동, 원심분리, 겔여과, 침전, 투석, 크로마토그래피(이온교화크로마토그래피, 친화력 크로마토그래피, 면역흡착 친화력 크로마토그래피, 역상 HPLC, 겔 침투 HPLC), 등전성 포커스 및 이의 다양한 변화 및 복합 방법을 포함하나 이에 국한되지 않는다.
또 다른 양태로서, 본 발명은 상기 융합 단백질을 코딩하는 뉴클레오타이드 서열을 가지는 핵산을 제공한다. 상기 핵산은 서열번호 5의 아미노산 서열을 가지는 단백질을 코딩하는 뉴클레오타이드 서열을 가지는 핵산일 수 있고, 더욱 바람직하게는, 서열번호 6의 뉴클레오타이드 서열을 가지는 핵산일 수 있다.
또 다른 양태로서, 본 발명은 상기 융합 단백질을 포함하는 뼈 또는 치아 재생용 조성물 및 뼈 질환 예방 또는 치료용 조성물을 제공한다. 상기 융합단백질은 뼈 또는 치아의 무기질 성분인 히드록시아파타이트(HA)에 결합하여 히드록시아파타이트(HA)에 조골세포의 부착을 증진시키며, 조골세포의 염기성 인산분해효소(alkaline phosphatase; ALP) 활성을 증진시켜 조골세포의 분화를 촉진시킨다.
본 발명에서 "염기성 인산분해효소(ALP)"는 뼈를 생성하는 세포인 조골세포(osteoblast)에 많이 존재하며, 뼈의 생성이 많아지는 모든 경우(예를 들면 골절, 종양에 의한 뼈의 파괴시 복구를 위해서 뼈의 생성이 증가한다), 조골세포의 활동이 증가하고 조골세포의 효소인 염기성 인산분해효소의 활성도 역시 증가한다.
본 발명의 뼈 질환 예방 또는 치료용 조성물은, 조골세포에 의한 염기성 인산분해효소(alkaline phosphatase; ALP)의 발현을 증가시켜 뼈 생성을 촉진하는 작용을 하며, 이러한 작용을 통하여 다양한 뼈 질환을 치료 또는 예방한다.
본 발명에 의해 예방 또는 치료될 수 있는 뼈질환의 예는 암세포의 뼈전이에 의해 초래되는 뼈의 손상, 골다공증, 골연화증, 구루병, 섬유성 골염, 무형성 골질환, 대사성 골질환, 골용해, 백혈구 감소증, 뼈의 기형, 고칼슘혈증 또는 신경압박 증후군을 포함하나 이에 제한되지 않는다.
본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함할 수 있다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸 히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정하는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.
본 발명의 약제학적 조성물은 경구 또는 비 경구 투여할 수 있으며, 본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여시간, 투여경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 또 다른 양태는 상기 조성물을 대상에게 투여하는 단계를 포함하는 뼈 질환의 예방 또는 치료 방법을 제공한다.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캡슐제 형태일 수 있으며, 분산제 또는 안정화제를 추가로 포함할 수 있다.
또한, 본 발명은 상기 융합 단백질을 히드록시아파타이트(HA) 로 구성된 구조물에 코팅하는 단계; 및 상기 코팅된 구조물에 조골세포를 부착시키는 단계를 포함하는 뼈 또는 치아 재생 방법을 제공하고자 한다. 상기 히드록시아파타이트(HA) 대신 옥시아파타이트, 트리칼슘포스페이트, 모노칼슘포스페이트, 육인산사칼슘, 칼슘메타포스페이트 등의 인산칼슘계 무기질을 사용할 수 있으며, 바람직하게는 히드록시아파타이트를 사용할 수 있으나 이에 제한되지 않는다.
또한, 본 발명은 히드록시아파타이트(HA) 로 구성된 구조물로서, 상기 단백질로 코팅된 것을 특징으로 하는 구조물을 제공하고자 한다. 상기 구조물은 뼈 또는 치아 재생을 위하여 뼈 관련 세포 유인을 위한 스캐폴드로 사용될 수 있다. 기존의 피브로넥틴에 비하여 본 발명의 융합 단백질은 히드록시아파타이트(HA)에 대한 결합 친화도가 높을 뿐만 아니라 조골세포의 부착 및 유지를 촉진시키므로, 조골세포의 분화를 향상시킬 수 있다.
본 발명의 융합 단백질은 히드록시아파타이트에 대한 결합 친화도가 높을 뿐만 아니라 조골세포의 부착 및 유지를 촉진시키고, 조골세포의 분화를 향상시켜 뼈 및 치아 재생용 조성물, 나아가 뼈 질환 예방 또는 치료용 조성물로 사용할 수 있다. 또한, 상기 단백질을 히드록시아파타이트(HA) 등으로 구성된 구조물에 코팅함으로써, 뼈 조직 공학 및 생의학에 적용할 수 있다.
도 1은 재조합 FNRGD/OC 융합 단백질의 발현을 SDS-PAGE로 확인한 사진이다. 재조합 FNRGD/OC은 히스티딘(His 6) 태깅된 융합 단백질 형태로 발현되었고, Ni-NTA컬럼을 이용하여 정제하였다. 용출된 물질을 환원 조건하에 SDS-PAGE을 실행하였고 쿠마시 블루(Coomassie Blue) 염색하여 검출하였다. 5 μ의 단백질을 15%(w/v) SDS-폴리아크릴아미드 젤 전기영동에 적용하였다. Mr 마커는 kDa으로 나타내었다.
도 2는 히드록시아파타이트(HA)에 단백질이 접착된 결과를 나타낸다. 히드록시아파타이트(HA) 디스크는 24 웰 접시 바닥에 놓여졌고, FNRGD 또는 FNRGD/OC 단백질(0.5μM)로 2시간 동안 37℃ 에서 고정되었다. BSA를 대조군으로 사용하였다. 결과는 O.D.값과 평균±표준표차(n=3)로 나타낸다.
도 3은 7일까지 동안 세포가 없는 배양 배지에서 인큐베이션하는 동안 히드록시아파타이트(HA)디스크로부터 FNRGD/OC 가 분리되는 프로파일을 Hig-tag 프루브로 평가한 것이다. 처음 고정된 FNRGD/OC의 대략 70%가 적어도 인큐베이션 7일 동안 남아있었다. 히드록시아파타이트(HA)디스크에 처음 고정된 FNRGD/OC단백질의 양을 100%로 정의한다. 각 데이터 점은 평균±표준표차(n=3)을 나타낸다.
도 4는 FNRGD/OC-고정된 히드록시아파타이트(HA)디스크 상에 MC3T3-E1 조골세포가 부착되는 정도를 확인한 결과이다. MC3T3-E1 세포를 FNRGD 또는 FNRGD/OC 단백질(0.5μM)로 고정된 히드록시아파타이트(HA) 디스크 상에 시딩하고, 37℃에서 1시간 동안 인큐베이션 하였다. 결과는 Crystal Violet으로 염색된 세포의 값으로 표시되고, 평균±표준표차(n=3)로 나타낸다.
도 5는 배양 1시간 후, FNRGD 또는 FNRGD/OC-고정된 히드록시아파타이트(HA) 디스크 상에서 배양된 MC3T3-E1 세포의 전자 현미경 사진이다.
도 6은 14일째에 FNRGD 또는 FNRGD/OC-고정된 히드록시아파타이트(HA) 디스크 상에서 배양된 MC3T3-E1 조골세포의 상대적 ALP활성을 나타낸다. 염기성 인산분해효소의 촉매능을 결정하기 위해, MC3T3-E1 조골세포을 히드록시아파타이트(HA) 디스크 상에 2주 동안 배양하였다. 처리되지 않은 히드록시아파타이트(HA) 디스크가 대조군으로 사용되었다. * p < 0.05 (n=3).
도 2는 히드록시아파타이트(HA)에 단백질이 접착된 결과를 나타낸다. 히드록시아파타이트(HA) 디스크는 24 웰 접시 바닥에 놓여졌고, FNRGD 또는 FNRGD/OC 단백질(0.5μM)로 2시간 동안 37℃ 에서 고정되었다. BSA를 대조군으로 사용하였다. 결과는 O.D.값과 평균±표준표차(n=3)로 나타낸다.
도 3은 7일까지 동안 세포가 없는 배양 배지에서 인큐베이션하는 동안 히드록시아파타이트(HA)디스크로부터 FNRGD/OC 가 분리되는 프로파일을 Hig-tag 프루브로 평가한 것이다. 처음 고정된 FNRGD/OC의 대략 70%가 적어도 인큐베이션 7일 동안 남아있었다. 히드록시아파타이트(HA)디스크에 처음 고정된 FNRGD/OC단백질의 양을 100%로 정의한다. 각 데이터 점은 평균±표준표차(n=3)을 나타낸다.
도 4는 FNRGD/OC-고정된 히드록시아파타이트(HA)디스크 상에 MC3T3-E1 조골세포가 부착되는 정도를 확인한 결과이다. MC3T3-E1 세포를 FNRGD 또는 FNRGD/OC 단백질(0.5μM)로 고정된 히드록시아파타이트(HA) 디스크 상에 시딩하고, 37℃에서 1시간 동안 인큐베이션 하였다. 결과는 Crystal Violet으로 염색된 세포의 값으로 표시되고, 평균±표준표차(n=3)로 나타낸다.
도 5는 배양 1시간 후, FNRGD 또는 FNRGD/OC-고정된 히드록시아파타이트(HA) 디스크 상에서 배양된 MC3T3-E1 세포의 전자 현미경 사진이다.
도 6은 14일째에 FNRGD 또는 FNRGD/OC-고정된 히드록시아파타이트(HA) 디스크 상에서 배양된 MC3T3-E1 조골세포의 상대적 ALP활성을 나타낸다. 염기성 인산분해효소의 촉매능을 결정하기 위해, MC3T3-E1 조골세포을 히드록시아파타이트(HA) 디스크 상에 2주 동안 배양하였다. 처리되지 않은 히드록시아파타이트(HA) 디스크가 대조군으로 사용되었다. * p < 0.05 (n=3).
<실시예 1> 세포 배양, 히드록시아파타이트(hydroxyapatite, HA) 제조, RNA 준비 및 cDNA 합성
MC3T3-E1 전조골세포(preosteoblastic cell)는 10% 열-불활성화된 우태아혈청(Invitrogen), 페니실린 G 소디움 100유닛/mL, 스트렙토마이신 설페이트 100㎍/mL, 및 암포테리신 B 0.25㎍/mL를 포함하는 α-MEM(Invitrogen)에서 5% CO2 분위기에서 37℃에서 배양하였다.
히드록시아파타이트(Ca10(PO4)6(OH)2, Alfa Aesar Co., Ward Hill, MA, USA) 분말은 직경 2.5cm의 금속 몰드에서 압축되었고 150MPa에서 냉등압프레스(cold-isostatically press)되었다. 히드록시아파타이트(HA) 디스크를 2시간동안 1250℃에서 소결하였다. 상기 디스크 표본은 1mm 높이, 20mm 직경을 가졌다. 세포 배양을 위하여, 모든 표본은 24시간동안 100% 에탄올에 침지되고 완전히 건조 처리되었다.
MC3T3-E1 세포의 총 RNA는 제조사의 프로토콜에 따라 easy-spin Total RNA Extraction Kit(iNtRON)을 이용하여 준비되었다. 그리고 2㎍ RNA 샘플을 cDNA합성에 사용하였다. 첫 번째 가닥 cDNA는 프라이머 올리고(dT)와 Super ScriptTMⅢ First-Strand Kit(Invitrogen)을 이용하여 합성하였고, 제조사의 프로토콜에 따라 추가 처리되었다.
<실시예 2> 융합단백질 발현 벡터의 제작 및 정제
본 발명자는 특정 세포 바인딩 서열 RGD를 포함하는 인간 피브로넥틴(FN)의 10번째 타입Ⅲ 도메인(FNRGD)을 포함하는 벡터를 제조하였다. 구체적으로 FNRGD를 증폭하기 위해 5'- CTCGAGCAACAATCAACAGTTTC-3'로 기재되는 정방향 프라이머(N-말단 앞에 SacⅠ제한효소 사이트 도입)와 5'- CTCGAGTGGTTTGTCAATTTC-3'로 기재되는 역방향 프라이머(COOH-말단에 SacⅠ제한효소 사이트 포함)를 사용하여 PCR(polymerase Chain Reaction)을 수행하였다. PCR은 프라이머 각 50pmol, 50mM KCl, 10mM Tris-HCl(pH 8.3), 1.5mM MgCl2, 100㎍/ml 젤라틴, 0.2mM dNTPs, 1.25 유닛의 taq polymerase(iNtRON)를 포함하는 30㎕ 반응 용액에서 수행하였다. PCR은 55℃에서 1분 동안 어닐링, 72℃에서 1분 동안 연장, 94℃에서 1분 동안 변성으로 수행하였다. 30회 반복수행 후, 상기 증폭된 PCR 산물을 제한효소 SacⅠ로 절단하였다. 절단된 PCR 산물을 pBAD/His-OC 벡터(Biotechnol Lett. 2007 Nov;29(11):1631-5 참고)의 SacⅠ 위치에 연결하여, 구조물 pBAD/His-FNRGD/OC을 생성하였다. OC는 뼈의 광물 구성성분인 히드록시아파타이트(HA)에 결합하기 위한 보존된 주요 도메인(18-95 a.a.)을 포함한다. 상기 벡터는 매우 조절된 발현을 위해 araBAD 프로모터를 포함하고, 친화성 정제를 위해 아미노-말단 폴리히스티딘 염기서열을 포함하였다.
재조합 FNRGD/OC의 발현을 위해, 대장균의 일종인 E.coli TOP 10 세포를 LB-엠피실린 배지에 접종하여 37℃에서 하룻밤 동안 배양하였다. A600 = 0.6에 도달했을 때, 전사 유도물질 L-아라비노스의 0.02%(w/v)로 전사 유도를 개시하였다. 3시간 후에, 원심분리기로 박테리아를 펠렛화하였고, 용해분리하고 초음파처리하였다. 14,000 x g에서 30분간 냉장 원심분리기에서 원심분리하여 용해된 추출물을 준비하고, 상등액은 새로운 튜브에 옮겼다.
헥사히스티딘 태그를 결합하여, 니켈-나이트릴로트라이아세트산(Ni-NTA) 레진 컬럼(Invitrogen)으로 초음파처리된 박테리아 상등액으로부터 분리된 조단백질을 정제하였다. 재조합 단백질의 정제 정도는 변성조건하에 10%(v/v) SDS-PAGE의 쿠마시 블루염색(Coomassie bule staining)으로 확인하였다.
L- 아라비노스로 유도한 결과, E.Coli TOP 10은 Mr=200,000의 단백질을 생성하였다(SDS-PAGE로 추정). 상기 크기의 단백질은 FNRGD/OC의 융합 단백질과 아미노 말단 His-Tag로 구성된 융합단백질로 예상된다(도 1).
<실시예 3> his-tag 프루브를 이용한 히드록시아파타이트(HA) 부착 분석
히드록시아파타이트(HA)에 FNRGD/OC 단백질이 결합하는 능력은 단백질 부착 분석(Ku et al. 2005)의 변형방법으로 측정하였다. 히드록시아파타이트(HA) 디스크를 6 웰 배양 접시의 바닥에 놓고, 오스테오칼신(OC, 대조군으로 사용), 피브로넥틴RGD(FNRGD) 또는 피브로넥틴RGD/오스테오칼신(FNRGD/OC) 융합 단백질 중 하나와 37℃에서 3시간 동안 부착하게 하였다. 결합 후, 디스크를 37℃에서 1시간 동안 홀스래디시퍼옥시다제(HRP)-접합된 히스티딘 항체(horseradish peroxidase (HRP)-conjugated His antibody, Santa Cruz Biotechnology, Santa Cruz, CA) 에 노출하였다. HRP에 대한 비색기질(Pierce)을 첨가하고, 흡광도 450㎚에서 측정하였다.
FN과 FNRGD/OC의 히드록시아파타이트(HA)에의 부착 특성을 정량적으로 비교한 결과, 도 2에서 나타내는 것처럼 FNRGD/OC 단백질은 FNRGD보다 히드록시아파타이트(HA)에 현저히 더 많이 결합하였다. 또한 도 3에 나타난 것처럼 히드록시아파타이트(HA)에서 FNRGD/OC가 분리되는 프로파일은 고정된 FNRGD/OC의 단백질이 배양 배지에서 7일 동안 처음 양의 70%을 유지함을 증명하였다.
<실시예 4> 세포 부착 분석
히드록시아파타이트(HA)에 부착된 FNRGD/OC의 생물학적 활성을 측정하기 위하여, FNRGD/OC 단백질이 세포 부착을 증진시키는 능력을 측정하였다.
24시간 동안 혈청 기아 상태인 MC3T3-E1 세포를 0.02%(w/v) 트립신이 들어있는 1mM EDTA로 세포를 수집하고, α-MEM에 재현탁하였다. 세포를 100㎎/㎖ 콩 트립신 저해제와 1%(w/v) BSA이 첨가된 α-MEM로 3차례 세척한 후, α-MEM 중 웰당 5 x 104개의 세포를 도말하였다. 24웰 플레이트를 4℃에서 하룻밤 동안 단백질과 반응시켜 단백질로 코팅하였고, 37℃에서 1시간 동안 0.5% BSA 포함한 PBS와 인큐베이션 하여 비특이적 부착을 차단하였다. 부착된 세포는 PBS로 2차례 세척하고, 3% (w/v) 파라포름알데하이드(Sigma)로 고정하고, 2% 에탄올/물(v/v)에 들어있는 0.25% (w/v) 크리스탈 바이올렛(Crystal violet, Sigma)용액으로 염색하였다. 멸균수로 플레이트 전체를 세척한 후 건조하였다. 570nm에서 흡광도를 측정하였고, 이것은 부착된 세포의 수와의 관계를 나타낸다.
단백질의 세포 부착 최대 증가 농도를 결정하기 위하여, MC3T3-E1 세포를 세럼-프리 배지에 재 현탁하고, 재조합 FNRGD 또는 FNRGD/OC가 고정화된 히드록시아파타이트(HA) 디스크 상에 도말하여 1시간 인큐베이션 한 후, 각 히드록시아파타이트(HA) 디스크 내 세포 개수를 계수하였다. 세포부착의 최대 증가는 0.5μM에서 있었으므로 0.5μM농도의 단백질을 실험에 사용하였다.
부착 실험 결과, 도 4에서 보이는 것처럼, 부착된 세포의 수는 FNRGD단백질 코팅된 플레이트에서 관찰된 것보다 FNRGD/OC단백질에서 더 높았다(p<0.05). 상기 결과는 FNRGD/OC 융합단백질이 뼈 무기물 히드록시아파타이트(HA)에 높은 친화성을 갖는 오스테오칼신(OC)의 특성을 유지하면서 세포 접착도 증진시킨다는 것을 의미한다.
<실시예 5> 염기성 인산분해 효소(alkaline phosphatase, ALP)의 활성 측정
ALP는 조골세포의 분화에서 뼈 형성 마커로 생각되어 왔다. 따라서 ALP활성에 대한 FNRGD/OC의 효과를 통하여 뼈 형성에 대한 FNRGD/OC의 효과를 예측할 수 있을 것이다.
ALP의 활성을 측정하기 위해, MC3T3 세포를 4일 동안 배양하고, 인산완충용액(PBS)으로 세척하였다. 그리고 1mM ZnCl2, 1mM MgCl2 과 1% 트립톤 X-100 을 포함하는 1.5M Tris-HCl(pH=10.2)로 4℃에서 10분간 용해하였다. 이어서 원심분리하고, 세포 용해물에 대하여 제조사의 방법에 따라 알칼리 인산 분석 키트(Alkaline Phosphate Assay Kit, Sigma Dignostics)로 ALP의 활성을 분석하였다. 염기성 인산분해효소가 존재하면 황색의 p-니트로페놀(p-Nitrophenol)을 생성하였고, 마이크로플레이트 판독기(BioRad Laboratories)를 이용하여 405㎚에서 흡광도를 측정하였다. ALP활성을 BCA 단백질 분석 키트(BCA protein Assay Kit, Sigma)를 이용하여 각 표본의 총 단백질 함량으로 표준화하였다. p-니트로페놀(sigma)로 표준곡선을 작성하였다. BCA 단백질 분석 프로토콜(Pierce)로 측정된 세포 용해물의 단백질 함량으로 각 값을 표준화하였다.
그 결과, 도 6에서 나타난 것처럼 FNRGD-고정된 히드록시아파타이트(HA) 디스크 상에 있는 세포에서는 ALP가 낮은 수준으로 발현하였다. 그러나 FNRGD/OC가 히드록시아파타이트(HA) 디스크에 고정된 후에는 ALP활성의 현저한 증가가 관찰되었다. 상기 결과는 히드록시아파타이트(HA) 디스크에 고정된 FNRGD/OC은 히드록시아파타이트(HA)디스크 상의 MC3TC-E1세포의 ALP활성의 발현을 자극하고 상기 ALP 활성은 히드록시아파타이트(HA) 에 고정된 FNRGD/OC로 증진된다는 것을 의미한다.
<110> Industry-Academic Cooperation Foundation, Dankook University
<120> Fusion protein using for bone and teeth regeneration
<130> PA100673/KR
<160> 8
<170> KopatentIn 1.71
<210> 1
<211> 103
<212> PRT
<213> Homo sapiens
<400> 1
Gln Gln Ser Thr Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala
1 5 10 15
Ala Thr Pro Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr
20 25 30
Val Arg Tyr Tyr Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro
35 40 45
Val Gln Glu Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser
50 55 60
Gly Leu Lys Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr
65 70 75 80
Gly Arg Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr
85 90 95
Arg Thr Glu Ile Asp Lys Pro
100
<210> 2
<211> 78
<212> PRT
<213> Mus musculus
<400> 2
Ser Asp Leu Thr Asp Ala Lys Pro Ser Gly Pro Glu Ser Asp Lys Ala
1 5 10 15
Phe Met Ser Lys Gln Glu Gly Asn Lys Val Val Asn Arg Leu Arg Arg
20 25 30
Tyr Leu Gly Ala Ser Val Pro Ser Pro Asp Pro Leu Glu Pro Thr Arg
35 40 45
Glu Gln Cys Glu Leu Asn Pro Ala Cys Asp Glu Leu Ser Asp Gln Tyr
50 55 60
Gly Leu Lys Thr Ala Tyr Lys Arg Ile Tyr Gly Ile Thr Ile
65 70 75
<210> 3
<211> 309
<212> DNA
<213> Homo sapiens
<400> 3
caacaatcaa cagtttctga tgttccgagg gacctggaag ttgttgctgc gacccccacc 60
agcctactga tcagctggga tgctcctgct gtcacagtga gatattacag gatcacttac 120
ggagaaacag gaggaaatag ccctgtccag gagttcactg tgcctgggag caagtctaca 180
gctaccatca gcggccttaa acctggagtt gattatacca tcactgtgta tgctgtcact 240
ggccgtggag acagccccgc aagcagcaag ccaatttcca ttaattaccg aacagaaatt 300
gacaaacca 309
<210> 4
<211> 237
<212> DNA
<213> Mus musculus
<400> 4
tctgacctca cagatgccaa gcccagcggc cctgagtctg acaaagcctt catgtccaag 60
caggagggca ataaggtagt gaacagactc cggcgctacc ttggagcctc agtccccagc 120
ccagatcccc tggagcccac ccgggagcag tgtgagctta accctgcttg tgacgagcta 180
tcagaccagt atggcttgaa gaccgcctac aaacgcatct acggtatcac tatttag 237
<210> 5
<211> 189
<212> PRT
<213> Artificial Sequence
<220>
<223> fusion protein
<400> 5
Gln Gln Ser Thr Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala
1 5 10 15
Ala Thr Pro Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr
20 25 30
Val Arg Tyr Tyr Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro
35 40 45
Val Gln Glu Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser
50 55 60
Gly Leu Lys Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr
65 70 75 80
Gly Arg Gly Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr
85 90 95
Arg Thr Glu Ile Asp Lys Pro Leu Gln Ile Cys Ser Trp Tyr His Ser
100 105 110
Asp Leu Thr Asp Ala Lys Pro Ser Gly Pro Glu Ser Asp Lys Ala Phe
115 120 125
Met Ser Lys Gln Glu Gly Asn Lys Val Val Asn Arg Leu Arg Arg Tyr
130 135 140
Leu Gly Ala Ser Val Pro Ser Pro Asp Pro Leu Glu Pro Thr Arg Glu
145 150 155 160
Gln Cys Glu Leu Asn Pro Ala Cys Asp Glu Leu Ser Asp Gln Tyr Gly
165 170 175
Leu Lys Thr Ala Tyr Lys Arg Ile Tyr Gly Ile Thr Ile
180 185
<210> 6
<211> 570
<212> DNA
<213> Artificial Sequence
<220>
<223> nucleotide encoding fusion protein
<400> 6
caacaatcaa cagtttctga tgttccgagg gacctggaag ttgttgctgc gacccccacc 60
agcctactga tcagctggga tgctcctgct gtcacagtga gatattacag gatcacttac 120
ggagaaacag gaggaaatag ccctgtccag gagttcactg tgcctgggag caagtctaca 180
gctaccatca gcggccttaa acctggagtt gattatacca tcactgtgta tgctgtcact 240
ggccgtggag acagccccgc aagcagcaag ccaatttcca ttaattaccg aacagaaatt 300
gacaaaccac tcgagatctg cagctggtac cattctgacc tcacagatgc caagcccagc 360
ggccctgagt ctgacaaagc cttcatgtcc aagcaggagg gcaataaggt agtgaacaga 420
ctccggcgct accttggagc ctcagtcccc agcccagatc ccctggagcc cacccgggag 480
cagtgtgagc ttaaccctgc ttgtgacgag ctatcagacc agtatggctt gaagaccgcc 540
tacaaacgca tctacggtat cactatttag 570
<210> 7
<211> 2328
<212> PRT
<213> Homo sapiens
<400> 7
Lys Ser Lys Arg Gln Ala Gln Gln Met Val Gln Pro Gln Ser Pro Val
1 5 10 15
Ala Val Ser Gln Ser Lys Pro Gly Cys Tyr Asp Asn Gly Lys His Tyr
20 25 30
Gln Ile Asn Gln Gln Trp Glu Arg Thr Tyr Leu Gly Asn Val Leu Val
35 40 45
Cys Thr Cys Tyr Gly Gly Ser Arg Gly Phe Asn Cys Glu Ser Lys Pro
50 55 60
Glu Ala Glu Glu Thr Cys Phe Asp Lys Tyr Thr Gly Asn Thr Tyr Arg
65 70 75 80
Val Gly Asp Thr Tyr Glu Arg Pro Lys Asp Ser Met Ile Trp Asp Cys
85 90 95
Thr Cys Ile Gly Ala Gly Arg Gly Arg Ile Ser Cys Thr Ile Ala Asn
100 105 110
Arg Cys His Glu Gly Gly Gln Ser Tyr Lys Ile Gly Asp Thr Trp Arg
115 120 125
Arg Pro His Glu Thr Gly Gly Tyr Met Leu Glu Cys Val Cys Leu Gly
130 135 140
Asn Gly Lys Gly Glu Trp Thr Cys Lys Pro Ile Ala Glu Lys Cys Phe
145 150 155 160
Asp His Ala Ala Gly Thr Ser Tyr Val Val Gly Glu Thr Trp Glu Lys
165 170 175
Pro Tyr Gln Gly Trp Met Met Val Asp Cys Thr Cys Leu Gly Glu Gly
180 185 190
Ser Gly Arg Ile Thr Cys Thr Ser Arg Asn Arg Cys Asn Asp Gln Asp
195 200 205
Thr Arg Thr Ser Tyr Arg Ile Gly Asp Thr Trp Ser Lys Lys Asp Asn
210 215 220
Arg Gly Asn Leu Leu Gln Cys Ile Cys Thr Gly Asn Gly Arg Gly Glu
225 230 235 240
Trp Lys Cys Glu Arg His Thr Ser Val Gln Thr Thr Ser Ser Gly Ser
245 250 255
Gly Pro Phe Thr Asp Val Arg Ala Ala Val Tyr Gln Pro Gln Pro His
260 265 270
Pro Gln Pro Pro Pro Tyr Gly His Cys Val Thr Asp Ser Gly Val Val
275 280 285
Tyr Ser Val Gly Met Gln Trp Leu Lys Thr Gln Gly Asn Lys Gln Met
290 295 300
Leu Cys Thr Cys Leu Gly Asn Gly Val Ser Cys Gln Glu Thr Ala Val
305 310 315 320
Thr Gln Thr Tyr Gly Gly Asn Leu Asn Gly Glu Pro Cys Val Leu Pro
325 330 335
Phe Thr Tyr Asn Gly Arg Thr Phe Tyr Ser Cys Thr Thr Glu Gly Arg
340 345 350
Gln Asp Gly His Leu Trp Cys Ser Thr Thr Ser Asn Tyr Glu Gln Asp
355 360 365
Gln Lys Tyr Ser Phe Cys Thr Asp His Thr Val Leu Val Gln Thr Gln
370 375 380
Gly Gly Asn Ser Asn Gly Ala Leu Cys His Phe Pro Phe Leu Tyr Asn
385 390 395 400
Asn His Asn Tyr Thr Asp Cys Thr Ser Glu Gly Arg Arg Asp Asn Met
405 410 415
Lys Trp Cys Gly Thr Thr Gln Asn Tyr Asp Ala Asp Gln Lys Phe Gly
420 425 430
Phe Cys Pro Met Ala Ala His Glu Glu Ile Cys Thr Thr Asn Glu Gly
435 440 445
Val Met Tyr Arg Ile Gly Asp Gln Trp Asp Lys Gln His Asp Met Gly
450 455 460
His Met Met Arg Cys Thr Cys Val Gly Asn Gly Arg Gly Glu Trp Thr
465 470 475 480
Cys Ile Ala Tyr Ser Gln Leu Arg Asp Gln Cys Ile Val Asp Asp Ile
485 490 495
Thr Tyr Asn Val Asn Asp Thr Phe His Lys Arg His Glu Glu Gly His
500 505 510
Met Leu Asn Cys Thr Cys Phe Gly Gln Gly Arg Gly Arg Trp Lys Cys
515 520 525
Asp Pro Val Asp Gln Cys Gln Asp Ser Glu Thr Gly Thr Phe Tyr Gln
530 535 540
Ile Gly Asp Ser Trp Glu Lys Tyr Val His Gly Val Arg Tyr Gln Cys
545 550 555 560
Tyr Cys Tyr Gly Arg Gly Ile Gly Glu Trp His Cys Gln Pro Leu Gln
565 570 575
Thr Tyr Pro Ser Ser Ser Gly Pro Val Glu Val Phe Ile Thr Glu Thr
580 585 590
Pro Ser Gln Pro Asn Ser His Pro Ile Gln Trp Asn Ala Pro Gln Pro
595 600 605
Ser His Ile Ser Lys Tyr Ile Leu Arg Trp Arg Pro Lys Asn Ser Val
610 615 620
Gly Arg Trp Lys Glu Ala Thr Ile Pro Gly His Leu Asn Ser Tyr Thr
625 630 635 640
Ile Lys Gly Leu Lys Pro Gly Val Val Tyr Glu Gly Gln Leu Ile Ser
645 650 655
Ile Gln Gln Tyr Gly His Gln Glu Val Thr Arg Phe Asp Phe Thr Thr
660 665 670
Thr Ser Thr Ser Thr Pro Val Thr Ser Asn Thr Val Thr Gly Glu Thr
675 680 685
Thr Pro Phe Ser Pro Leu Val Ala Thr Ser Glu Ser Val Thr Glu Ile
690 695 700
Thr Ala Ser Ser Phe Val Val Ser Trp Val Ser Ala Ser Asp Thr Val
705 710 715 720
Ser Gly Phe Arg Val Glu Tyr Glu Leu Ser Glu Glu Gly Asp Glu Pro
725 730 735
Gln Tyr Leu Asp Leu Pro Ser Thr Ala Thr Ser Val Asn Ile Pro Asp
740 745 750
Leu Leu Pro Gly Arg Lys Tyr Ile Val Asn Val Tyr Gln Ile Ser Glu
755 760 765
Asp Gly Glu Gln Ser Leu Ile Leu Ser Thr Ser Gln Thr Thr Ala Pro
770 775 780
Asp Ala Pro Pro Asp Pro Thr Val Asp Gln Val Asp Asp Thr Ser Ile
785 790 795 800
Val Val Arg Trp Ser Arg Pro Gln Ala Pro Ile Thr Gly Tyr Arg Ile
805 810 815
Val Tyr Ser Pro Ser Val Glu Gly Ser Ser Thr Glu Leu Asn Leu Pro
820 825 830
Glu Thr Ala Asn Ser Val Thr Leu Ser Asp Leu Gln Pro Gly Val Gln
835 840 845
Tyr Asn Ile Thr Ile Tyr Ala Val Glu Glu Asn Gln Glu Ser Thr Pro
850 855 860
Val Val Ile Gln Gln Glu Thr Thr Gly Thr Pro Arg Ser Asp Thr Val
865 870 875 880
Pro Ser Pro Arg Asp Leu Gln Phe Val Glu Val Thr Asp Val Lys Val
885 890 895
Thr Ile Met Trp Thr Pro Pro Glu Ser Ala Val Thr Gly Tyr Arg Val
900 905 910
Asp Val Ile Pro Val Asn Leu Pro Gly Glu His Gly Gln Arg Leu Pro
915 920 925
Ile Ser Arg Asn Thr Phe Ala Glu Val Thr Gly Leu Ser Pro Gly Val
930 935 940
Thr Tyr Tyr Phe Lys Val Phe Ala Val Ser His Gly Arg Glu Ser Lys
945 950 955 960
Pro Leu Thr Ala Gln Gln Thr Thr Lys Leu Asp Ala Pro Thr Asn Leu
965 970 975
Gln Phe Val Asn Glu Thr Asp Ser Thr Val Leu Val Arg Trp Thr Pro
980 985 990
Pro Arg Ala Gln Ile Thr Gly Tyr Arg Leu Thr Val Gly Leu Thr Arg
995 1000 1005
Arg Gly Gln Pro Arg Gln Tyr Asn Val Gly Pro Ser Val Ser Lys Tyr
1010 1015 1020
Pro Leu Arg Asn Leu Gln Pro Ala Ser Glu Tyr Thr Val Ser Leu Val
1025 1030 1035 1040
Ala Ile Lys Gly Asn Gln Glu Ser Pro Lys Ala Thr Gly Val Phe Thr
1045 1050 1055
Thr Leu Gln Pro Gly Ser Ser Ile Pro Pro Tyr Asn Thr Glu Val Thr
1060 1065 1070
Glu Thr Thr Ile Val Ile Thr Trp Thr Pro Ala Pro Arg Ile Gly Phe
1075 1080 1085
Lys Leu Gly Val Arg Pro Ser Gln Gly Gly Glu Ala Pro Arg Glu Val
1090 1095 1100
Thr Ser Asp Ser Gly Ser Ile Val Val Ser Gly Leu Thr Pro Gly Val
1105 1110 1115 1120
Glu Tyr Val Tyr Thr Ile Gln Val Leu Arg Asp Gly Gln Glu Arg Asp
1125 1130 1135
Ala Pro Ile Val Asn Lys Val Val Thr Pro Leu Ser Pro Pro Thr Asn
1140 1145 1150
Leu His Leu Glu Ala Asn Pro Asp Thr Gly Val Leu Thr Val Ser Trp
1155 1160 1165
Glu Arg Ser Thr Thr Pro Asp Ile Thr Gly Tyr Arg Ile Thr Thr Thr
1170 1175 1180
Pro Thr Asn Gly Gln Gln Gly Asn Ser Leu Glu Glu Val Val His Ala
1185 1190 1195 1200
Asp Gln Ser Ser Cys Thr Phe Asp Asn Leu Ser Pro Gly Leu Glu Tyr
1205 1210 1215
Asn Val Ser Val Tyr Thr Val Lys Asp Asp Lys Glu Ser Val Pro Ile
1220 1225 1230
Ser Asp Thr Ile Ile Pro Ala Val Pro Pro Pro Thr Asp Leu Arg Phe
1235 1240 1245
Thr Asn Ile Gly Pro Asp Thr Met Arg Val Thr Trp Ala Pro Pro Pro
1250 1255 1260
Ser Ile Asp Leu Thr Asn Phe Leu Val Arg Tyr Ser Pro Val Lys Asn
1265 1270 1275 1280
Glu Glu Asp Val Ala Glu Leu Ser Ile Ser Pro Ser Asp Asn Ala Val
1285 1290 1295
Val Leu Thr Asn Leu Leu Pro Gly Thr Glu Tyr Val Val Ser Val Ser
1300 1305 1310
Ser Val Tyr Glu Gln His Glu Ser Thr Pro Leu Arg Gly Arg Gln Lys
1315 1320 1325
Thr Gly Leu Asp Ser Pro Thr Gly Ile Asp Phe Ser Asp Ile Thr Ala
1330 1335 1340
Asn Ser Phe Thr Val His Trp Ile Ala Pro Arg Ala Thr Ile Thr Gly
1345 1350 1355 1360
Tyr Arg Ile Arg His His Pro Glu His Phe Ser Gly Arg Pro Arg Glu
1365 1370 1375
Asp Arg Val Pro His Ser Arg Asn Ser Ile Thr Leu Thr Asn Leu Thr
1380 1385 1390
Pro Gly Thr Glu Tyr Val Val Ser Ile Val Ala Leu Asn Gly Arg Glu
1395 1400 1405
Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser Thr Val Ser Asp Val Pro
1410 1415 1420
Arg Asp Leu Glu Val Val Ala Ala Thr Pro Thr Ser Leu Leu Ile Ser
1425 1430 1435 1440
Trp Asp Ala Pro Ala Val Thr Val Arg Tyr Tyr Arg Ile Thr Tyr Gly
1445 1450 1455
Glu Thr Gly Gly Asn Ser Pro Val Gln Glu Phe Thr Val Pro Gly Ser
1460 1465 1470
Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys Pro Gly Val Asp Tyr Thr
1475 1480 1485
Ile Thr Val Tyr Ala Val Thr Gly Arg Gly Asp Ser Pro Ala Ser Ser
1490 1495 1500
Lys Pro Ile Ser Ile Asn Tyr Arg Thr Glu Ile Asp Lys Pro Ser Gln
1505 1510 1515 1520
Met Gln Val Thr Asp Val Gln Asp Asn Ser Ile Ser Val Lys Trp Leu
1525 1530 1535
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> 8
<211> 95
<212> PRT
<213> Mus musculus
<400> 8
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
Claims (14)
- Arg-Gly-Asp(RGD) 서열을 포함하는 피브로넥틴 도메인 및 서열번호 2의 아미노산 서열로 구성된 인간 유래 오스테오칼신 도메인을 포함하는 융합 단백질.
- 제1항에 있어서, 상기 단백질은 히드록시아파타이트(HA)에 결합하고 인테그린 매개 세포 부착을 촉진하는 것인 융합 단백질.
- 제1항에 있어서, 상기 피브로넥틴 도메인은 피브로넥틴의 10번째 타입Ⅲ 반복 단위이고 RGD 서열을 포함하는 것인 융합 단백질.
- 삭제
- 제1항에 있어서, 상기 피브로넥틴 도메인은 서열번호 1의 아미노산 서열로 구성되는 융합 단백질.
- 삭제
- 제1항에 있어서, 상기 단백질은 서열번호 5의 아미노산 서열로 구성되는 것을 특징으로 하는 융합 단백질.
- 제1항의 단백질을 코딩하는 뉴클레오타이드 서열로 구성되는 핵산.
- 제8항에 있어서, 상기 핵산은 서열번호 5의 아미노산 서열로 구성된 단백질을 코딩하는 뉴클레오타이드 서열로 구성되는 핵산.
- 제9항에 있어서, 상기 핵산은 서열번호 6의 뉴클레오타이드 서열로 구성되는 핵산.
- 제1항의 단백질을 포함하는 뼈 또는 치아 재생용 조성물.
- 삭제
- 제1항의 단백질을 히드록시아파타이트(HA) 로 구성된 구조물에 코팅하는 단계; 및 상기 코팅된 구조물에 조골세포를 부착시키는 단계를 포함하는 뼈 또는 치아 재생 방법.
- 히드록시아파타이트(HA) 로 구성된 구조물로서, 제1항의 단백질로 코팅된 것을 특징으로 하는 구조물.
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| PCT/KR2011/007011 WO2012070758A2 (ko) | 2010-11-26 | 2011-09-23 | 치아 및 뼈 재생을 위한 융합 단백질 |
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| KR101317515B1 (ko) * | 2012-06-20 | 2013-10-15 | 인하대학교 산학협력단 | 피브로넥틴-오스테오칼신 융합 단백질이 코팅된 뼈 재생용 스캐폴드 |
| WO2015147616A1 (ko) * | 2014-03-28 | 2015-10-01 | 연세대학교 산학협력단 | Rgd 모티프를 포함하는 펩타이드 또는 단백질을 포함하는 신경염증 예방, 억제 또는 치료용 조성물 |
| KR101595063B1 (ko) * | 2014-04-24 | 2016-02-18 | 단국대학교 천안캠퍼스 산학협력단 | 세포결합 서열, 헤파린 결합 도메인 및 오스테오칼신 도메인을 포함하는 융합단백질 및 이를 포함하는 약학 조성물 |
| KR102353524B1 (ko) * | 2019-02-27 | 2022-01-20 | 주식회사 대웅제약 | 알부민이 결합된, Slit3 단백질의 LRRD2를 포함하는 골 관련 질환 예방 또는 치료용 조성물 |
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Non-Patent Citations (1)
| Title |
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| osteocalcin과 fibronectin의 융합 단백질에 관한 연구, 인하대학교 대학원 의학석사논문. 김지현 (2007.06).. * |
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| Publication number | Publication date |
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| WO2012070758A3 (ko) | 2012-07-19 |
| WO2012070758A2 (ko) | 2012-05-31 |
| KR20120057429A (ko) | 2012-06-05 |
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