KR20180034291A - Kit for treating osteoarthritis with alleviating pain - Google Patents
Kit for treating osteoarthritis with alleviating pain Download PDFInfo
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- KR20180034291A KR20180034291A KR1020170125591A KR20170125591A KR20180034291A KR 20180034291 A KR20180034291 A KR 20180034291A KR 1020170125591 A KR1020170125591 A KR 1020170125591A KR 20170125591 A KR20170125591 A KR 20170125591A KR 20180034291 A KR20180034291 A KR 20180034291A
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- mesenchymal stem
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Abstract
Description
본 발명은 STAT3 억제제가 처리된 간엽줄기세포를 유효성분으로 포함하는 정맥내 투여용 조성물 및 간엽줄기세포를 유효성분으로 포함하는 관절강내 투여용 조성물을 포함하는 통증이 경감되는 골관절염 치료용 키트, 및 이를 이용한 골관절염 예방 및 치료를 위한 정보 제공 방법에 관한 것이다.The present invention relates to a pain relieving kit for treating osteoarthritis comprising a composition for intravenous administration containing a mesenchymal stem cell treated with a STAT3 inhibitor as an active ingredient and a composition for intraarticular administration containing mesenchymal stem cells as an active ingredient, And a method for providing information for prevention and treatment of osteoarthritis using the same.
골관절염은 퇴행성 관절염으로도 명명되는 관절염의 일종으로서, 특정한 기질적 원인이 없이 주로 노년에 많이 발생되며 만성적으로 진행되면 관절구조의 변형으로 보행 장애 등의 운동 장애를 수반한다. 골관절염은 주로 관절연골(cartilage)의 점진적인 손상이나 퇴행성 변화로 인해 관절을 이루는 뼈와 인대 등에 손상이 일어나서 염증과 통증이 발생된다. Osteoarthritis is a kind of arthritis, which is also called degenerative arthritis. It occurs mainly in old age without any specific cause, and when it progresses chronically, deformation of joint structure leads to movement disorder such as walking disorder. Osteoarthritis is mainly caused by progressive damage or degenerative changes of the cartilage, resulting in damage to the bones and ligaments of the joints, resulting in inflammation and pain.
골관절염이 진행될 때 TNF-α, IL-1 등의 염증성 사이토카인(cytokine)의 생성이 증가하고 콜라게네이즈(collagenase), 스트로멜라이신(stromelysin) 등과 같은 MMPs의 분비가 증가되어 관절연골의 파괴가 이루어지게 된다. 또한 MMPs는 IL-1, TNF-α 등을 유도시키게 되는데 이로 인하여 근육, 건, 인대 등과 같은 조직에도 영향을 끼쳐 심한 통증을 일으킨다.When osteoarthritis progresses, the production of inflammatory cytokines such as TNF-α and IL-1 is increased and the secretion of MMPs such as collagenase and stromelysin is increased, leading to destruction of articular cartilage . In addition, MMPs induce IL-1, TNF-α, etc., which in turn affect tissues such as muscles, tendons, ligaments, etc., resulting in severe pain.
현재 골관절염의 치료를 위해서는, 아세트아미노펜, 트라마돌, 비스테로이드성 항염제(NSAIDs), 디아세린, 글루코사민 등의 약물이 사용되고 있으나, 골관절염의 통증을 일시적으로 경감시키는데 그치고 있다. 이에 따라, 골관절염을 치료하면서도 통증을 효과적으로 경감시킬 수 있는 치료법에 대한 필요성이 대두되고 있다.Drugs such as acetaminophen, tramadol, nonsteroidal anti-inflammatory drugs (NSAIDs), diacerein, and glucosamine have been used for the treatment of osteoarthritis at present, but they only temporarily alleviate the pain of osteoarthritis. Accordingly, there is a need for a treatment method that effectively alleviates pain while treating osteoarthritis.
본 발명의 목적은 STAT3(Signal transducer and activator of transcription 3) 억제제가 처리된 간엽줄기세포를 유효성분으로 포함하는 정맥내 투여용 조성물; 및 간엽줄기세포를 유효성분으로 포함하는 관절강내 투여용 조성물을 포함하는, 통증이 경감되는 골관절염 치료용 키트를 제공하는 것이다.An object of the present invention is to provide a composition for intravenous administration comprising mesenchymal stem cells treated with STAT3 (signal transducer and activator of transcription 3) inhibitor as an active ingredient; And mesenchymal stem cells as an effective ingredient. The present invention also provides a kit for treating osteoarthritis in which pain is alleviated.
본 발명의 또 다른 목적은 STAT3(Signal transducer and activator of transcription 3) 억제제가 처리된 간엽줄기세포를 유효성분으로 포함하는 조성물을 정맥내 투여하고, 동시에 간엽줄기세포를 유효성분으로 포함하는 조성물을 관절강내 투여하는 단계를 포함하는 골관절염 예방 및 치료를 위한 정보 제공 방법을 제공하는 것이다.It is another object of the present invention to provide a composition comprising, as an active ingredient, a mesenchymal stem cell treated with a STAT3 (signal transducer and activator of transcription 3) inhibitor, intravenously, and simultaneously administering a composition comprising mesenchymal stem cells as an active ingredient, And a method for providing information for prevention and treatment of osteoarthritis.
상기 목적을 달성하기 위하여, 본 발명은 STAT3(Signal transducer and activator of transcription 3) 억제제가 처리된 간엽줄기세포를 유효성분으로 포함하는 정맥내 투여용 조성물; 및 간엽줄기세포를 유효성분으로 포함하는 관절강내 투여용 조성물을 포함하는, 통증이 경감되는 골관절염 치료용 키트를 제공한다.In order to achieve the above object, the present invention provides a composition for intravenous administration comprising mesenchymal stem cells treated with STAT3 (signal transducer and activator of transcription 3) inhibitor as an active ingredient; And mesenchymal stem cells as an active ingredient. The present invention also provides a kit for treating osteoarthritis in which pain is alleviated.
본 발명의 일 실시예에 있어서, 상기 관절강내 투여용 조성물은 STAT3 억제제가 처리될 수 있다.In one embodiment of the present invention, the composition for intra-articular administration may be treated with a STAT3 inhibitor.
본 발명의 일 실시예에 있어서, 상기 STAT3 억제제는 STA-21 (8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12(2H)-trione), SD282, 메트포민, AG-490 ((E)-2-Cyano-3-(3,4-dihydrophenyl)-N-(phenylmethyl)-2-propenamide), 아티프리모드 (Atiprimod; 3-(8,8-dipropyl-3-azaspiro[4.5]decan-3-yl)-N,N- diethylpropan-1-amine), 오라노핀 (Auranofin; 3,4,5-triacetyloxy-6- (acetyloxymethyl) oxane-2-thiolate; triethylphosphanium), 오로싸이오말레이트 (Aurothiomalate; Sodium 2-(auriosulfanyl)-3-carboxypropanoate), BMS-354825 (Dasatinib; N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate), CADPE (3-(3,4-dihydroxy-phenyl)-acrylic acid 2-(3,4-dihydroxy-phenyl)-ethyl ester), 스타틱 (Stattic; 6-nitro-1,1-dioxide-benzo[b]thiophene), 도베실레이트 (Dobesilate; calcium 2,5-dihydroxybenzenesulfonate), 에탄올(Ethanol), NCX-4016(NO-Aspirin), 넬피나비어(Nelfinavir; (3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylphenyl)formamido]-4-(phenylsulfanyl)butyl]-decahydroisoquinoline-3-carboxamide), PDP(phosphododecapeptide), PS-341(볼테조밉(Bortezomib); [(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid), R115777(티피파르닙(tipifarnib); 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one), S31-M2001(N-Hexyl-2-(1-naphthalenyl)-5-[[4-(phosphonooxy)phenyl]), 스타틴계 화합물, 소듐살리실레이트(Sodium Salicylate), 카페익산(Caffeic acid; 3-(3,4-Dihydroxyphenyl)-2-propenoic acid 3,4-Dihydroxy-cinnamic acid trans-Caffeate 3,4-Dihydroxy-trans-cinnamate)), 에모딘(Emodin; 1,8-Dihydroxy-3-(hydroxymethyl)-9,10-anthracenedione), 우르솔릭산(Ursolic acid; 3-beta-3-hydroxy-urs-12-ene-28-oic-acid), 레스베라트롤(Resveratrol; 3,5,4'-trihydroxy-trans-stilbene), 레티노익산(Retinoic acid; (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid), EGCG(Epigallocatechin gallate; [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl] 3,4,5-trihydroxybenzoate), Sr11302((E,E,Z,E)-3-Methyl-7-(4-methylphenyl)-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid), 탄시논 IIA(Tanshinone IIA; 1,6,6-Trimethyl-6,7,8,9-tetrahydrophenanthro[1,2-b]furan-10,11-dione) 및 커큐민(curcumin; (1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione)으로 이루어진 군으로부터 선택되는 하나 이상일 수 있다. 예를 들어, 상기 STAT3 억제제는 STA-21, SD282 또는 메트포민일 수 있다.In one embodiment of the present invention, the STAT3 inhibitor is selected from the group consisting of STA-21 (8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12 (E) -2-Cyano-3- (3,4-dihydrophenyl) -N- (phenylmethyl) -2-propenamide, Atiprimod 3- (8,8-dipropyl-3-azaspiro [4.5 ] decan-3-yl) -N, N-diethylpropan-1-amine, Auranofin (3,4,5-acetyloxymethyl) oxane-2-thiolate, (2-chloro-6-methylphenyl) -2 - [[6- [4- (2-hydroxyethyl) -1- (3,4-dihydroxy-phenyl) -acrylic acid 2- (3,4-dihydroxy-phenyl) -methyl-4-pyrimidinyl amino] -5-thiazole carboxamide monohydrate), CADPE ester, stattic, 6-nitro-1,1-dioxide-benzo [b] thiophene, calcium 2,5-dihydroxybenzenesulfonate, ethanol, NCX- Aspirin, Nelfinavir ((3S, 4aS, 8aS) -N-tert- 3-carboxamide, PDP (phosphododecapeptide), 3-hydroxy-2 - [(2R, 3R) -2-hydroxy- PS-341 (Bortezomib; 2-ylcarbonyl) amino] propanoyl} amino) butyl] boronic acid, R115777 (tipifarnib (R) (1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methylquinolin-2 (N-Hexyl-2- (1-naphthalenyl) -5 - [[4- (phosphonooxy) phenyl], statin compound, sodium salicylate, caffeic acid 3- 4-Dihydroxyphenyl) -2-
본 발명의 일 실시예에 있어서, 상기 정맥내 투여용 조성물의 투여 후 바로 상기 관절강내 투여용 조성물을 투여하거나, 상기 관절강내 투여용 조성물을 투여한 후 바로 상기 정맥내 투여용 조성물을 투여하거나, 또는 상기 정맥내 투여용 조성물과 상기 관절강내 투여용 조성물을 동시에 투여할 수 있다. In one embodiment of the present invention, the composition for intra-articular administration is administered immediately after administration of the composition for intravenous administration, the composition for intravenous administration is administered immediately after administration of the composition for intra-articular administration, Alternatively, the composition for intravenous administration and the composition for intraarticular administration may be administered simultaneously.
본 발명의 일 실시예에 있어서, 상기 STAT3 억제제가 처리된 간엽줄기세포는 통증을 경감시킬 수 있다.In one embodiment of the present invention, the STAT3 inhibitor treated mesenchymal stem cells may alleviate the pain.
본 발명의 일 실시예에 있어서, 상기 간엽줄기세포는 골관절염 환자의 말초혈액 또는 지방조직으로부터 분리된 것일 수 있다.In one embodiment of the present invention, the mesenchymal stem cells may be isolated from peripheral blood or adipose tissue in osteoarthritis patients.
또한 본 발명은 STAT3(Signal transducer and activator of transcription 3) 억제제가 처리된 간엽줄기세포를 유효성분으로 포함하는 조성물을 정맥내 투여하고, 동시에 간엽줄기세포를 유효성분으로 포함하는 조성물을 관절강내 투여하는 단계를 포함하는 골관절염 예방 및 치료를 위한 정보 제공 방법을 제공한다.The present invention also relates to a method for the treatment and / or prophylaxis of cancer, comprising intravenously administering a composition comprising mesenchymal stem cells treated with STAT3 (signal transducer and activator of transcription 3) inhibitor as an active ingredient and simultaneously administering a composition comprising mesenchymal stem cells as an active ingredient A method for providing information for prevention and treatment of osteoarthritis.
본 발명의 일 실시예에 있어서, 상기 간엽줄기세포를 유효성분으로 포함하는 조성물을 관절강내 투여는 STAT3 억제제가 처리될 수 있다.In one embodiment of the present invention, the intraarticular administration of a composition comprising mesenchymal stem cells as an active ingredient may be treated with a STAT3 inhibitor.
본 발명의 일 실시예에 있어서, 상기 STAT3 억제제는 STA-21 (8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12(2H)-trione), SD282, 메트포민, AG-490 ((E)-2-Cyano-3-(3,4-dihydrophenyl)-N-(phenylmethyl)-2-propenamide), 아티프리모드 (Atiprimod; 3-(8,8-dipropyl-3-azaspiro[4.5]decan-3-yl)-N,N- diethylpropan-1-amine), 오라노핀 (Auranofin; 3,4,5-triacetyloxy-6- (acetyloxymethyl) oxane-2-thiolate; triethylphosphanium), 오로싸이오말레이트 (Aurothiomalate; Sodium 2-(auriosulfanyl)-3-carboxypropanoate), BMS-354825 (Dasatinib; N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate), CADPE (3-(3,4-dihydroxy-phenyl)-acrylic acid 2-(3,4-dihydroxy-phenyl)-ethyl ester), 스타틱 (Stattic; 6-nitro-1,1-dioxide-benzo[b]thiophene), 도베실레이트 (Dobesilate; calcium 2,5-dihydroxybenzenesulfonate), 에탄올(Ethanol), NCX-4016(NO-Aspirin), 넬피나비어(Nelfinavir; (3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylphenyl)formamido]-4-(phenylsulfanyl)butyl]-decahydroisoquinoline-3-carboxamide), PDP(phosphododecapeptide), PS-341(볼테조밉(Bortezomib); [(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid), R115777(티피파르닙(tipifarnib); 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one), S31-M2001(N-Hexyl-2-(1-naphthalenyl)-5-[[4-(phosphonooxy)phenyl]), 스타틴계 화합물, 소듐살리실레이트(Sodium Salicylate), 카페익산(Caffeic acid; 3-(3,4-Dihydroxyphenyl)-2-propenoic acid 3,4-Dihydroxy-cinnamic acid trans-Caffeate 3,4-Dihydroxy-trans-cinnamate)), 에모딘(Emodin; 1,8-Dihydroxy-3-(hydroxymethyl)-9,10-anthracenedione), 우르솔릭산(Ursolic acid; 3-beta-3-hydroxy-urs-12-ene-28-oic-acid), 레스베라트롤(Resveratrol; 3,5,4'-trihydroxy-trans-stilbene), 레티노익산(Retinoic acid; (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid), EGCG(Epigallocatechin gallate; [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl] 3,4,5-trihydroxybenzoate), Sr11302((E,E,Z,E)-3-Methyl-7-(4-methylphenyl)-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid), 탄시논 IIA(Tanshinone IIA; 1,6,6-Trimethyl-6,7,8,9-tetrahydrophenanthro[1,2-b]furan-10,11-dione) 및 커큐민(curcumin; (1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione)으로 이루어진 군으로부터 선택되는 하나 이상일 수 있다. 예를 들어, 상기 STAT3 억제제는 STA-21, SD282 또는 메트포민일 수 있다.In one embodiment of the present invention, the STAT3 inhibitor is selected from the group consisting of STA-21 (8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12 (E) -2-Cyano-3- (3,4-dihydrophenyl) -N- (phenylmethyl) -2-propenamide, Atiprimod 3- (8,8-dipropyl-3-azaspiro [4.5 ] decan-3-yl) -N, N-diethylpropan-1-amine, Auranofin (3,4,5-acetyloxymethyl) oxane-2-thiolate, (2-chloro-6-methylphenyl) -2 - [[6- [4- (2-hydroxyethyl) -1- (3,4-dihydroxy-phenyl) -acrylic acid 2- (3,4-dihydroxy-phenyl) -methyl-4-pyrimidinyl amino] -5-thiazole carboxamide monohydrate), CADPE ester, stattic, 6-nitro-1,1-dioxide-benzo [b] thiophene, calcium 2,5-dihydroxybenzenesulfonate, ethanol, NCX- Aspirin, Nelfinavir ((3S, 4aS, 8aS) -N-tert- 3-carboxamide, PDP (phosphododecapeptide), 3-hydroxy-2 - [(2R, 3R) -2-hydroxy- PS-341 (Bortezomib; 2-ylcarbonyl) amino] propanoyl} amino) butyl] boronic acid, R115777 (tipifarnib (R) (1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methylquinolin-2 (N-Hexyl-2- (1-naphthalenyl) -5 - [[4- (phosphonooxy) phenyl], statin compound, sodium salicylate, caffeic acid 3- 4-Dihydroxyphenyl) -2-
본 발명의 일 실시예에 있어서, STAT3 억제제가 처리된 간엽줄기세포를 유효성분으로 포함하는 조성물을 정맥내 투여하는 것은 골관절염의 통증을 경감시킬 수 있다.In one embodiment of the present invention, intravenous administration of a composition comprising the STAT3 inhibitor-treated mesenchymal stem cells as an active ingredient may alleviate the pain of osteoarthritis.
본 발명의 일 실시예에 있어서, 상기 간엽줄기세포는 골관절염 환자의 말초혈액 또는 지방조직으로부터 분리된 것일 수 있다.In one embodiment of the present invention, the mesenchymal stem cells may be isolated from peripheral blood or adipose tissue in osteoarthritis patients.
본 발명에 따른 STAT3 억제제가 처리된 간엽줄기세포는 염증유발인자의 발현을 효과적으로 억제할 수 있고, 항염증인자의 발현을 효과적으로 증가시키며, 케모카인 수용체(chemokine receptor)의 발현을 증가시키는 효과가 우수하다.The STAT3 inhibitor-treated mesenchymal stem cells according to the present invention are capable of effectively inhibiting the expression of inflammatory factors, effectively increasing the expression of anti-inflammatory agents, and enhancing the expression of chemokine receptors.
환자 유래의 간엽줄기세포는 일반적인 줄기세포를 사용하는 경우보다 줄기세포의 연골보호나 골관절염 염증 제어 효능을 더욱 개선할 수 있으며, 면역거부반응 등의 부작용을 최소화 할 수 있다. 다만 환자 유래의 간엽줄기세포는 줄기세포는 고령화 줄기세포일 경우가 많고, 자체의 기능이 저하되어 있기 때문에, 이를 포함하는 조성물은 면역질환의 치료제로서 더욱 유용하게 사용될 수 있는 효과가 있다.The patient-derived mesenchymal stem cells can further improve cartilage protection and osteoarthritic inflammation control efficacy of stem cells, and can minimize side effects such as immune rejection and the like, as compared with the use of normal stem cells. However, in the case of mesenchymal stem cells derived from a patient, stem cells are often aged stem cells, and their functions are deteriorated. Therefore, a composition containing the mesenchymal stem cells can be more effectively used as a therapeutic agent for immune diseases.
또한, 본 발명에 따른 키트를 사용하여 STAT3 억제제가 처리된 간엽줄기세포를 정맥내 투여하고, 동시에 간엽줄기세포를 관절강내 투여함으로써, 관절염의 치료하면서 통증을 효과적으로 경감시킬 수 있다.In addition, by using the kit according to the present invention, the STAT3 inhibitor-treated mesenchymal stem cells can be administered intravenously, and at the same time, the mesenchymal stem cells can be administered intraarticularly to effectively alleviate the pain while treating arthritis.
도 1은 본 발명의 일 실시예에서 간엽줄기세포 또는 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 때 통증 정도를 나타낸 도이다.
도 2는 투여 후 경과(0, 3, 11, 22 및 29일)에 따라 일 실시예에서 간엽줄기세포 또는 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 때 통증 정도를 나타낸 도이다.
도 3은 일 실시예에서 간엽줄기세포 또는 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 때 micro-CT로 연골 손상 정도를 나타낸 도이다.
도 4는 일 실시예에서 간엽줄기세포 또는 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 때 H&E 염색으로 연골 손상 정도를 나타낸 도이다.
도 5는 일 실시예에서 간엽줄기세포 또는 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 때 염증성 사이토카인 발현을 나타낸 도이다.
도 6은 본 발명의 일 실시예에서 간엽줄기세포 또는 STA-21이 처리된 간엽줄기세포를 관절강내 투여했을 때 통증 정도를 나타낸 도이다.
도 7은 본 발명의 일 실시예에서 간엽줄기세포를 관절강내 투여하고 동시에 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 때의 통증 정도를 나타낸 도이다.
도 8은 본 발명의 일 실시예에서 연골 손상 정도를 나타내는 micro-CT 분석 결과를 나타낸 도이다.
도 9는 본 발명의 일 실시예에서 간엽줄기세포를 관절강내 투여하고 동시에 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 때의 Ganglion 조직 내에 통증 마커 CGRP를 확인한 결과를 나타낸 도이다.
도 10은 본 발명의 일 실시예에서 STA-21이 처리된 간엽줄기세포를 관절강내 투여하고 동시에 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 때의 통증 정도를 나타낸 도이다.
도 11은 본 발명의 일 실시예에서 연골 손상 정도를 확인하기 위하여 H&E 염색한 결과를 나타낸 도이다.
도 12는 본 발명의 일 실시예에서 연골 손상 정도를 확인하기 위하여 C. Micro CT 분석을 통하여 골 볼륨(%)을 확인한 결과를 나타낸 도이다.
도 13은 명의 일 실시예에서 STA-21이 처리된 간엽줄기세포를 관절강내 투여하고 동시에 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 때의 통증 마커 TRPV1를 확인한 결과를 나타낸 도이다.
도 14는 in vitro 내 STA21 처리된 MSC의 타깃 세포 활성 조절 확인한 결과를 나타낸 도이다.
도 15는 본 발명의 일 실시예에서 SD-282 및 메트포민에 의한 통증 조절 및 연골보호 인자 발현 정도를 나타낸 도이다.
도 16은 본 발명의 일 실시예에서 SD-282 및 메트포민에 의한 항염증 및 연골보호에 대한 결과를 나타낸 도이다.FIG. 1 is a graph showing the degree of pain when mesenchymal stem cells or STA-21-treated mesenchymal stem cells are intravenously administered in an embodiment of the present invention.
FIG. 2 is a graph showing the degree of pain when mesenchymal stem cells or STA-21-treated mesenchymal stem cells are intravenously administered according to the time after administration (
FIG. 3 is a graph showing the degree of cartilage damage by micro-CT when mesenchymal stem cells or STA-21-treated mesenchymal stem cells are administered intravenously in one embodiment.
FIG. 4 is a graph showing the degree of cartilage damage by H & E staining when mesenchymal stem cells or STA-21-treated mesenchymal stem cells are administered intravenously in one embodiment.
FIG. 5 is a graph showing the expression of inflammatory cytokines when mesenchymal stem cells or STA-21-treated mesenchymal stem cells are administered intravenously in one embodiment.
FIG. 6 is a graph showing the degree of pain when mesenchymal stem cells or STA-21-treated mesenchymal stem cells are administered in an articular cavity according to an embodiment of the present invention.
FIG. 7 is a graph showing the degree of pain when mesenchymal stem cells are administered intra-articularly, and STA-21-treated mesenchymal stem cells are intravenously administered in an embodiment of the present invention.
FIG. 8 is a graph showing the result of micro-CT analysis showing the extent of cartilage damage in an embodiment of the present invention.
FIG. 9 is a graph showing the results of identifying pain marker CGRP in ganglion tissue when mesenchymal stem cells are administered intra-articularly and simultaneously treated with STA-21-treated mesenchymal stem cells in an embodiment of the present invention.
FIG. 10 is a graph showing the degree of pain when STA-21-treated mesenchymal stem cells are administered intra-articularly and STA-21-treated mesenchymal stem cells are intravenously administered in an embodiment of the present invention.
FIG. 11 is a graph showing the results of H & E staining to check cartilage damage in an embodiment of the present invention.
FIG. 12 is a graph showing the result of checking bone volume (%) through C. Micro CT analysis to check the degree of cartilage damage in one embodiment of the present invention.
FIG. 13 is a graph showing the results of identifying STA-21-treated mesenchymal stem cells and STA-21-treated mesenchymal stem cells in a single intravenous administration of TRPV1.
FIG. 14 is a graph showing the result of confirming target cell activity regulation of MSC treated with STA21 in vitro. FIG.
15 is a graph showing the degree of pain control and cartilage protective factor expression by SD-282 and metformin in one embodiment of the present invention.
Figure 16 shows the results for anti-inflammatory and cartilage protection by SD-282 and metformin in one embodiment of the present invention.
이하 첨부된 도면을 참조하여 본 발명의 실시예들을 상세히 설명한다. 이하의 설명에 있어, 당업자에게 주지 저명한 기술에 대해서는 그 상세한 설명을 생략할 수 있다. 또한, 본 발명을 설명함에 있어서, 관련된 공지 기능 또는 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우에는 그 상세한 설명을 생략할 수 있다. 또한, 본 명세서에서 사용되는 용어(terminology)들은 본 발명의 바람직한 실시예를 적절히 표현하기 위해 사용된 용어들로서, 이는 사용자, 운용자의 의도 또는 본 발명이 속하는 분야의 관례 등에 따라 달라질 수 있다.Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. In the following description, detailed description of known techniques well known to those skilled in the art may be omitted. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear. Also, terminologies used herein are terms used to properly represent preferred embodiments of the present invention, which may vary depending on the user, intent of the operator, or custom in the field to which the present invention belongs.
따라서 본 용어들에 대한 정의는 본 명세서 전반에 걸친 내용을 토대로 내려져야 할 것이다. 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.Therefore, the definition of these terms should be based on the contents throughout this specification. Throughout the specification, when an element is referred to as "comprising ", it means that it can include other elements as well, without excluding other elements unless specifically stated otherwise.
본 발명의 용어, "STATs(Signal Transducer and Transcriptions)"는 STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6의 7개의 subunit 형태를 가지는 전사인자이다. STATs은 N-터미널 도메인(ND), 코일드-코일 도메인(CCD), DNA-바인딩 도메인(DBD), 링커 도메인(LD), Src 호몰로지2(SH2) 및 전사활성 도메인(TAD)이 포함된 6가지 별개의 구조적 도메인을 공유하며, 그 중에 STAT3는 활성화에 의해 인산화되는 C-말단에 중요한 티로신(tyrosine)과 세린(serine) 잔기(Tyrosine 705, Serine 727 residues for STAT3)를 가지고 있다. 특히, STAT3는 다양한 경로를 통해 지속적으로 활성화 되어 종양형성을 촉진하는 역할을 하며, 또한 STAT3는 다양한 사이토카인과 성장인자-인터페론, 표피의 성장인자, 혈소판 유래된 성장인자, 인터루킨5, 인터루킨6, 간세포 성장인자, LIF(leukemia inhibitory factor), 뼈 형성유전 단백질2, 호르몬 렙틴, Src와 Ras같은 발암 단백질에 대한 반응으로써 티로신 705, 세린 727의 두 잔기에 인산화를 통하여 활성화된다. STAT3는 인간 세포에서 여러 유전자의 전사에 관여하는 전사조절인자이며, 정상적인 경우에는 외부로부터 사이토카인이나 성장 요소들에 의한 신호전달에 반응하여, 세포질에 존재하던 STAT3는 핵 안으로 이동하여 세포의 발달, 분화, 생장, 생존, 신생혈관합성 그리고 면역기능 등을 위한 유전자들을 조절한다, 그러나, STAT3가 비정상적일 경우에는 STAT3는 암의 발생에 중요한 기능을 한다. 많은 수의 악성종양, 동물모델 실험, 암 환자에서 활성화된 STAT3가 발견되었으며 STAT3에 의해서 암을 유발하고 발전시키는 여러 다양한 유전자의 발현을 조절한다. STAT3는 종양 세포에 대항하는 면역 활성화에 필요한 중재자의 발현을 억제하는 것으로 알려져 있고, 또한, STAT3의 활성은 유전자발현 프로그램을 변경하면서 다양한 면역 세포에서 STAT3을 활성화시키는 인자들의 생산을 촉진함으로써 항암면역 반응을 억제하기도 한다.The term " STATs (Signal Transducer and Transcriptions) "of the present invention is a transcription factor having seven subunit forms of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STATs are those that comprise the N-terminal domain (ND), the coiled-coil domain (CCD), the DNA-binding domain (DBD), the linker domain (LD), the Src homology 2 (SH2) It shares six distinct structural domains, among which STAT3 has important C-terminal tyrosine and serine residues (Tyrosine 705, Serine 727 residues for STAT3) that are phosphorylated by activation. In particular, STAT3 is continuously activated through various pathways to promote tumorigenesis, and STAT3 is also involved in various cytokine and growth factor-interferon, epidermal growth factor, platelet-derived growth factor,
본 발명에서 용어, "간엽줄기세포"는 골수(bone marrow), 혈액, 진피 및 골막에서 분리되는 줄기세포로서, 다양한 세포 예컨대 지방세포, 연골세포 및 뼈세포 등으로 분화할 수 있는 전능성(pluripotent) 또는 다능성(multipotent) 세포를 의미한다. The term "mesenchymal stem cells" in the present invention refers to stem cells isolated from bone marrow, blood, dermis and periosteum, and pluripotent stem cells capable of differentiating into various cells such as adipocytes, chondrocytes, Or multipotent cells.
또한, 본 발명에서 사용된 "간엽줄기세포"는 골관절염 환자로부터 분리한 간엽줄기세포를 의미한다. 상기 간엽줄기세포는 동물, 바람직하게는 포유동물, 보다 바람직하게는 인간의 간엽줄기세포일 수 있다. 간엽줄기세포를 분리 및 배양하는 과정은 당업계에 잘 알려져 있으며, 예컨대, 미국특허 제5,486,359호에 개시되어 있으며, 상기 특허 문헌은 본 명세서에 참조로서 삽입된다. 또한, 상기 간엽줄기세포는 공지된 방법에 따라 골수의 조혈모세포로부터 부착특성에 의해 분리한 후 분화능력을 잃지 않은 상태에서 증식시켜 얻을 수 있다.As used herein, "mesenchymal stem cells" means mesenchymal stem cells isolated from osteoarthritis patients. The mesenchymal stem cells may be an animal, preferably a mammal, more preferably a human mesenchymal stem cell. The process of isolating and culturing mesenchymal stem cells is well known in the art and is disclosed, for example, in U.S. Patent No. 5,486,359, which is incorporated herein by reference. In addition, the mesenchymal stem cells can be obtained by separating the mesenchymal stem cells from the hematopoietic stem cells of bone marrow according to a known method, and then proliferating without losing their differentiation ability.
보다 구체적으로는, 인간 또는 마우스를 포함하는 포유동물, 바람직하게는, 인간의 간엽줄기세포 소스, 예컨대, 혈액 또는 골수로부터 간엽줄기세포를 분리한다. 상기 골수는 경골, 대퇴골, 척수 또는 장골로부터 추출할 수 있다. 이어, 골수로부터 세포를 얻고, 이들 세포를 적합한 배지에서 배양한다. 배양과정에서 부유 세포를 제거하고 배양 플레이트에 부착된 세포들을 계대 배양하여, 최종적으로 구축된(established) 간엽줄기세포를 수득한다. 상기 과정에서 이용되는 배지로는, 줄기세포의 배양에 이용되는 일반적인 어떠한 배지도 이용할 수 있다. 바람직하게는, 혈청(예컨대, 우태아 혈청, 말 혈청 및 인간 혈청)이 함유된 배지이다. 본 발명에서 이용될 수 있는 배지는, 예를 들어, RPMI 시리즈, Eagles's MEM (Eagle's minimum essential medium, Eagle, H. Science 130:432(1959)), α-MEM (Stanner, C.P. et al., Nat. New Biol. 230:52(1971)), Iscove's MEM (Iscove, N. et al., J. Exp. Med. 147:923(1978)), DMEM (Dulbecco's modifA ation of Eagle's medium, Dulbecco, R.et al., VirProcy 8:396(1959)) 등을 포함하나, 이에 한정되는 것은 아니다. 상기 배지에는, 다른 성분, 예를 들어, 항생제 또는 항진균제(예컨대, 페니실린, 스트렙토마이신) 및 글루타민 등이 포함될 수 있다. 배지 및 배양에 대한 일반적인 설명은 R. Ian Freshney, Culture of Animal Cells, Alan R. Liss, Inc., New York (1984)에 기재되어 있으며, 이 문헌은 본 명세서에 참조로서 삽입된다.More specifically, it isolates mesenchymal stem cells from a mammalian animal, preferably a human mesenchymal stem cell source, such as blood or bone marrow, including human or mouse. The bone marrow can be extracted from the tibia, femur, spinal cord or iliac bone. Cells are then obtained from the bone marrow, and these cells are cultured in a suitable medium. In the course of culturing, the floating cells are removed and the cells attached to the culture plate are subcultured to finally obtain established mesenchymal stem cells. As the medium used in the above process, any medium generally used for culturing stem cells can be used. Preferably, it is a medium containing serum (for example, fetal bovine serum, horse serum and human serum). Mediums which can be used in the present invention include, for example, RPMI series, Eagles ' s MEM (Eagle's minimum essential medium, Eagle, H. Science 130: Dulbecco's modification of Eagle's medium, Dulbecco, R., et al., J. Exp. Med., 147: 923 (1978)), Iscove's MEM (Iscove, N. et al. et al., VirProcy 8: 396 (1959)), but are not limited thereto. The medium may include other components such as antibiotics or antifungal agents (e.g., penicillin, streptomycin) and glutamine. A general description of media and culture is provided in R. Ian Freshney, Culture of Animal Cells, Alan R. Liss, Inc., New York (1984), which is incorporated herein by reference.
또한, 간엽줄기세포의 확인은, 예컨대, 유세포 분석을 통하여 할 수 있다. 이러한 유세포 분석은, 간엽줄기세포의 특이한 표면 마커를 이용하여 실시된다. 예컨대, 간엽줄기세포는 CD44, CD29 및/또는 MHC 클래스 I에 대하여 양성 반응을 나타낸다. 본 발명의 바람직한 구현예에 따르면, 본 발명에서 이용되는 간엽줄기세포는 표면 마커 CD44, CD29 및 CD105에 대하여 양성 반응을 나타내며, CD34, CD45 및 HLA-DR(Human Leukocyte Antigen - antigen D Related)에 대해서는 음성 반응을 나타낸다. 줄기세포와 표면 마커를 언급하면서 사용되는 용어양성 반응은 표면 마커에 대한 항체를 줄기세포에 처리하는 경우, 줄기세포의 표면 항원과 특이적으로 결합하는 양상을 의미한다. In addition, identification of mesenchymal stem cells can be performed, for example, through flow cytometry. Such flow cytometry analysis is carried out using a specific surface marker of mesenchymal stem cells. For example, mesenchymal stem cells are positive for CD44, CD29 and / or MHC class I. According to a preferred embodiment of the present invention, the mesenchymal stem cells used in the present invention are positive for the surface markers CD44, CD29 and CD105. For CD34, CD45 and HLA-DR (Human Leukocyte Antigen-antigen D Related) Negative reaction. A term used to refer to stem cells and surface markers refers to the way in which antibodies against surface markers are specifically bound to surface antigens of stem cells when treated with stem cells.
본 발명은 STAT3 억제제가 처리된 간엽줄기세포를 유효성분으로 포함하는 정맥내 투여용 조성물 및 간엽줄기세포를 유효성분으로 포함하는 관절강내 투여용 조성물을 포함하는 통증이 경감되는 골관절염 치료용 키트, 및 이를 이용한 골관절염 골관절염 예방 및 치료를 위한 정보 제공 방법을 제공한다.The present invention relates to a pain relieving kit for treating osteoarthritis comprising a composition for intravenous administration containing a mesenchymal stem cell treated with a STAT3 inhibitor as an active ingredient and a composition for intraarticular administration containing mesenchymal stem cells as an active ingredient, Thereby providing an information providing method for preventing and treating osteoarthritis of osteoarthritis.
상기 STAT3 억제제가 처리된 간엽줄기세포를 포함하는 정맥내 투여용 조성물과 간엽줄기세포를 포함하는 관절강내 투여용 조성물은 동시에 투여될 수 있다. 이때, “동시에” 투여된다는 것은, 상기 STAT3 억제제가 처리된 간엽줄기세포를 포함하는 조성물을 정맥내 투여한 후 상기 간엽줄기세포를 포함하는 조성물을 관절강내 투여하거나, 상기 간엽줄기세포를 포함하는 조성물을 관절강내 투여한 후 상기 STAT3 억제제가 처리된 간엽줄기세포를 포함하는 조성물을 투여하거나, 또는 정맥내 투여용 조성물과 상기 관절강내 투여용 조성물을 동시에 투여하는 것을 의미한다. The composition for intravenous administration containing the STAT3 inhibitor-treated mesenchymal stem cells and the composition for intra-articular administration including mesenchymal stem cells may be administered simultaneously. Herein, " simultaneously administered " means that the composition containing the mesenchymal stem cells treated with the STAT3 inhibitor is administered intravenously, the composition containing the mesenchymal stem cells is administered into the joints or the composition containing the mesenchymal stem cells Quot; refers to administering a composition comprising mesenchymal stem cells treated with the STAT3 inhibitor, or administering the composition for intravenous administration and the composition for intra-articular administration simultaneously.
본 발명의 일실시예에 있어서, 상기 STAT3 억제제는 STA-21(8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12(2H)-trione), SD282, 메트포민, AG-490((E)-2-Cyano-3-(3,4-dihydrophenyl)-N-(phenylmethyl)-2-propenamide), 아티프리모드(Atiprimod; 3-(8,8-dipropyl-3-azaspiro[4.5]decan-3-yl)-N,N- diethylpropan-1-amine), 오라노핀(Auranofin; 3,4,5-triacetyloxy-6- (acetyloxymethyl) oxane-2-thiolate; triethylphosphanium), 오로싸이오말레이트(Aurothiomalate; Sodium 2-(auriosulfanyl)-3-carboxypropanoate), BMS-354825(Dasatinib; N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate), CADPE(3-(3,4-dihydroxy-phenyl)-acrylic acid 2-(3,4-dihydroxy-phenyl)-ethyl ester), 스타틱(Stattic; 6-nitro-1,1-dioxide-benzo[b]thiophene), 도베실레이트(Dobesilate; calcium 2,5-dihydroxybenzenesulfonate), 에탄올(Ethanol), NCX-4016(NO-Aspirin), 넬피나비어(Nelfinavir; (3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylphenyl)formamido]-4-(phenylsulfanyl)butyl]-decahydroisoquinoline-3-carboxamide), PDP(phosphododecapeptide), PS-341(볼테조밉(Bortezomib); [(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid), R115777(티피파르닙(tipifarnib); 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one), S31-M2001(N-Hexyl-2-(1-naphthalenyl)-5-[[4-(phosphonooxy)phenyl]), 스타틴계 화합물, 소듐살리실레이트(Sodium Salicylate), 카페익산(Caffeic acid; 3-(3,4-Dihydroxyphenyl)-2-propenoic acid 3,4-Dihydroxy-cinnamic acid trans-Caffeate 3,4-Dihydroxy-trans-cinnamate)), 에모딘(Emodin; 1,8-Dihydroxy-3-(hydroxymethyl)-9,10-anthracenedione), 우르솔릭산(Ursolic acid; 3-beta-3-hydroxy-urs-12-ene-28-oic-acid), 레스베라트롤(Resveratrol; 3,5,4'-trihydroxy-trans-stilbene), 레티노익산(Retinoic acid; (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid), EGCG(Epigallocatechin gallate; [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl] 3,4,5-trihydroxybenzoate), Sr11302((E,E,Z,E)-3-Methyl-7-(4-methylphenyl)-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid), 탄시논 IIA(Tanshinone IIA; 1,6,6-Trimethyl-6,7,8,9-tetrahydrophenanthro[1,2-b]furan-10,11-dione) 및 커큐민(curcumin; (1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione)으로 이루어진 군 중에서 선택되는 것일 수 있으며, 예를 들어, STA-21, SD282 또는 메트포민일 수 있다.In one embodiment of the present invention, the STAT3 inhibitor is selected from the group consisting of STA-21 (8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12 (E) -2-Cyano-3- (3,4-dihydrophenyl) -N- (phenylmethyl) -2-propenamide, Atiprimod 3- (8,8-dipropyl-3-azaspiro [4.5 ] decan-3-yl) -N, N-diethylpropan-1-amine, Auranofin (3,4,5-acetyloxymethyl) oxane-2-thiolate, (2-chloro-6-methylphenyl) -2 - [[6- [4- (2-hydroxyethyl) -1- (3,4-dihydroxy-phenyl) -acrylic acid 2- (3,4-dihydroxy-phenyl) -methyl-4-pyrimidinyl amino] -5-thiazole carboxamide monohydrate), CADPE ester, stattic, 6-nitro-1,1-dioxide-benzo [b] thiophene, calcium 2,5-dihydroxybenzenesulfonate, ethanol, NCX- Aspirin, Nelfinavir (3S, 4aS, 8aS) -N-tert-butyl-2- [ 3-carboxamide), PDP (phosphododecapeptide), PS-341 (bortezomib), 3-hydroxy-3 - [(3-hydroxy-2-methylphenyl) Bortezomib); 2-ylcarbonyl) amino] propanoyl} amino) butyl] boronic acid, R115777 (tipifarnib (R) (1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methylquinolin-2 (N-Hexyl-2- (1-naphthalenyl) -5 - [[4- (phosphonooxy) phenyl], statin compound, sodium salicylate, caffeic acid 3- 4-Dihydroxyphenyl) -2-propenoic acid 3,4-Dihydroxy-cinnamic acid trans-Caffeate 3,4-Dihydroxy-trans- cinnamate), Emodin (1,8-Dihydroxy- , 10-anthracenedione, 3-beta-3-hydroxy-urs-12-ene-28-oic acid, resveratrol, 3,5,4'-trihydroxy- Retinoic acid (2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid ), EGCG (Epigallocatechin gallate; [(2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl] 3,4,5-trihydroxybenzoate), Sr11302 , E, Z, E) - 2-cyclohexen-1-yl) -2,4,6,8-nonatetraenoic acid, Tanshinone IIA (2-methyl- ; 1,6,6-Trimethyl-6,7,8,9-tetrahydrophenanthro [1,2-b] furan-10,11-dione and curcumin (1E, 6E) -hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione), and may be, for example, STA-21, SD282 or metformin.
상기 STAT3 억제제는 1x105~1x107 세포수의 간엽줄기세포에 0.1μM~100μM의 농도로 처리하여 37℃의 온도에서 24~72시간 배양하여 면역질환 치료능이 우수한 간엽줄기세포를 수득할 수 있다.The STAT3 inhibitor can be obtained by treating mesenchymal stem cells at a concentration of 1 x 10 5 to 1 x 10 7 cells at a concentration of 0.1 μM to 100 μM and culturing the cells at 37 ° C. for 24 to 72 hours to obtain mesenchymal stem cells excellent in the ability to treat immune diseases.
상기 STAT3 억제제 중, "스타틴계 화합물"은 실라스타틴(Cilastatin), 나이스타틴(Nystatin), 로바스타틴(Lovastatin), 소마토스타틴(Somatostatin), 프라바스타틴(Pravastatin), 심바스타틴(Simvastatin), 플루바스타틴(Fluvastatin), 아토바스타틴(Atorvastatin), 세르바스타틴(Cervastatin), 울리나스타틴(Ulinastatin) 또는 로슈바스타틴(Rosuvastatin)인 것일 수 있다. Among the STAT3 inhibitors, the "statin compounds" include compounds such as Cilastatin, Nystatin, Lovastatin, Somatostatin, Pravastatin, Simvastatin, Fluvastatin, Or atorvastatin, cervastatin, ulinastatin or rosuvastatin. The term " atorvastatin "
본 발명의 일실시예에 있어서, 상기 STAT3 억제제가 처리된 간엽줄기세포는 CD44, CD29 및 CD105는 양성이며, CD34, CD45 및 HLA-DR(Human Leukocyte Antigen - antigen D Related)는 음성의 면역학적 특징을 갖는 것일 수 있다.In one embodiment of the present invention, the STAT3 inhibitor-treated mesenchymal stem cells are positive for CD44, CD29, and CD105, and the CD34, CD45, and HLA-DR (Human Leukocyte Antigen-antigen D Related) Lt; / RTI >
본 발명의 일실시예에 있어서, 상기 STAT3 억제제가 처리된 간엽줄기세포는 인터루킨-6(Interleukin-6, IL-6), VEGF(Vascular endothelial growth factor) 또는 인터루킨-1β(Interleukin-1 beta, IL-1β)의 인자의 발현이 억제되는 것일 수 있다.In one embodiment of the present invention, the STAT3 inhibitor-treated mesenchymal stem cells are selected from the group consisting of Interleukin-6 (IL-6), VEGF (Vascular Endothelial Growth Factor) or Interleukin-1 beta -1?) Can be suppressed.
본 발명의 일실시예에 있어서, 상기 간엽줄기세포는 말초혈액 또는 지방조직으로부터 분리된 것일 수 있다.In one embodiment of the present invention, the mesenchymal stem cells may be isolated from peripheral blood or adipose tissue.
본 발명의 용어, "치료"란, 달리 언급되지 않는 한, 상기 용어가 적용되는 질환 또는 질병, 또는 상기 질환 또는 질병의 하나 이상의 증상을 역전시키거나, 완화시키거나, 그 진행을 억제하거나, 또는 예방하는 것을 의미하며, 본원에서 사용된 상기 치료란 용어는 치료하는 행위를 말한다. 따라서 포유동물에 있어서 골관절염과 같은 면역질환의 치료 또는 치료요법은 하기의 하나 이상을 포함할 수 있다:The term "treatment" of the present invention means, unless otherwise stated, reversing, alleviating, inhibiting the progress of, or preventing the disease or condition to which the term applies, And the term " treatment " as used herein refers to an act of treating. The therapeutic or therapeutic treatment of an immune disorder such as osteoarthritis in a mammal may thus include one or more of the following:
(1) 면역질환의 성장을 저해함, 즉, 그 발달을 저지시킴;(1) inhibiting the growth of the immune system, i.e., inhibiting its development;
(2) 면역질환의 확산을 예방함, 즉, 전이를 예방함;(2) preventing the spread of immune diseases, i.e., preventing metastasis;
(3) 면역질환을 경감시킴;(3) relieving immune diseases;
(4) 면역질환의 재발을 예방함; 및(4) preventing recurrence of immune disorders; And
(5) 면역질환의 증상을 완화함(palliating)(5) palliating symptoms of immune disorders
본 발명에 따른 키트의 조성물은 약학적으로 유효한 양의 STAT3 억제제가 처리된 간엽줄기세포 또는 간엽줄기세포를 단독으로 포함하거나 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 포함할 수 있다. 상기에서 약학적으로 유효한 양이란 면역질환의 증상을 예방, 개선 및 치료하기에 충분한 양을 말한다.The composition of the kit according to the present invention may comprise a mesenchymal stem cell or mesenchymal stem cell treated with a STAT3 inhibitor in a pharmaceutically effective amount, alone or in combination with one or more pharmaceutically acceptable carriers, excipients or diluents. A pharmaceutically effective amount as used herein refers to an amount sufficient to prevent, ameliorate, and treat symptoms of an immune disease.
또한, 상기에서 "약학적으로 허용되는"이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다. The term "pharmaceutically acceptable" as used herein refers to a composition that is physiologically acceptable and does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like when administered to humans. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.
또한, 본 발명의 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 멸균 주사용액, 멸균 분말의 형태일 수 있다. In addition, the compositions of the present invention may be formulated using methods known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal. The formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatine capsules, sterile injectable solutions, sterile powders.
또한, 본 발명에 조성물의 활성 성분의 투여량은 투여 경로, 환자의 연령, 성별, 체중 및 환자의 중증도 등의 여러 인자에 따라 적절히 선택될 수 있고, 본 발명에 따른 조성물은 골관절염의 증상을 예방, 개선 또는 치료하는 효과를 가지는 공지의 화합물과 병행하여 투여할 수 있다. The dose of the active ingredient of the composition according to the present invention can be appropriately selected according to various factors such as administration route, age, sex, weight and severity of the patient, and the composition according to the present invention can prevent the symptoms of osteoarthritis , Or the like, in combination with known compounds having an effect of improving or treating.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여방식, 수용자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물의 투여량은 바람직하게는 1일 당 1 x 103 ~1 x 1012 세포/kg 이다.The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on such factors as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, route of administration, excretion rate, . The dosage of the pharmaceutical composition of the present invention is preferably 1 x 10 3 to 1 x 10 12 cells / kg per day.
이하 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다. Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not limited to these embodiments.
제조예 1 : 간엽줄기세포(mesenchymal stem cell, MSC)의 획득 및 배양Production Example 1: Acquisition and culture of mesenchymal stem cell (MSC)
본 발명자들은 하기의 과정을 통하여, 간엽줄기세포를 획득하였다. 우선, 골관절염 환자에서 외과적 수술 후에 얻어진 지방 조직을 10% 페니실린-스트렙토마이신을 포함한 PBS로 10회 이상 세척하여 혈액과 이물질을 제거한 후, 조직을 0.2~0.3g이 되도록 잘게 절단하였다. 0.2% 콜라게나아제(Roche, Sandhofer Strasse, Mannheim, Germany) 용액에 넣어서 37℃의 수욕, 100rpm에서 1시간 동안 반응시켰다. 100㎛ 메쉬를 이용하여 콜라게나아제에 의해서 분해된 용액층과 분해 되지 않은 조각을 분리한 후, 분리된 콜라게나아제 용액에 동량의 PBS를 첨가하였다. 이어, 4℃, 1200rpm에서 5분간 원심분리하여 상층액인 지질과 지방층을 제거하고, 콜라게나아제 상층액을 제거하였다. 가라앉은 간엽줄기세포로부터 남은 콜라게나아제 용액을 제거하기 위해서 MSCGM[mesenchymal stem cell growth media: MSC 기본 배지 (Cambrex, Walkersville, MD, 미국), 간엽세포 성장보조물(Cambrex, Walkersville, MD, 미국), 4mM L-글루타민 및 페니실린(0.025 unit/500 ㎖)/스트렙토마이신(0.025 mg/500 ㎖)]를 넣어 다시 4℃, 1200 rpm에서 5분간 원심분리 하였다. MSCGM은 우태아혈청을 포함하는 DMEM(Dulbecco's modified Eagle's medium)에 기초한 배지이다. 이어, 상층액을 제거하고, 얻어진 간엽줄기세포는 배양접시에 접종하여 MSCGM으로 37℃, 5% CO2 항온기에서 배양하였다. 이틀에 한번 씩 배양액을 교체하면서 배양하였다. The present inventors obtained mesenchymal stem cells through the following procedure. First, in osteoarthritis patients, the fat tissue obtained after surgical operation was washed with PBS containing 10% penicillin-streptomycin more than 10 times to remove blood and foreign matter, and then the tissue was cut to 0.2-0.3 g. 0.2% collagenase (Roche, Sandhofer Strasse, Mannheim, Germany), and reacted at 100 rpm for 1 hour in a water bath at 37 ° C. The solution layer decomposed by the collagenase was separated from the undegraded fragments using a 100 μm mesh, and then an equal volume of PBS was added to the separated collagenase solution. Then, the mixture was centrifuged at 4 ° C and 1200 rpm for 5 minutes to remove lipids and fat layers, and the collagenase supernatant was removed. (Cambrex, Walkersville, MD, USA), a mesenchymal stem cell growth medium (Cambrex, Walkersville, MD, USA), and a mesenchymal stem cell growth medium 4 mM L-glutamine and penicillin (0.025 unit / 500 ml) / streptomycin (0.025 mg / 500 ml)] and centrifuged at 4 ° C and 1200 rpm for 5 minutes. MSCGM is a medium based on DMEM (Dulbecco's modified Eagle's medium) containing fetal bovine serum. Subsequently, the supernatant was removed, and the obtained mesenchymal stem cells were inoculated on a culture dish and cultured in MSCGM at 37 DEG C in a 5% CO 2 incubator. The cultures were incubated while changing the culture medium once every two days.
제조예 2 : STA-21이 처리된 간엽줄기세포의 제조Production Example 2: Preparation of STA-21-Treated Mesenchymal Stem Cells
3x105 세포수의 상기 제조예 1의 간엽줄기세포에 5μM 농도의 STA-21를 처리한 후 37℃의 온도에서 24~72시간 배양하여 STA-21이 처리된 간엽줄기세포를 제조하였다.STA-21-treated mesenchymal stem cells were prepared by treating the mesenchymal stem cells of Preparation Example 1 with 3x10 5 cells at a concentration of 5 μM STA-21 at 37 ° C for 24 to 72 hours.
제조예 3: 골관절염 동물 모델Preparation Example 3: Osteoarthritis Animal Model
본 발명의 키트의 골관절염 통증완화 효과를 실험하기 위해 골관절염 동물모델을 제작하였다.An osteoarthritic animal model was prepared to test the osteoarthritic pain relief effect of the kit of the present invention.
구체적으로, 골관절염 동물모델을 제작하기 위해 200~250g인 5주령 수컷 Wistar 랫(rat)를 21~22℃의 온도에서 명암주기(light-dark cycle)를 12시간 간격으로 사육하였고 살균한 물과 사료를 공급하여 키웠다. 이후 골관절염 유도를 위해 랫(rat)의 오른쪽 무릎에 3mg/50μl의 용량으로 모노소듐 아이도아세테이트(Monosodium iodoacetate, MIA, Sigma, ST. Louis, MO)를 투여하여 골관절염을 유도하였다. MIA는 생리식염수에 용해시켜 투여하였다. Specifically, 5-week-old male Wistar rats (200-250 g) were incubated at 21-22 ° C for 12 hours in light-dark cycle to produce osteoarthritic animal models. The sterilized water and feed . Osteoarthritis was induced by administering monosodium iodoacetate (MIA, Sigma, St. Louis, MO) at a dose of 3 mg / 50 μl to the right knee of a rat for induction of osteoarthritis. MIA was administered by dissolving in physiological saline solution.
실시예 1 : 투여 경로에 따른 STA-21이 처리된 간엽줄기세포의 통증 경감 효과 Example 1: Pain relief effect of STA-21-treated mesenchymal stem cells according to administration route
투여 경로에 따른 STA-21이 처리된 간엽줄기세포의 통증 경감 효과를 확인하기 위해 제조예 3의 골관절염 동물모델에 제조예 2의 3x105 세포수의 STA-21이 처리된 간엽줄기세포를 관절강내 주사(intraarticular injection)(STA21 OA-MSC IA) 또는 정맥내 주사(intravenous injection)(STA21 OA-MSC IV)로 주입하였다. 또한, 비교예로서 제조예 1의 간엽줄기세포 단독으로 정맥내 주사(OA-MSC IV) 또는 관절강내 주사(OA-MSC IA)로 주입하고 대조군(MIA)으로는 MIA만을 투여하였다.In order to confirm the pain relief effect of STA-21-treated mesenchymal stem cells according to the administration route, STA-21-treated mesenchymal stem cells of 3x10 5 cells of Preparation Example 2 were administered to the osteoarthritis animal model of Preparation Example 3 Were injected with intraarticular injection (STA21 OA-MSC IA) or intravenous injection (STA21 OA-MSC IV). As a comparative example, mesenchymal stem cells of Preparation Example 1 were injected intravenously (OA-MSC IV) or intraarticularly (OA-MSC IA), and only MIA was administered as a control (MIA).
실시예 1-1. 정맥내 주사(IV)에 따른 STA-21이 처리된 간엽줄기세포의 통증 경감 효과 Example 1-1. Effect of intravenous injection (IV) on pain relief of STA-21 treated mesenchymal stem cells
투여 2일 후 Dynamic plantat aesthsiometer(Ugo Basile, Comerio, Italy)를 이용하여 통증을 측정하였다. 기계의 통증 측정 방법은 측정 기계 위에 그물로 된 판을 얹고 그 위에 아크릴로 된 동물고정틀 안에 랫(rat)을 넣은 후, 측정기계로 약물이 주입된 오른발에 찔러 주었다. 찌른 후에 기계가 자동적으로 발을 떼는데 걸리는 시간(s, 초)과 얼마만큼의 무게를 주었을 때 발을 떼는지(g)를 측정하여 그때 나오는 시간과 무게를 기재하여 통증 측정 그래프를 그렸다. 그 결과를 도 1 및 2에 나타내었다.Pain was measured 2 days after administration using a dynamic plantar aesthsiometer (Ugo Basile, Comerio, Italy). To measure the pain of a machine, a net plate was placed on a measuring machine, a rat was placed in an acrylic animal pouch, and the paw was pushed into the right foot with a measuring instrument. After stabbing, we measured the time (s, second) that the machine automatically took to release the foot, and the amount of foot release (g) when the weight was given. The results are shown in Figs. 1 and 2. Fig.
도 1에 나타낸 바와 같이, MIA만을 투여한 군에 비해 정맥내 투여된 OA 환자 유래 MSC를 주입한 군(OA-MSC IV)이 통증을 완화시킴을 확인할 수 있었으며, 특히, 정맥내 투여된 STA-21이 처리된 간엽줄기세포가 OA 환자 유래 MSC에 비해 통증을 더 경감시킴을 확인할 수 있었다.As shown in FIG. 1, OA-MSC IV-administered group (OA-MSC IV) from intravenously administered OA patients alleviated the pain, compared with the group administered with only MIA. In particular, intravenous administration of STA- 21-treated mesenchymal stem cells compared with MSCs derived from OA patients.
도 2에 나타낸 바와 같이, 투여 후 경과(0, 3, 11, 22 및 29일)에 따라 정맥내 투여된 STA-21이 처리된 간엽줄기세포가 OA 환자 유래 MSC에 비해 통증을 더 경감시킴을 확인하였다. 특히, 투여 후 경과가 지나도 통증 경감 효과가 지속됨을 확인하였다. As shown in FIG. 2, STA-21 treated mesenchymal stem cells administered intravenously according to the elapsed time after administration (0, 3, 11, 22 and 29 days) Respectively. In particular, it was confirmed that the pain relief effect persisted even after the administration.
또한, 각 투여군의 연골 손상 정도를 확인하기 위하여, 랫의 대퇴골(Femur) 및 경골(Tibia)을 채취하여 micro-CT로 관찰하여 연골 파괴 정도를 확인하였다. 그 결과를 도 3에 나타내었다.The femur and tibia of the rats were collected and examined with micro-CT to confirm the degree of cartilage destruction in each treatment group. The results are shown in Fig.
도 3에 나타낸 바와 같이, MIA만을 투여한 군보다 정맥내 투여된 OA 환자 유래 MSC를 주입한 군(OA-MSC IV)이 연골 손상이 억제되었으며, 상기 OA-MSC IV군 보다 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 경우(STA21-MSC IV) 더욱 연골 손상이 완화됨을 확인하였다. As shown in FIG. 3, cartilage damage was suppressed by OA-MSC IV group injected with MSC derived from OA patients administered intravenously, compared to the group administered with MIA alone, and STA-21 was treated more than OA-MSC IV group (STA21-MSC IV) in the case of intravenous injection of mesenchymal stem cells.
또한, 상기 각 군의 연골 손상 정도를 분석하기 위하여 H&E 염색을 수행하였으며, 각 군의 총 Mankin score, OARSI score 및 structure를 확인하였다(도 4). 또한, 각 군의 연골에서 발현되는 염증성 사이토 카인을 발현하는 세포를 분석하기 위하여, il-6, TNF-a, HIF2-a, IL-6(beta) IHC 염색을 수행하였으며, 이를 확인하였다(도 5). 그 결과를 도 4 및 5에 나타내었다. H & E staining was performed to analyze the degree of cartilage damage in each group, and the total Mankin score, OARSI score and structure of each group were confirmed (FIG. 4). IL-6, TNF-a, HIF2-a and IL-6 (beta) IHC staining were performed to analyze cells expressing inflammatory cytokines expressed in cartilage of each group 5). The results are shown in Figs.
도 4에 나타낸 바와 같이, STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 경우(STA21-MSC IV), MIA만을 투여한 군과 정맥내 투여된 OA 환자 유래 MSC를 주입한 군(OA-MSC IV)보다 연골 손상이 감소됨을 확인하였다. As shown in FIG. 4, in the case of intravenously administering STA-21-treated mesenchymal stem cells (STA21-MSC IV), the group administered with MIA alone and the group injected with MSC derived from intravenously administered OA (OA- MSC IV).
또한, 도 5에 나타낸 바와 같이, STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 경우(STA21-MSC IV) MIA만을 투여한 군과 비교하여 염증성 사이토카인 발현을 억제하여, 통증을 경감시킴을 확인하였다.In addition, as shown in FIG. 5, when STA-21-treated mesenchymal stem cells were intravenously administered (STA21-MSC IV), inflammatory cytokine expression was suppressed and pain was reduced as compared with the MIA- Respectively.
실시예 1-2. 관절강내 주사(IA)에 따른 STA-21이 처리된 간엽줄기세포의 통증 경감 효과 Examples 1-2. The effect of STA-21-treated mesenchymal stem cells on pain relief by intra-articular injection (IA)
관절강내 주사에 따른 각 군의 통증 경감 효과 확인은 상기 실시예 1-1에 기재된 기계의 통증 측정 방법에 따라 측정하였다. 그 결과를 도 6에 나타내었다.The pain relief effect of each group according to the intra-articular injection was measured according to the machine's pain measuring method described in Example 1-1 above. The results are shown in Fig.
도 6에 나타낸 바와 같이, OA 환자 유래 MSC를 관절강내로 투여했을 때 정맥내 투여에 비해 통증억제 효과는 떨어지지만 연골 보호 효과는 더 좋은 것을 확인할 수 있었다. 또한, 관절강내 투여된 STA-21이 처리된 간엽줄기세포는 OA 환자 유래 MSC에 비해 연골 보호 및 통증 억제 둘 다에서 더 적은 효과를 나타냄을 확인할 수 있었다. As shown in FIG. 6, when MSC derived from OA patients was administered into the joints, the pain suppressing effect was lower than that of intravenous administration, but the cartilage protective effect was better. In addition, it was confirmed that the mesenchymal stem cells treated with STA-21 administered in the joints were less effective in both cartilage protection and pain suppression than MSCs derived from OA patients.
실시예 2 : 본 발명의 키트에 의한 골관절염 치료 효과 분석Example 2: Analysis of therapeutic effect of osteoarthritis by the kit of the present invention
실시예 2-1. 본 발명의 키트에 의한 통증 억제 효과 확인Example 2-1. Confirming the pain relief effect of the kit of the present invention
제조예 3의 골관절염 동물모델에게 제조예 1의 3x105 세포수의 간엽줄기세포를 관절강내 주사(intraarticular injection)로 주입하고 제조예 2의 3x105 세포수의 STA-21이 처리된 간엽줄기세포를 정맥내 주사(intravenous injection)로 주입하였다(STA21 IV + OA IA). 비교예로서 STA-21이 처리된 간엽줄기세포 단독으로 정맥내 주사(STA21 OA-MSC IA)로 주입하거나 간엽줄기세포 단독으로 관절강내 주사(OA-MSC IA)로 주입하였다. 대조군(MIA)으로는 MIA만을 투여하였다.The osteoarthritis animal model of Preparation Example 3 was injected with 3x10 5 cells of mesenchymal stem cells of Preparation Example 1 by intraarticular injection and cultured with 3x10 5 cells of STA-21-treated mesenchymal stem cells of Preparation Example 2 And injected intravenously (STA21 IV + OA IA). As a comparative example, STA-21-treated mesenchymal stem cells were injected intravenously (STA21 OA-MSC IA) or mesenchymal stem cells alone (OA-MSC IA). MIA alone was administered as a control (MIA).
투여 후 2일이 경과한 다음부터 투여 후 28일 까지 실시예 1과 같은 방법으로 통증정도를 확인하고 그 결과를 도 7에 나타내었다.The pain level was confirmed in the same manner as in Example 1 from 2 days after administration to 28 days after administration, and the results are shown in FIG.
도 7에 볼 수 있는 바와 같이, 간엽줄기세포를 관절강내 주사로 주입하고 동시에 STA-21이 처리된 간엽줄기세포를 정맥내 주사로 주입했을 때(STA21 IV + OA IA), 비교예(STA21 OA-MSC IA 또는 OA-MSC IA)에 비해 개선된 통증 억제 효과를 나타냄을 확인할 수 있었다. 또한, 투여 후 시간이 경과하여도 통증 억제 효과는 지속됨을 확인하였다.As shown in FIG. 7, when mesenchymal stem cells were injected by intra-articular injection and STA-21-treated mesenchymal stem cells were injected by intravenous injection (STA21 IV + OA IA) -MSC IA or OA-MSC IA). In addition, it was confirmed that the pain control effect persisted even after the administration time.
실시예 2-2. 본 발명의 키트에 의한 연골 손상 억제 효과 확인Example 2-2. Confirming cartilage damage inhibitory effect by the kit of the present invention
각 투여군의 연골 손상 정도를 확인하기 위하여, 랫의 대퇴골(Femur) 및 경골(Tibia)을 채취하여 micro-CT로 관찰하여 연골 파괴 정도를 확인하였다(도 8). In order to confirm the degree of cartilage damage in each administration group, the femur and tibia of the rat were collected and observed with micro-CT to confirm the degree of cartilage destruction (FIG. 8).
도 8에 나타낸 바와 같이, 간엽줄기세포를 관절강내 투여하고 동시에 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 경우(STA21 IV + OA IA), 비교예(STA21 OA-MSC IA 또는 OA-MSC IA)에 비해 연골 파괴가 억제된 것이 관찰되었다. As shown in FIG. 8, when mesenchymal stem cells were intraarticularly administered and STA-21-treated mesenchymal stem cells were intravenously administered (STA21 IV + OA IA), the comparative example (STA21 OA-MSC IA or OA- MSC IA) was observed in the control group.
실시예 2-3: 본 발명의 키트에 의한 조직 내에 통증 마커 확인 및 신경 통증 억제 효과 확인Example 2-3: Confirmation of the pain marker in the tissue by the kit of the present invention and the inhibitory effect on nerve pain
통증 측정(in vivo)에서의 효과를 정량적으로 확인하기 위하여 동물 희생 시 척추를 따로 분리하고 척추의 등쪽 부분을 제거해 나가면서 척수를 드러나게 하였다. 그 후 요추 1~5번 사이에 있는 Dorsal Root Ganglion 조직을 채취하여 면역염색법을 통하여 통증 전달물질인 CGRP 발현량의 확인을 통해 직접적으로 통증의 억제를 관찰하였다. 그 결과를 도 9에 나타내었다. In order to quantitatively confirm the effects of in vivo measurements, the spine was separated during animal sacrifice and the spinal cord was exposed while removing the dorsal part of the spine. Then, Dorsal Root Ganglion tissue between lumbar spine 1 ~ 5 was taken and immunostaining was performed to confirm the inhibition of pain directly by confirming the amount of CGRP expression. The results are shown in Fig.
도 9의 조직결과에서 볼 수 있는 것과 같이, 엽줄기세포를 관절강내 투여하고 동시에 STA-21이 처리된 간엽줄기세포를 정맥내 투여했을 경우(STA21 IV + OA IA), 비교예(STA21 OA-MSC IA 또는 OA-MSC IA)에 비해 통증 전달물질인 CGRP 발현량이 낮아짐을 확인하여, 연골파괴 뿐만 아니라 직접적인 신경 통증 억제도 이루어지는 것을 확인할 수 있다.As can be seen from the tissue results in FIG. 9, STA21-treated mesenchymal stem cells were intravenously administered (STA21 IV + OA IA) and staphylococcal stem cells (STA21 OA- MSC IA or OA-MSC IA), it was confirmed that not only cartilage destruction but also direct neuropathy was suppressed.
실시예 3 : STA-21이 모두 처리된 본 발명의 키트에 의한 골관절염 치료 효과 분석Example 3: Analysis of the effect of treating osteoarthritis with the kit of the present invention in which STA-21 was all treated
실시예 3-1. 본 발명의 키트에 의한 통증 억제 효과 확인Example 3-1. Confirming the pain relief effect of the kit of the present invention
제조예 3의 골관절염 동물모델에게 제조예 1의 3x105 세포수의 STA-21이 처리된 간엽줄기세포를 관절강내 주사(intraarticular injection)로 주입하고 제조예 2의 3x105 세포수의 STA-21이 처리된 간엽줄기세포를 정맥내 주사(intravenous injection)로 주입하였다(STA21 OA-MSC IA+IV). 비교예로서 STA-21이 처리된 간엽줄기세포 단독으로 정맥내 주사(STA21 OA-MSC IV)로 주입하거나, STA-21이 처리된 간엽줄기세포 단독으로 관절강내 주사(STA21 OA-MSC IA)로 주입하였다. 대조군(MIA)으로는 MIA만을 투여하였다.The osteoarthritis animal model of Preparation Example 3 was injected with intraarticular injection of STA-21-treated mesenchymal stem cells of 3x10 5 cells of Preparation Example 1, and STA-21 of 3x10 5 cells of Preparation Example 2 Treated mesenchymal stem cells were injected intravenously (STA21 OA-MSC IA + IV). As a comparative example, STA-21-treated mesenchymal stem cells were injected intravenously (STA21 OA-MSC IV) or STA-21-treated mesenchymal stem cells alone (STA21 OA-MSC IA) Respectively. MIA alone was administered as a control (MIA).
투여 후 0, 5, 12, 20, 29일이 경과한 다음부터 실시예 1과 같은 방법으로 통증정도를 확인하고 그 결과를 도 10에 나타내었다.After 0, 5, 12, 20, and 29 days after administration, the degree of pain was confirmed in the same manner as in Example 1, and the results are shown in FIG.
도 10에 볼 수 있는 바와 같이, STA-21이 처리된 간엽줄기세포를 관절강내 주사로 주입하고 동시에 STA-21이 처리된 간엽줄기세포를 정맥내 주사로 주입했을 때(STA21 OA-MSC IA+IV), 비교예(STA21 OA-MSC IA 또는 STA21 OA-MSC IA)에 비해 개선된 통증 억제 효과를 나타냄을 확인할 수 있었다. 또한, 투여 후 시간이 경과하여도 통증 억제 효과는 지속됨을 확인하였다.As shown in FIG. 10, when STA-21-treated mesenchymal stem cells were injected by intra-articular injection and STA-21-treated mesenchymal stem cells were injected by intravenous injection (STA21 OA-MSC IA + IV), and Comparative Example (STA21 OA-MSC IA or STA21 OA-MSC IA). In addition, it was confirmed that the pain control effect persisted even after the administration time.
실시예 3-2. 본 발명의 키트에 의한 연골 손상 억제 효과 확인Example 3-2. Confirming cartilage damage inhibitory effect by the kit of the present invention
각 투여군의 연골 손상 정도를 확인하기 위하여, H&E 염색을 수행하였으며, 각 군의 총 Mankin score, OARSI score 및 structure를 확인하였다(도 11). 또한, C. Micro CT 분석을 통하여 골 볼륨(%)을 분석하였다(도 12). 그 결과를 도 11 및 도 12에 나타내었다.H & E staining was performed to confirm the degree of cartilage damage in each administration group, and the total Mankin score, OARSI score and structure of each group were confirmed (FIG. 11). In addition, bone volume (%) was analyzed through C. Micro CT analysis (FIG. 12). The results are shown in Figs. 11 and 12. Fig.
도 11 및 도 12에 나타낸 바와 같이, STA-21이 처리된 간엽줄기세포를 관절강내 주사로 주입하고 동시에 STA-21이 처리된 간엽줄기세포를 정맥내 주사로 주입했을 때(STA21 OA-MSC IA+IV), 비교예(STA21 OA-MSC IA 또는 STA21 OA-MSC IA)에 비해 ankin score, OARSI score 및 structurerk 낮고, 골 볼륨(%)가 높음을 확인하여, 연골 파괴가 억제된 것이 관찰되었다.As shown in FIG. 11 and FIG. 12, when STA-21-treated mesenchymal stem cells were injected by intra-articular injection and STA-21-treated mesenchymal stem cells were injected by intravenous injection (STA21 OA-MSC IA (OA-MSC IA or STA21 OA-MSC IA) compared to the control group (STA21 + OVA + IV), and OARSI score and structurerk were low and bone volume (%) were high.
실시예 3-3: 본 발명의 키트에 의한 조직 내에 통증 마커 확인 및 신경 통증 억제 효과 확인Example 3-3: Confirmation of pain marker in the tissue by the kit of the present invention and inhibition of neuropathy
통증 측정(in vivo)에서의 효과를 정량적으로 확인하기 위하여, 각 군이 투여된 신경절 내의 통증 마커인 TRPV1을 확인하기 위하여 IHC 염색하여 이를 확인하였다. 그 결과를 도 13에 나타내었다. In order to quantitatively confirm the effects of in vivo measurements, IHC staining was performed to identify TRPV1, a pain marker in the ganglion in which each group was administered. The results are shown in Fig.
도 13의 조직결과에서 볼 수 있는 것과 같이, STA-21이 처리된 간엽줄기세포를 관절강내 주사로 주입하고 동시에 STA-21이 처리된 간엽줄기세포를 정맥내 주사로 주입했을 때(STA21 OA-MSC IA+IV), 비교예(STA21 OA-MSC IA 또는 STA21 OA-MSC IA)에 비해 신경절 내의 통증 마커인 TRPV1 활성이 현저히 감소됨을 확인하였다. As shown in FIG. 13, when STA-21-treated mesenchymal stem cells were injected by intramuscular injection and STA-21-treated mesenchymal stem cells were injected by intravenous injection (STA21 OA- MSC IA + IV) and the comparative example (STA21 OA-MSC IA or STA21 OA-MSC IA), TRPV1 activity as a pain marker in the ganglion was markedly reduced.
실시예 3-4: in vitro 내 STA21 처리된 MSC의 타깃 세포 활성 조절 확인Example 3-4: Control of target cell activity of STA21-treated MSCs in vitro
STA21-MSC의 in vitro 내 효력을 평가하고 타겟 세포의 활성을 조절하기 위하여, Sta21-MSC와 연골세포(chondrocyte)(A), 파골세포(osteoclast)(B), 조골세포(osteoblast)(c)를 각각 공조 배양하여, 각 세포의 활성인자를 분석하였다. 각 세포는 1X104으로 공조 배양하였으며, 공조 배양시 3uM의 trans well을 사용하였다. 아래의 플래이트에 타깃 세포를 seeding 하였으며, trans well 에는 STA21-MSC 를 seeding하였다. 그 결과를 도 14에 나타내었다.Sta21-MSC and chondrocyte (A), osteoclast (B), osteoblast (c), and osteoblast (c) were used to evaluate the in vitro efficacy of STA21- Were co-cultured, and the activity factors of each cell were analyzed. Each cell was air-conditioned with 1 × 10 4 , and 3 μM transwell was used for air-conditioning culture. The target cells were seeded in the following plate, and STA21-MSC was seeded in the trans well. The results are shown in Fig.
도 14에 나타낸 바와 같이, 연골세포(Chondrocyte)와 공조 배양시 카다볼릭 팩터인 ADAMTS5의 활성은 억제 되었으며, 아나볼릭 인자인 TIMP1, 3의 활성은 증가됨을 확인하였다. 또한, 파골 세포와의 공조 배양시, 파골세포 활성 인자인 cathepsin-K의 활성이 억제됨을 확인하였다. 또한, 조골 세포와의 공조 배양시 조골세포에서 활성되는 염증성 인자인 IL-6, IL-1b의 활성이 현저히 억제됨을 확인하였다. 따라서, 상기와 결과로 STA21 처리된 MSC는 연골 손상 및 염증 반응을 일으킬 수 있는 타깃 세포의 활성을 조절 할 수 있는 효과가 존재함을 in vitro 상으로 확인하였다.As shown in FIG. 14, the activity of ADAMTS5, which is a cadaveric factor, in chondrocyte cultures was inhibited and the activity of anabolic factors TIMP1, 3 was increased. In addition, it was confirmed that the activity of cathepsin-K, an osteoclast activator, was inhibited when cultured with osteoclasts. In addition, it was confirmed that the activity of IL-6, IL-1b, which is an inflammatory factor activated in osteoblasts, is significantly inhibited when cultured with osteoblasts. Therefore, as a result, the MSC treated with STA21 confirmed in vitro that there is an effect of regulating the activity of the target cells which may cause cartilage damage and inflammatory reaction.
실시예 4: SD-282에 의한 통증 조절 및 연골보호 인자 발현 Example 4: Regulation of pain and expression of cartilage protective factor by SD-282
중간엽 줄기세포를 다른 자극 없이 메트포민과 SD282를 처리 하고 3일 동안 배양하여 ELISA (효소결합 면역흡착 분석법)를 통해 염증성 cytokine을 측정하였다. 도 15으로부터 통증과 더불어 염증관련 Factor 인 IL-6 cytokine은 SD282 및 메트포민에 의해 억제되었고, 항염증 인자인 IL-10 cytokine 발현량은 SD282에 의해 증가된 것을 확인할 수 있었다. 따라서 염증과 더불어 통증 메커니즘과도 연관이 있는 항염요소는 증가시키고 염증요소는 감소시켜 통증과 염증의 매개인자를 효과적으로 조절할 수 있음을 확인했다.Mesenchymal stem cells were treated with metformin and SD282 without any stimulation and cultured for 3 days, and inflammatory cytokines were measured by ELISA (enzyme linked immunosorbent assay). 15, IL-6 cytokine, which is an inflammation-related factor, was inhibited by SD282 and metformin, and the amount of IL-10 cytokine, an anti-inflammatory agent, was increased by SD282. Thus, it has been confirmed that anti-inflammatory factors associated with inflammation as well as pain mechanisms are increased, and inflammatory factors are reduced to effectively control pain and inflammatory mediators.
실시예 5: SD-282에 의한 항염증 및 연골보호Example 5: Anti-inflammatory and cartilage protection by SD-282
연골세포에 IL-1beta를 처리하여 골관절염 연골과 유사한 상태로 만들어 주고 메트포민과 SD282를 처리하여 하룻동안 배양 후 RNA추출과, cDNA합성을 거쳐 중합효소연쇄반응 (PCR)을 통하여 연골 합성요소와 파괴 요소를 정량 분석하였다. 도 16에서 볼 수 있는 바와 같이, 연골 파괴 인자인 MMP-13은 SD282가 메트포민과 유사하게 억제하는 것을 확인하였고, 연골 보호 인자인 TIMP1의 발현량은 메트포민보다 SD282에 의해 더 크게 증가된 것을 관찰할 수 있었다. 따라서 SD282에 의해 Chondrogenesis mechanism을 활성화시키고 그로인해 Anabolic factor는 증가키시고 catabolic factor는 감소시켜 연골보호와 재생에 뛰어난 효과를 기대할 수 있다.The cartilage cells were treated with IL-1beta to make them similar to osteoarthritic cartilage, and cultured with metformin and SD282 for one day. RNA extraction, cDNA synthesis, and polymerase chain reaction (PCR) Were quantitatively analyzed. As can be seen from FIG. 16, MMP-13, a cartilage-destroying factor, was found to inhibit SD282 similarly to metformin, and the expression level of TIMP1, a cartilage protective factor, was significantly increased by SD282 than metformin I could. Therefore, by activating the chondrogenesis mechanism by SD282, anabolic factor can be increased and catabolic factor can be decreased, so that an excellent effect on cartilage protection and regeneration can be expected.
Claims (11)
간엽줄기세포를 유효성분으로 포함하는 관절강내 투여용 조성물을 포함하는, 통증이 경감되는 골관절염 치료용 키트.A composition for intravenous administration comprising an mesenchymal stem cell treated with STAT3 (signal transducer and activator of transcription 3) inhibitor as an active ingredient; And
A kit for treating pain-relieved osteoarthritis comprising a composition for intra-articular administration comprising mesenchymal stem cells as an active ingredient.
상기 관절강내 투여용 조성물은 STAT3 억제제가 처리된 것을 특징으로 하는 키트.The method according to claim 1,
Wherein the composition for intra-articular administration is a STAT3 inhibitor.
상기 STAT3 억제제는 STA-21 (8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12(2H)-trione), SD282 (N,N-Ethyl-4-fluorophenyl biguanide), 메트포민, AG-490 ((E)-2-Cyano-3-(3,4-dihydrophenyl)-N-(phenylmethyl)-2-propenamide), 아티프리모드 (Atiprimod; 3-(8,8-dipropyl-3-azaspiro[4.5]decan-3-yl)-N,N- diethylpropan-1-amine), 오라노핀 (Auranofin; 3,4,5-triacetyloxy-6- (acetyloxymethyl) oxane-2-thiolate; triethylphosphanium), 오로싸이오말레이트 (Aurothiomalate; Sodium 2-(auriosulfanyl)-3-carboxypropanoate), BMS-354825 (Dasatinib; N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate), CADPE (3-(3,4-dihydroxy-phenyl)-acrylic acid 2-(3,4-dihydroxy-phenyl)-ethyl ester), 스타틱 (Stattic; 6-nitro-1,1-dioxide-benzo[b]thiophene), 도베실레이트 (Dobesilate; calcium 2,5-dihydroxybenzenesulfonate), 에탄올(Ethanol), NCX-4016(NO-Aspirin), 넬피나비어(Nelfinavir; (3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylphenyl)formamido]-4-(phenylsulfanyl)butyl]-decahydroisoquinoline-3-carboxamide), PDP(phosphododecapeptide), PS-341(볼테조밉(Bortezomib); [(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid), R115777(티피파르닙(tipifarnib); 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one), S31-M2001(N-Hexyl-2-(1-naphthalenyl)-5-[[4-(phosphonooxy)phenyl]), 스타틴계 화합물, 소듐살리실레이트(Sodium Salicylate), 카페익산(Caffeic acid; 3-(3,4-Dihydroxyphenyl)-2-propenoic acid 3,4-Dihydroxy-cinnamic acid trans-Caffeate 3,4-Dihydroxy-trans-cinnamate)), 에모딘(Emodin; 1,8-Dihydroxy-3-(hydroxymethyl)-9,10-anthracenedione), 우르솔릭산(Ursolic acid; 3-beta-3-hydroxy-urs-12-ene-28-oic-acid), 레스베라트롤(Resveratrol; 3,5,4'-trihydroxy-trans-stilbene), 레티노익산(Retinoic acid; (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid), EGCG(Epigallocatechin gallate; [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl] 3,4,5-trihydroxybenzoate), Sr11302((E,E,Z,E)-3-Methyl-7-(4-methylphenyl)-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid), 탄시논 IIA(Tanshinone IIA; 1,6,6-Trimethyl-6,7,8,9-tetrahydrophenanthro[1,2-b]furan-10,11-dione) 및 커큐민(curcumin; (1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione)으로 이루어진 군으로부터 선택되는 하나 이상인 것인 키트.3. The method according to claim 1 or 2,
The STAT3 inhibitor may be selected from the group consisting of STA-21 (8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12 (2H) -trione), SD282 (N, N- (E) -2-Cyano-3- (3,4-dihydrophenyl) -N- (phenylmethyl) -2-propenamide, Atiprimod 3- (8,8-dipropyl- azaspiro [4.5] decan-3-yl) -N, N-diethylpropan-1-amine, Auranofin (3,4,5-triacetyloxy- 6- (acetyloxymethyl) oxane-2-thiolate, Aurothiomalate (Sodium 2- (auriosulfanyl) -3-carboxypropanoate), BMS-354825 (Dasatinib; N- (2-chloro-6- methylphenyl) -2 - [[6- [4- (2- -1-piperazinyl] -2-methyl-4-pyrimidinyl] amino] -5-thiazole carboxamide monohydrate), CADPE (3- (3,4-dihydroxy- ) -ethyl ester, Stattic (6-nitro-1,1-dioxide-benzo [b] thiophene, Dobesilate (calcium 2,5-dihydroxybenzenesulfonate), Ethanol, NCX-4016 (NO-Aspirin), Nelfinavir (3S, 4aS, 8aS) -N-tert-butyl-2 -Decahydroisoquinoline-3-carboxamide), PDP (phosphododecapeptide), PS-341 (manufactured by Dainippon Ink and Chemicals, Incorporated) (Bortezomib; 2-ylcarbonyl) amino] propanoyl} amino) butyl] boronic acid, R115777 (tipifarnib (R) (1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methylquinolin-2 (N-Hexyl-2- (1-naphthalenyl) -5 - [[4- (phosphonooxy) phenyl], statin compound, sodium salicylate, caffeic acid 3- 4-Dihydroxyphenyl) -2-propenoic acid 3,4-Dihydroxy-cinnamic acid trans-Caffeate 3,4-Dihydroxy-trans- cinnamate), Emodin (1,8-Dihydroxy- , 10-anthracenedione, 3-beta-3-hydroxy-urs-12-ene-28-oic acid, resveratrol, 3,5,4'-trihydroxy- Retinoic acid (2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid ), EGCG (Epigallocatechin gallate; [(2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl] 3,4,5-trihydroxybenzoate), Sr11302 , E, Z, E) -3 -Methyl-7- (4-methylphenyl) -9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraenoic acid), Tanshinone IIA (Tanshinone IIA; 1,6,6-Trimethyl-6,7,8,9-tetrahydrophenanthro [1,2-b] furan-10,11-dione and curcumin (1E, 6E) -hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione).
상기 정맥내 투여용 조성물과 상기 관절강내 투여용 조성물은 동시에 투여되는 것인 키트.The method according to claim 1,
Wherein the composition for intravenous administration and the composition for intra-articular administration are administered simultaneously.
상기 STAT3 억제제가 처리된 간엽줄기세포는 통증을 경감시키는 것인 키트.The method according to claim 1,
Wherein said STAT3 inhibitor treated mesenchymal stem cells alleviate pain.
상기 간엽줄기세포는 골관절염 환자의 말초혈액 또는 지방조직으로부터 분리된 것인 키트.The method according to claim 1,
Wherein said mesenchymal stem cells are isolated from peripheral blood or adipose tissue in osteoarthritis patients.
상기 간엽줄기세포를 유효성분으로 포함하는 조성물을 관절강내 투여는 STAT3 억제제가 처리된 것을 특징으로 하는 방법.8. The method of claim 7,
Wherein the composition comprising the mesenchymal stem cells as an active ingredient is administered to the joints by treatment with a STAT3 inhibitor.
상기 STAT3 억제제는 STA-21(8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12(2H)-trione), SD282, 메트포민, AG-490 ((E)-2-Cyano-3-(3,4-dihydrophenyl)-N-(phenylmethyl)-2-propenamide), 아티프리모드(Atiprimod; 3-(8,8-dipropyl-3-azaspiro[4.5]decan-3-yl)-N,N- diethylpropan-1-amine), 오라노핀(Auranofin; 3,4,5-triacetyloxy-6- (acetyloxymethyl) oxane-2-thiolate; triethylphosphanium), 오로싸이오말레이트(Aurothiomalate; Sodium 2-(auriosulfanyl)-3-carboxypropanoate), BMS-354825(Dasatinib; N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate), CADPE(3-(3,4-dihydroxy-phenyl)-acrylic acid 2-(3,4-dihydroxy-phenyl)-ethyl ester), 스타틱(Stattic; 6-nitro-1,1-dioxide-benzo[b]thiophene), 도베실레이트(Dobesilate; calcium 2,5-dihydroxybenzenesulfonate), 에탄올(Ethanol), NCX-4016(NO-Aspirin), 넬피나비어(Nelfinavir; (3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylphenyl)formamido]-4-(phenylsulfanyl)butyl]-decahydroisoquinoline-3-carboxamide), PDP(phosphododecapeptide), PS-341(볼테조밉(Bortezomib); [(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid), R115777(티피파르닙(tipifarnib); 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one), S31-M2001(N-Hexyl-2-(1-naphthalenyl)-5-[[4-(phosphonooxy)phenyl]), 스타틴계 화합물, 소듐살리실레이트(Sodium Salicylate), 카페익산(Caffeic acid; 3-(3,4-Dihydroxyphenyl)-2-propenoic acid 3,4-Dihydroxy-cinnamic acid trans-Caffeate 3,4-Dihydroxy-trans-cinnamate)), 에모딘(Emodin; 1,8-Dihydroxy-3-(hydroxymethyl)-9,10-anthracenedione), 우르솔릭산(Ursolic acid; 3-beta-3-hydroxy-urs-12-ene-28-oic-acid), 레스베라트롤(Resveratrol; 3,5,4'-trihydroxy-trans-stilbene), 레티노익산(Retinoic acid; (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid), EGCG(Epigallocatechin gallate; [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl] 3,4,5-trihydroxybenzoate), Sr11302((E,E,Z,E)-3-Methyl-7-(4-methylphenyl)-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid), 탄시논 IIA(Tanshinone IIA; 1,6,6-Trimethyl-6,7,8,9-tetrahydrophenanthro[1,2-b]furan-10,11-dione) 및 커큐민(curcumin; (1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione)으로 이루어진 군으로부터 선택되는 하나 이상인 것인 방법. 9. The method according to claim 7 or 8,
The STAT3 inhibitor may be selected from the group consisting of STA-21 (8-hydroxy-3-methyl-3,4-dihydrotetraphene-1,7,12 2H-trione), SD282, metformin, AG- 3- (3,4-dihydrophenyl) -N- (phenylmethyl) -2-propenamide, Atiprimod 3- (8,8-dipropyl-3-azaspiro [4.5] decan- Diethylpropan-1-amine, Auranofin, 3,4,5-acetyloxymethyl oxane-2-thiolate, Aurothiomalate (Sodium 2- (auriosulfanyl) -3-carboxypropanoate), BMS-354825 (Dasatinib; N- (2-chloro-6-methylphenyl) -2 - [[6- [4- (2-hydroxyethyl) pyrimidinyl amino] -5-thiazole carboxamide monohydrate, CADPE (3- (3,4-dihydroxy-phenyl) -acrylic acid 2- dihydroxybenzenesulfonate, ethanol, NCX-4016 (NO-Aspirin), Nelfinavir (Nelfinavir), and the like. (3S, 4aS, 8aS) -N-tert-butyl-2 - [(2R, 3R) -2-hydroxy- 3 - [(3-hydroxy- nyl) formamido] -4- (phenylsulfanyl) butyl] decahydroisoquinoline-3-carboxamide), PDP (phosphododecapeptide), PS-341 (Bortezomib; 2-ylcarbonyl) amino] propanoyl} amino) butyl] boronic acid, R115777 (tipifarnib (R) (1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methylquinolin-2 (N-Hexyl-2- (1-naphthalenyl) -5 - [[4- (phosphonooxy) phenyl], statin compound, sodium salicylate, caffeic acid 3- 4-Dihydroxyphenyl) -2-propenoic acid 3,4-Dihydroxy-cinnamic acid trans-Caffeate 3,4-Dihydroxy-trans- cinnamate), Emodin (1,8-Dihydroxy- , 10-anthracenedione, 3-beta-3-hydroxy-urs-12-ene-28-oic acid, resveratrol, 3,5,4'-trihydroxy- Retinoic acid (2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid ), EGCG (Epigallocatechin gallate; [(2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl] 3,4,5-trihydroxybenzoate), Sr11302 , E, Z, E) -3 -Methyl-7- (4-methylphenyl) -9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraenoic acid), Tanshinone IIA (Tanshinone IIA; 1,6,6-Trimethyl-6,7,8,9-tetrahydrophenanthro [1,2-b] furan-10,11-dione and curcumin (1E, 6E) -hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione).
STAT3(Signal transducer and activator of transcription 3) 억제제가 처리된 간엽줄기세포를 유효성분으로 포함하는 조성물을 정맥내 투여하는 것은 골관절염의 통증을 경감시키는 것인 방법. 8. The method of claim 7,
Wherein intravenous administration of a composition comprising as an active ingredient mesenchymal stem cells treated with STAT3 (signal transducer and activator of transcription 3) inhibitor alleviates the pain of osteoarthritis.
상기 간엽줄기세포는 골관절염 환자의 말초혈액 또는 지방조직으로부터 분리된 것인 방법.
8. The method of claim 7,
Wherein said mesenchymal stem cells are isolated from peripheral blood or adipose tissue in osteoarthritis patients.
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