KR20190117153A - A composition for prevention or treatment of bone diseases comprising lycopi herba extract - Google Patents
A composition for prevention or treatment of bone diseases comprising lycopi herba extract Download PDFInfo
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- KR20190117153A KR20190117153A KR1020180040306A KR20180040306A KR20190117153A KR 20190117153 A KR20190117153 A KR 20190117153A KR 1020180040306 A KR1020180040306 A KR 1020180040306A KR 20180040306 A KR20180040306 A KR 20180040306A KR 20190117153 A KR20190117153 A KR 20190117153A
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Abstract
Description
본 발명은 택란 추출물을 유효성분으로 함유하는 골 질환 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, ameliorating or treating bone diseases, which contains the taxane extract as an active ingredient.
뼈(bone)는 인체의 연조직과 체중을 지탱해주고 내부기관을 둘러싸서 내부 장기를 외부의 충격으로부터 보호한다. Bones support the soft tissues and weight of the body and surround internal organs to protect internal organs from external shocks.
또한 뼈는 근육이나 장기를 구조적으로 지탱할 뿐만 아니라 체내의 칼슘이나 다른 필수 무기질 즉 인이나 마그네슘과 같은 물질을 저장하는 인체의 중요한 부분 중 하나이다.Bones are also an important part of the human body that not only structurally supports muscles or organs, but also stores calcium and other essential minerals such as phosphorus and magnesium in the body.
따라서 성장이 끝난 성인의 뼈는 오래된 뼈는 제거하고 새로운 뼈로 대체하는 생성과 흡수 과정을 역동적, 지속적으로 반복 재생하면서 균형을 유지하게 되는데, 이를 골 재형성(bone remodeling)이라고 한다. Thus, bones of grown adults are balanced by dynamically and continuously regenerating the production and absorption process of removing old bones and replacing them with new bones. This is called bone remodeling.
뼈의 순환(turnover)은 성장과 스트레스에 의해서 일어나는 뼈의 미세한 손상을 회복시키고 그 기능을 유지하는데 필수적이다. 성인에서는 매년 골격의 약 10-30 %가 골흡수-골형성의 리모델링을 통하여 재형성된다.Bone turnover is essential to repair and maintain microscopic damage to bone caused by growth and stress. In adults, about 10-30% of the skeleton is remodeled each year through bone resorption-bone remodeling.
뼈 재형성에는 크게 두 종류의 세포, 뼈를 생성하는 조골세포(osteoblast) 및 뼈를 파괴하는 파골세포(osteoclast)가 관여하며 서로 밀접한 연관성으로 골의 항상성이 유지된다.Bone remodeling involves two types of cells, osteoblasts that produce bone, and osteoclasts that destroy bone, and bone homeostasis is maintained in close association with each other.
예를 들어, 조골세포는 RANKL(receptor activator of nuclear factor-κκB ligand), 및 그의 미끼 수용체인 OPG(osteoprotegerin)과 같은 물질의 분비를 통해 골흡수를 담당하는 파골세포의 분화를 조절함으로써 체내의 골 항상성을 유지한다.Osteoblasts, for example, regulate the differentiation of osteoclasts responsible for bone resorption through the secretion of substances such as receptor activator of nuclear factor-κκB ligand (RANKL) and its decoy receptor OPG (osteoprotegerin). Maintain homeostasis.
즉, RANKL이 파골 전구세포 표면 수용체인 RANK에 결합하면 파골 전구 세포가 파골세포로 성숙화되어 골흡수가 일어나며, OPG가 RANKL과 결합하면 RANKL과 RANK간 결합이 차단되어 파골세포의 형성이 억제된다.That is, when RANKL binds to RANK, an osteoclast progenitor cell surface receptor, osteoclast progenitor cells mature into osteoclasts, and bone resorption occurs. When OPG binds to RANKL, binding between RANKL and RANK is blocked and inhibition of osteoclast formation.
전구세포로부터 형성되는 파골세포는 오래된 뼈를 흡수 또는 파괴하며, 뼈에 축적된 소량의 칼슘을 혈류로 방출시켜 신체기능 유지에 사용한다(William J. et al., NATURE.,423, pp.337342, 2033).Osteoclasts, which are formed from progenitor cells, absorb or destroy old bone, and release small amounts of calcium accumulated in the bone into the bloodstream to maintain body function (William J. et al., NATURE., 423, pp. 337342). , 2033).
상기 대사는 물리적 영향, 호르몬 체계 및 국소 인자에 의해 조절되는데, 여러 요인에 의해 골 흡수가 골 형성을 초과하여 골량이 한계 이하로 감소하게 되면 골조직의 손상을 동반한 각종 골질환이 발생한다.The metabolism is regulated by physical effects, hormonal systems, and local factors. When bone resorption exceeds bone formation and the amount of bone decreases below the limit by various factors, various bone diseases with damage to bone tissues occur.
이러한 골조직 손상을 동반한 질환의 치료와 관련하여 과거에는 주로 골 무기질, 즉 칼슘과 인의 대사 이상만을 중심으로 연구가 진행되어 왔으며, 그 기전 규명에 있어서 진전을 보지 못하였다. 따라서, 파골세포 분화 억제 물질을 개발하기 위하여 많은 연구가 진행되고 있다.In the past, studies on the treatment of diseases involving bone tissue damage have been conducted mainly on the metabolic abnormalities of bone minerals, that is, calcium and phosphorus, and no progress has been made in identifying the mechanism. Therefore, many studies have been conducted to develop osteoclast differentiation inhibitors.
한편, 한의학에서 주로 사용하는 한약재들은 발병 원인 및 증상이 복합적으로 나타나는 만성, 난치성 질환의 예방 및 치료에 있어 멀티 타겟 기전에 의해 보다 근본적인 치료제로서의 가능성이 대두되고 있다.On the other hand, Chinese medicine mainly used in oriental medicine has emerged as a more fundamental therapeutic agent due to the multi-target mechanism in the prevention and treatment of chronic and refractory diseases in which the complex causes and symptoms of the onset.
또한, 이러한 한약재를 원료로 사용하는 치료제의 경우 화학 약품 사용에 따라 발생할 수 있는 다양한 부작용을 최소화할 수 있기 때문에, 현존하는 의약품 성분의 대체 소재로 주목 받고 있다.In addition, in the case of a therapeutic using a herbal medicine as a raw material can minimize the various side effects that can occur according to the use of chemicals, it is attracting attention as an alternative material of the existing pharmaceutical ingredients.
본 발명은 전술한 종래 기술의 문제점을 해결하기 위한 것으로, 본 발명의 목적은 천연물 유래의 성분을 함유하여 부작용을 최소화하면서도 골 질환의 개선 효과가 우수한 조성물을 제공하는 것이다.The present invention is to solve the above-mentioned problems of the prior art, an object of the present invention to provide a composition excellent in improving the bone disease while minimizing side effects by containing components derived from natural products.
또한, 본 발명은 상기 천연물 유래 성분을 포함하는 골 질환 개선용 건강기능식품을 제공하는 것을 목적으로 한다.In addition, an object of the present invention to provide a health functional food for bone disease improvement comprising the natural-derived components.
본 발명의 일 측면에 따르면, 택란(Lycopi Herba) 추출물을 유효성분으로 포함하는 골 질환의 예방 또는 치료용 약학적 조성물이 제공된다.According to one aspect of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of bone diseases, including lanthanum ( Lycopi Herba ) extract as an active ingredient.
일 실시예에 있어서, 상기 조성물은 RANK 신호 경로(RANK signaling pathway)를 억제할 수 있다.In one embodiment, the composition may inhibit the RANK signaling pathway.
일 실시예에 있어서, 상기 조성물은 c-Fos 또는 NFATc1의 발현을 하향 조절할 수 있다.In one embodiment, the composition can down regulate the expression of c-Fos or NFATc1.
일 실시예에 있어서, 상기 조성물은 파골세포의 분화를 억제할 수 있다.In one embodiment, the composition may inhibit the differentiation of osteoclasts.
일 실시예에 있어서, 상기 추출물은 물, 알코올, 에틸아세테이트, 아세톤, 핵산, 디클로로메탄 또는 이들의 혼합 용매로 추출될 수 있다.In one embodiment, the extract may be extracted with water, alcohol, ethyl acetate, acetone, nucleic acid, dichloromethane or a mixed solvent thereof.
일 실시예에 있어서, 상기 골 질환은 골다공증, 골 형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군에서 하나 이상 선택될 수 있다.In one embodiment, the bone disease may be at least one selected from the group consisting of osteoporosis, bone dysplasia, osteomalacia, bone loss, fractures, bone defects and hip reduction.
본 발명의 다른 측면에 따르면, 택란(Lycopi Herba) 추출물을 유효성분으로 포함할 수 있다.According to another aspect of the present invention, it is possible to include a taxlan ( Lycopi Herba ) extract as an active ingredient.
본 발명의 일 측면에 따르면, 약학적 조성물 내지 건강기능식품의 일 성분으로 천연 한약재인 택란 추출물을 사용함으로써 부작용을 최소화하면서도 골 질환 개선 효과를 향상시킬 수 있다.According to one aspect of the present invention, by using a medicinal extract of natural medicinal herbs as a component of the pharmaceutical composition or health functional food can improve the bone disease improvement effect while minimizing side effects.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 상세한 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.It is to be understood that the effects of the present invention are not limited to the above effects, and include all effects deduced from the configuration of the invention described in the detailed description or claims of the present invention.
도 1은 택란 추출물(wLH) 처리에 따른 세포 생존률을 측정한 결과이다.
도 2는 파골세포 분화에 대한 택란 추출물 처리 농도에 따른 (A) TRAP 염색, (B) TRAP 양성 다핵형 파골세포의 수(osteoclast number) 및 (C) TRAP 효소 활성(TRAP activity)의 분석 결과이다.
도 3은 파골세포 골 흡수능에 대한 택란 추출물 처리 농도에 따른 (A) TRAP 염색 및 파골세포에 의한 흡수 구멍(Pit) 이미지 및 (B) 흡수 면적(Pit area/Total area)의 그래프이다.
도 4는 택란 추출물 처리에 대한 NFATc1 단백질의 발현량을 웨스턴 블롯(western blot) 방법으로 측정한 결과이다.
도 5는 택란 추출물 처리에 대한 c-Fos 단백질의 발현량을 웨스턴 블롯(western blot) 방법으로 측정한 결과이다.
도 6은 택란 추출물 처리에 대한 TRAP, NFATc1, c-Fos, CTK, MMP-9 및 CAII mRNA의 발현량을 실시간 정량 중합효소 연쇄반응(Real-time quantitative PCR)으로 측정한 결과이다.Figure 1 is the result of measuring the cell survival rate according to the treatment with talan extract (wLH).
Figure 2 shows the results of analysis of (A) TRAP staining, (B) osteoclast number and (C) TRAP enzyme activity (TRAP activity) according to the concentration of talan extract treatment for osteoclast differentiation .
Figure 3 is a graph of (A) TRAP staining and absorption holes (Pit) image and (B) Pit area / Total area by osteoclasts according to the concentration of the talan extract treatment for osteoclast bone absorption capacity.
4 is a result of Western blot measurement of the expression of NFATc1 protein for the treatment of talan extract.
Figure 5 is the result of measuring the expression of c-Fos protein expression by Western blot method for the treatment of talan extract.
Figure 6 is the result of measuring the expression level of TRAP, NFATc1, c-Fos, CTK, MMP-9 and CAII mRNA for the treatment of talan extract by real-time quantitative PCR (Real-time quantitative PCR).
본 명세서에서 사용되는 용어는 본 발명에서의 기능을 고려하면서 가능한 현재 널리 사용되는 일반적인 용어들을 선택하였으나, 이는 당 분야에 종사하는 기술자의 의도 또는 판례, 새로운 기술의 출현 등에 따라 달라질 수 있다. 또한, 특정한 경우는 출원인이 임의로 선정한 용어도 있으며, 이 경우 해당되는 발명의 설명 부분에서 상세히 그 의미를 기재할 것이다. 따라서 본 발명에서 사용되는 용어는 단순한 용어의 명칭이 아닌, 그 용어가 가지는 의미와 본 발명의 전반에 걸친 내용을 토대로 정의되어야 한다.The terminology used herein is to select general terms that are currently widely used as possible in consideration of the functions in the present invention, but may vary according to the intention or precedent of the person skilled in the art, the emergence of new technologies and the like. In addition, in certain cases, there is also a term arbitrarily selected by the applicant, in which case the meaning will be described in detail in the description of the invention. Therefore, the terms used in the present invention should be defined based on the meanings of the terms and the contents throughout the present invention, rather than the names of the simple terms.
다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다.Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art. Terms such as those defined in the commonly used dictionaries should be construed as having meanings consistent with the meanings in the context of the related art, and are not construed in ideal or excessively formal meanings unless expressly defined in this application. Do not.
수치 범위는 상기 범위에 정의된 수치를 포함한다. 본 명세서에 걸쳐 주어진 모든 최대의 수치 제한은 낮은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 낮은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 최소의 수치 제한은 더 높은 수치 제한이 명확히 쓰여져 있는 것처럼 모든 더 높은 수치 제한을 포함한다. 본 명세서에 걸쳐 주어진 모든 수치 제한은 더 좁은 수치 제한이 명확히 쓰여져 있는 것처럼, 더 넓은 수치 범위 내의 더 좋은 모든 수치 범위를 포함할 것이다.The numerical range includes the numerical values defined in the range. All maximum numerical limits given throughout this specification include all lower numerical limits as if the lower numerical limits were clearly written. All minimum numerical limits given throughout this specification include all higher numerical limitations as if the higher numerical limit were clearly written. All numerical limitations given throughout this specification will include all better numerical ranges within the broader numerical range, as the narrower numerical limitations are clearly written.
이하, 본 발명의 실시예를 상세히 기술하나, 하기 실시예에 의해 본 발명이 한정되지 아니함은 자명하다.Hereinafter, examples of the present invention will be described in detail, but the present invention is not limited by the following examples.
본 발명의 일 측면에 따른 골 질환의 예방 또는 치료용 약학적 조성물이 택란(Lycopi Herba) 추출물을 유효성분으로 포함할 수 있다.The pharmaceutical composition for preventing or treating bone diseases according to an aspect of the present invention may include a lylan extract ( Lycopi Herba ) as an active ingredient.
본 발명자들은 파골세포 분화 억제 활성을 갖는 우수한 식물 생약을 발굴하기 위해, 다양한 생약 원료에 대한 추출 방법을 구체화하였으며 파골세포 분화 억제 활성이 극대화된 상기 골 질환의 예방 또는 치료용 조성물을 개발하였다.The inventors of the present invention have specified extraction methods for various herbal raw materials and have developed a composition for preventing or treating bone diseases in which the osteoclast differentiation inhibitory activity is maximized, in order to discover excellent plant herbals having osteoclast differentiation inhibitory activity.
상기 “택란(Lycopi Herba)”은 꿀풀과(Labiatae) 식물인 쉽싸리(Lycopus lucidus Turcz.)의 꽃이 피기 전의 지상부로서, “호란, 용조 또는 호포”로도 호칭된다.The "check box (Lycopi Herba)" is referred to as the above-ground before the flowering of the Lamiaceae (Labiatae) plants in swipssari (Lycopus lucidus Turcz.), As the "Horan, yongjo or hopo".
상기 택란은 주로 산과 들의 습한 곳에서 서식하며, 여름철 꽃이 피는 시기에 전초를 베어 햇볕에서 말려 사용한다. 상기 택란은 냄새가 없고 맛은 쓰고 매우며 성질은 약간 따뜻하며, 산후 복통과 부종, 월경 장애, 상처, 타박상, 부스럼 등의 치료에 사용되어 왔다.The talank is mainly inhabited by mountains and wetlands, and is used when the flowers are cut in the summer when the flowers bloom in the sun. The talan is odorless, tastes very bitter and has a slightly warm nature, and has been used to treat postpartum abdominal pain and swelling, menstrual disorders, wounds, bruises, swelling and the like.
그러나, 상기 택란이 골다공증과 같은 골 질환의 개선 효과 또는 관련한 작용 기전이나 효능은 현재까지 알려진 바 없으며, 본 발명자들은 상기 택란 추출물의 파골세포 분화 억제 활성 효과를 규명하고자 하였다.However, there is no known effect or mechanism of action or efficacy of the taxlans in the treatment of bone diseases such as osteoporosis, and the present inventors tried to identify the osteoclast differentiation inhibitory effect of the taxlan extract.
상기 조성물은 파골세포(osteoclast)의 분화를 억제할 수 있다. 상기 파골세포는 척추 동물의 뼈가 성장하는 과정에서 불필요하게 된 뼈 조직을 파괴 또는 흡수하는 대형의 다핵세포로서 뼈의 밀도를 저하시키고 골다공증을 포함하는 다양한 골 질환을 유발할 수 있다.The composition can inhibit the differentiation of osteoclasts (osteoclast). The osteoclasts are large multinucleated cells that destroy or absorb bone tissue that is unnecessary during the growth of the bones of vertebrates, which can reduce bone density and cause various bone diseases including osteoporosis.
상기 조성물은 RANK 신호 경로(RANK signaling pathway)를 억제할 수 있고, c-Fos 또는 NFATc1의 발현을 하향 조절할 수 있다.The composition may inhibit the RANK signaling pathway and may down-regulate the expression of c-Fos or NFATc1.
상기 파골세포의 분화는 RANKL이 RANK 수용체와 결합되어 개시될 수 있다. 구체적으로, 상기 RANKL이 RANK에 결합하면 TRAF6(tumor necrosis factor receptor-associated factor 6)와 같은 생물 분자가 활성화될 수 있다.Differentiation of the osteoclasts may be initiated by RANKL binding to the RANK receptor. Specifically, when RANKL binds to RANK, biological molecules such as tumor necrosis factor receptor-associated factor 6 (TRAF6) may be activated.
상기 TRAF 패밀리 멤버인 TRAF2, TRAF5, TRAF6는 파골세포의 분화에 필요한 NF-Kb 및 AP-1(activator protein-1) 등의 전사인자를 활성화할 수 있다. The TRAF family members TRAF2, TRAF5, and TRAF6 can activate transcription factors such as NF-Kb and AP-1 (activator protein-1) required for osteoclast differentiation.
상기 RANKL 신호에 의해 활성화된 TRAF6는 PI3K, TAK1(transforming growth factor β-activated kinase), Akt/PKB, 및 JNK, ERK, p38을 포함하는 MAPKs, NF-kB, c-Fos, Fra-1, CREB(cyclic-AMP-responsive-element-binding protein), NFATc1(nuclear factor of activated T cells cytoplasmic 1) 등을 활성화할 수 있다.TRAF6 activated by the RANKL signal is PI3K, transforming growth factor β-activated kinase (TAK1), Akt / PKB, and MAPKs including JNK, ERK, p38, NF-kB, c-Fos, Fra-1, CREB (cyclic-AMP-responsive-element-binding protein), NFATc1 (nuclear factor of activated T cells cytoplasmic 1) and the like can be activated.
상기 경로에 의해 카텝신 K(cathepsin K), TRAP(tartrate-resistant acid phospatase), 칼시토닌 수용체 및 OSCAR(osteoclast-associated receptor) 등 파골세포-특이적 유전자들이 발현될 수 있다. By this route, osteoclast-specific genes such as cathepsin K, catapsin-resistant acid phospatase (TRAP), calcitonin receptor, and osteocelast-associated receptor (OSCAR) can be expressed.
상기 택란 추출물은 파골세포 분화에 직접적으로 관련된 RANK 신호 경로(RANK signaling pathway)를 억제하며, 상기 신호 경로에 관여하는 핵심 기전인 c-Fos 또는 NFATc1의 발현을 하향 조절함으로써 골 형성을 촉진할 수 있다.The talan extract inhibits the RANK signaling pathway directly related to osteoclast differentiation and may promote bone formation by down-regulating the expression of c-Fos or NFATc1, a key mechanism involved in the signaling pathway. .
상기 “추출물”은 용매와 추출재료를 특정 조건하에서 접촉시킴으로써 추출재료에 함유된 유효성분을 분리해낸 것으로, 상기 추출물은 택란에 대한 추출 공정에 의해 원료 내의 유효성분을 포함할 수 있다.The "extract" is to separate the active ingredient contained in the extract material by contacting the solvent and the extract material under specific conditions, the extract may include the active ingredient in the raw material by the extraction process for the taxane.
상기 택란 추출물은 천연물로부터 추출물을 추출하는 당업계에 공지된 통상적인 방법에 따라, 즉, 통상적인 온도, 압력의 조건 하에서 통상적인 용매를 사용하여 추출할 수 있다. 예컨대, 상기 택란 추출물은 물, 알코올, 에틸아세테이트, 아세톤, 핵산, 디클로로메탄 또는 이들의 혼합 용매를 사용하여 추출할 수 있으며, 바람직하게는 물을 사용할 수 있다. The taxane extract may be extracted according to a conventional method known in the art for extracting the extract from natural products, that is, using a conventional solvent under the conditions of conventional temperature, pressure. For example, the taxane extract may be extracted using water, alcohol, ethyl acetate, acetone, nucleic acid, dichloromethane or a mixed solvent thereof, preferably water.
또한, 상기 추출 방법은 열수 추출, 냉침 추출, 환류 추출, 초음파 추출 등의 다양한 방법을 사용할 수 있으며, 바람직하게는 열수 추출을 사용할 수 있으나 이에 제한되는 것은 아니다.In addition, the extraction method may use a variety of methods, such as hot water extraction, cold extraction, reflux extraction, ultrasonic extraction, preferably hot water extraction, but is not limited thereto.
상기 골 질환은 조골세포의 활성 촉진 또는 파골세포의 활성 억제를 통해 골량 증가가 필요 또는 요구되는, 상태 또는 질병을 의미하는 것으로 골다공증, 골 형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군에서 하나 이상 선택될 수 있으나, 파골세포 분화 촉진에 의해 발생하는 질환 또는 병태라면 특별히 제한되지 않는다.The bone disease refers to a condition or disease that requires or requires an increase in bone mass through promoting the activity of osteoblasts or inhibiting the activity of osteoclasts. Osteoporosis, bone dysplasia, osteomalacia, osteopenia, fracture, bone defect, and hip reduction One or more may be selected from the group consisting of, but is not particularly limited as long as it is a disease or condition caused by promoting osteoclast differentiation.
상기 “유효성분으로 포함하는”은 투여하고자 하는 개체에 대한 치료적 또는 예방적 효과를 제공하기에 충분한 택란 추출물을 포함하는 것을 의미하며, 택란 추출물은 생체 안전성이 우수하므로 당업자가 다양한 변수를 고려하여 양적 상한을 적절히 조정할 수 있다.The term "comprising as an active ingredient" means that it contains a sufficient amount of lanthanum extract to provide a therapeutic or prophylactic effect on the subject to be administered, taxan extract is excellent in biosafety, so those skilled in the art The upper limit of quantity can be adjusted suitably.
상기 “예방”은 동물의 병리학적 세포의 발생 또는 세포의 손상, 소실의 정도의 감소를 의미한다. 예방은 완전할 수 있으며 또는 부분적일 수도 있다. 이 경우에는 개체 내의 병리학적 세포의 발생 또는 파골세포 증식 등이 상기 골 질환 예방 및 치료용 조성물을 사용 하지 않은 경우와 비교하여 감소하는 현상을 의미할 수 있다. The term "prevention" means a reduction in the extent of the development of pathological cells or damage or loss of cells in the animal. Prevention can be complete or partial. In this case, the occurrence of pathological cells or osteoclast proliferation in an individual may mean a phenomenon of decreasing compared to the case where the composition for preventing and treating bone diseases is not used.
또한, 상기 “치료”는 골 질환의 하나 이상의 증상을 개선하거나, 증상의 진행을 저지하는 것을 의미하며, 통상적으로 사용되는 치료의 의미를 포괄할 수 있다.In addition, the "treatment" is meant to ameliorate one or more symptoms of bone disease, or to arrest the progression of symptoms, can encompass the meaning of commonly used treatments.
상기 택란 추출물은 화학물질 등과 달리 천연물 유래의 물질을 그대로 이용하는 것이므로, 이의 섭취 내지 투여에 따른 치명적인 부작용의 발생을 최소화할 수 있다.Unlike the chemicals and the like, since the talan extract is to use a substance derived from natural products as it is, it is possible to minimize the occurrence of fatal side effects due to its ingestion or administration.
본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 추가로 포함할 수 있다. 발명의 용어 "약학적으로 허용 가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" of the invention is meant to exhibit properties that are not toxic to cells or humans exposed to the composition.
약학적으로 허용 가능한 담체를 포함하는 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. Compositions comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. When formulated, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.
상기 담체, 부형제 및 희석제로는 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 생리식염수, 메틸히드록시벤조에이트, 프로필히드록 시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유, 덱스트린, 칼슘카보네이트, 프로필렌글리콜 및 리퀴드 파라핀으로 이루어진 군에서 선택된 하나 이상일 수 있으나, 이에 한정되는 것은 아니며, 통상의 담체, 부형제 또는 희석제 모두 사용 가능하다. 상기 성분들은 상기 유효성분인 택란 추출물에 독립적으로 또는 조합하여 추가될 수 있다.The carrier, excipient and diluent may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, Polyvinyl pyrrolidone, saline, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, dextrin, calcium carbonate, propylene glycol and liquid paraffin, It is not limited to this, and any conventional carrier, excipient or diluent can be used. The ingredients may be added independently or in combination with the talan extract, the active ingredient.
또한, 상기 조성물은 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제제화 하여 사용할 수 있다.In addition, the composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, suppositories, and sterile injectable solutions.
상기 경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 택란 추출물과 이의 분획물들에 적어도 하나 이상의 부형제, 예컨대, 전분, 칼슘카보네이트, 수크로오스, 락토오스, 또는 젤라틴 등을 혼합하여 조제할 수 있다. 상기 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제가 사용될 수도 있다.The solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations include at least one excipient such as starch, calcium carbonate, sucrose, lactose in the taxane extract and fractions thereof. Or gelatin can be mixed and prepared. In addition to the above excipients, lubricants such as magnesium styrate and talc may be used.
본 명세서에서 사용된 용어 “분획물(fraction)”은 각종 구성성분 또는 혼합물로부터 각각의 성분 또는 특정의 그룹으로 분리하는 조작, 즉 크로마토그래피, 전기영동, 원심분리 등을 사용하여 분리된 각 성분 내지 그룹을 의미한다.As used herein, the term “fraction” refers to each component or group that is separated using various operations, such as chromatography, electrophoresis, centrifugation, or the like, to separate each component or specific group from various components or mixtures. Means.
상기 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 사용될 수 있으며, 단순희석제인 물, 리퀴드 파라핀 외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.As the liquid preparation for oral administration, suspensions, contents, emulsions, syrups, etc. may be used, and various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are simple diluents, may be used. have.
상기 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 사용될 수 있다. 상기 비수성용제, 현탁제로는 프로필렌 글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르가 사용될 수 있다. 상기 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴이 사용될 수 있다.Sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories may be used in the preparations for parenteral administration. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate may be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerogelatin may be used.
상기 택란 추출물을 포함하는 약학적 조성물은 약제학적으로 유효한 양이 대상체에 투여될 수 있다. The pharmaceutical composition comprising the talan extract may be administered to the subject in a pharmaceutically effective amount.
상기 “약제학적으로 유효한 양”은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.The term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level is determined by the type of disease, the severity, the activity of the drug, and the drug. Sensitivity, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts.
상기 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 바람직하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical compositions may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. In consideration of all the above factors, it is desirable to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 구체적인 실시예에서, 본 발명자들은 택란을 열수추출 후 동결 건조하여 분말 엑스를 수득하였다. 수득된 택란 추출물은 세포독성이 없고(도 1), 파골세포의 골 흡수능을 감소시키며(도 2), 파골세포의 분화와 관련된 유전자의 발현을 억제할 수 있다(도 3 내지 6). In a specific embodiment of the present invention, the present inventors obtained freeze-dried taklan after hot water extraction to obtain a powder X. The obtained talan extract is non-cytotoxic (FIG. 1), decreases the osteoclast uptake of osteoclasts (FIG. 2), and can inhibit the expression of genes associated with the differentiation of osteoclasts (FIGS. 3 to 6).
따라서, 상기 택란 추출물은 골 질환의 주요 원인으로 알려진 파골세포 분화를 효과적으로 억제하는 조성물로서 유용하게 사용될 수 있다.Therefore, the talan extract may be usefully used as a composition that effectively inhibits osteoclast differentiation, which is known as a major cause of bone disease.
본 발명의 다른 측면은 택란(Lycopi Herba) 추출물을 유효성분으로 포함하는 골 질환의 예방 또는 개선용 건강기능식품을 제공한다.Another aspect of the present invention provides a dietary supplement for the prevention or improvement of bone diseases, including lanthanum ( Lycopi Herba ) extract as an active ingredient.
즉, 상기 조성물은 약학 조성물 뿐만 아니라 식품 조성물일 수도 있다. 상기 식품은 육류, 스낵류, 낙농제품, 음료수 등을 예시할 수 있으나 이에 한정되는 것은 아니며, 통상적인 건강기능식품을 모두 포함하는 개념으로 이해될 수 있다.That is, the composition may be a food composition as well as a pharmaceutical composition. The food may be exemplified by meat, snacks, dairy products, beverages, and the like, but is not limited thereto and may be understood as a concept including all of general health functional foods.
상기 건강기능식품은 건강기능식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, 상기 기능성은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미할 수 있다.The health functional food means a food manufactured and processed using raw materials or ingredients having functional properties useful for the human body according to the law on health functional foods, and the functional properties control nutrients or physiologically on the structure and function of the human body. It may mean ingestion for the purpose of obtaining a useful effect for health use such as action.
상기 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 상기 식품 첨가물은 다른 규정이 없는 한 식품의약품안전처에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 적합성 여부를 판단할 수 있다.The health functional food may include a conventional food additive, and unless otherwise specified, the food additive may comply with the standards and standards for the item in accordance with the General Regulations and General Test Act of the Food Additives Act approved by the Ministry of Food and Drug Safety. Compliance can be determined by
상기 식품 첨가물 공전에 기재된 품목은 예컨대 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류를 들 수 있다.The items described in the food additive orbital are, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamon acid, natural additives such as color pigments, licorice extract, crystalline cellulose, high pigment, guar gum, sodium L-glutamate preparations, and noodles. Mixed preparations, such as an added alkali, a preservative, and a tar pigment, are mentioned.
상기 건강기능식품은 골 질환 개선을 위한 식품 및 음료 등에 다양하게 이용될 수 있으며, 예컨대, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강기능성 보조 식품, 식품 첨가제 등에 사용될 수 있다.The health functional food may be used in a variety of foods and beverages for improving bone diseases, for example, various foods, beverages, gum, tea, vitamin complexes, health functional supplements, food additives and the like.
상기 건강기능식품은 골 질환 개선을 목적으로, 전체 중량 대비 1.0 내지 10.0 중량%의 상기 조성물을 포함할 수 있다. 상기 조성물이 1.0 중량% 미만이면 골 질환 개선 효과가 충분히 구현되지 않을 수 있고 10.0 중량% 초과이면 제품 본연의 품질이 구현되지 않거나 비용 효율이 저하될 수 있다.The health functional food may include 1.0 to 10.0% by weight of the composition relative to the total weight for the purpose of improving bone disease. When the composition is less than 1.0% by weight, the bone disease improvement effect may not be sufficiently realized, and when the composition is more than 10.0% by weight, the inherent quality of the product may not be realized or the cost efficiency may be reduced.
또한, 상기 건강기능식품은 골 질환 개선을 목적으로 정제, 과립, 분말, 캅셀, 액상의 용액 및 환으로 이루어진 군에서 선택된 어느 하나의 제형으로 제조 및 가공될 수 있다.In addition, the health functional food may be prepared and processed in any one formulation selected from the group consisting of tablets, granules, powders, capsules, liquid solutions and pills for the purpose of improving bone disease.
구체적으로 상기 정제 형태의 건강기능식품은 택란 추출물 또는 이의 분획물, 부형제, 결합제, 붕해제 및 다른 첨가제와의 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축 성형하거나, 상기 혼합물을 직접 압축 성형하여 제조할 수 있다. 또한, 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수 있으며, 필요에 따라 적당한 제피제로 제피할 수도 있다.Specifically, the health functional food in the form of tablets is granulated with a method of extracting a talan extract or a fraction thereof, excipients, binders, disintegrants and other additives in a conventional manner, and then compression-molded with a lubricant or the like, It can be produced by direct compression molding. In addition, the health functional food in the form of tablets may contain a mating agent and the like, if necessary, may be coated with a suitable coating agent.
상기 캅셀 형태의 건강기능식품 중 경질캅셀제는 통상의 경질캅셀에 가지 추출물 및 부형제 등의 첨가제와의 혼합물 또는 그의 입상물 또는 제피한 입상물을 충진하여 제조할 수 있으며, 연질캅셀제는 택란 추출물 또는 이의 분획물, 및 부형제 등의 첨가제와의 혼합물을 젤라틴 등 캅셀기제에 충진하여 제조할 수 있다.The hard capsules of the health functional food in the form of capsules may be prepared by filling a mixture with additives such as eggplant extracts and excipients, or granular or peeled granules thereof in a conventional hard capsule, and the soft capsules may be a taxane extract or The mixture with the fractions and additives such as excipients can be prepared by filling in a capsule base such as gelatin.
상기 연질캅셀제는 필요에 따라 글리세린 또는 솔비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.The soft capsule agent may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, as necessary.
상기 환 형태의 건강기능식품은 택란 추출물 또는 이의 분획물, 부형제, 결합제, 붕해제 등의 혼합물을 적당한 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 적당한 제피제로 제피를, 또는 전분, 탈크 또는 적당한 물질로 환의를 입힐 수도 있다.The cyclic health functional food may be prepared by molding a lanthanum extract or a mixture thereof, an excipient, a binder, a disintegrating agent, etc. by a suitable method, and if necessary, coating the skin with starch sugar or other suitable coating agent, or starch, talc. Or they may be greeted with a suitable substance.
상기 과립형태의 건강기능식품은 택란 추출물 또는 이의 분획물, 부형제, 결합제, 붕해제 등의 혼합물을 적당한 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다The health functional food in the form of granules may be prepared into granules by a suitable method, such as a mixture of talan extract or fractions thereof, excipients, binders, disintegrants, etc., may contain a flavoring agent, a mating agent, if necessary.
또한, 상기 부형제, 결합제, 붕해제, 활택제, 교미제, 착향제 등에 대한 용어 정의는 당업계에 공지된 문헌에 기재된 것으로 그 기능 등이 동일 내지 유사한 것들을 포함할 수 있다.In addition, the definitions of the excipients, binders, disintegrants, glidants, copulation agents, flavoring agents and the like are described in documents known in the art and may include those having the same or similar functions.
이하, 첨부된 도면을 참고하여 본 발명의 실시예에 관하여 상세히 서술하나, 하기 실시예에 의해 본 발명이 제한되지 아니함은 자명하다.Hereinafter, with reference to the accompanying drawings will be described in detail with respect to embodiments of the present invention, it is apparent that the present invention is not limited by the following examples.
제조예 1 : 택란 열수 추출물(wLH)의 제조Preparation Example 1 Preparation of Talc Hot Water Extract (wLH)
택란 500g을 증류수 5000mL에 첨가하여 100℃에서 2시간 동안 전탕 후 2시간 냉각하고, 여과한 후, 동결건조하여 택란 건조 분말 엑기스를 수득하였다. 세포 배양시 사용한 택란은 0.22㎛ 멸균 필터로 여과하여 사용하였다.500 g of taxane was added to 5000 mL of distilled water, followed by annealing at 100 ° C. for 2 hours, cooling for 2 hours, filtration, and lyophilization to obtain a taxane dry powder extract. The taxane used in cell culture was used by filtration with a 0.22 μm sterile filter.
제조예 2 : 세포 배양Preparation Example 2 Cell Culture
마우스의 대식세포주인 RAW264.7 세포는 한국세포주은행(Korean Cell line bank, NO. 40071)에서 분양받아 사용하였다.RAW264.7 cells, which are macrophages of mice, were distributed and used in Korean Cell line bank (NO. 40071).
10% FBS(Fetal Bovine Serum) 및 1%의 P/S(페니실린 및 스트렙토마이신)를 포함하는 DMEM(Dulbecco's Modified Eagle Medium) 배지에 상기 세포를 분주하여 95%의 습도, 37℃, 5% CO2의 조건에서 배양하였다.Dispense the cells in DMEM (Dulbecco's Modified Eagle Medium) medium containing 10% FBS (Fetal Bovine Serum) and 1% P / S (penicillin and streptomycin) to obtain 95% humidity, 37 ° C., 5% CO 2 The culture was carried out under the following conditions.
실시예 1 : 세포독성 분석Example 1 Cytotoxicity Assay
택란 추출물의 세포독성을 알아보기 위해 상기 제조예 1의 택란 추출물을 상기 제조예 2의 세포에 처리한 후 MTT assay를 이용하여 세포 증식을 측정하였다.In order to determine the cytotoxicity of the talan extract, the talan extract of Preparation Example 1 was treated to the cells of Preparation Example 2, and then cell proliferation was measured by MTT assay.
구체적으로, 상기 세포를 24시간 동안 안정화 후 배양액에 택란 추출물 0, 1, 10, 100 μg/mL을 각각 처리한 후 동일한 조건의 배양기에서 24시간 동안 배양하였다.Specifically, the cells were stabilized for 24 hours, and then treated with 0, 1, 10, and 100 μg / mL of the thylan extract in the culture, and then cultured for 24 hours in the incubator under the same conditions.
배양된 세포들은 MTT assay solution 처리 후 570nm에서 흡광도를 측정하였다.The cultured cells were measured for absorbance at 570 nm after treatment with MTT assay solution.
세포 독성 측정 결과는 시료의 흡광도를 대조군(택란 추출물 0 μg/mL, control, con)의 흡광도에 대한 백분율로 표시하였다.The cytotoxicity measurement results indicate the absorbance of the sample as a percentage of the absorbance of the control (talan extract 0 μg / mL, control, con).
측정 결과, 택란 추출물 1, 10, 100 μg/mL을 처리하였을 때 세포 독성이 나타나지 않았다(도 1).As a result, the cytotoxicity was not observed when the
실시예 2 : 파골세포 분화능 평가Example 2 Evaluation of Osteoclast Differentiation Capacity
택란 추출물이 파골세포 분화에 미치는 영향을 알아보기 위해 상기 제조예 2의 세포에 RANKL을 처리하여 파골세포로의 분화를 유도하고, TRAP(tartrate-resistant acid phosphatase) 염색법을 이용하여 파골세포 분화능을 분석하였다.In order to determine the effect of taxane extract on osteoclast differentiation, RANKL was treated to cells of Preparation Example 2 to induce differentiation into osteoclasts, and analyzed osteoclast differentiation capacity using TRAP (tartrate-resistant acid phosphatase) staining. It was.
구체적으로, 상기 제조예 2의 RAW 264.7 세포에 RANKL 100 ng/mL를 처리하고 택란 추출물 0, 1, 10, 100 μg/mL을 각각 처리한 후 5일 동안 배양하였다. 배양된 세포는 TRAP assay kit를 사용하여 염색하였다.Specifically,
현미경을 사용하여, 100배율에서 핵이 3개 이상인 TRAP 양성 다핵형 파골세포(MNCs)를 파골세포로 계수하였다. RAW 264.7 세포에 RANKL을 처리하지 않은 세포는 정상군(normal, nor)으로 하였다.Using a microscope, TRAP positive multinucleated osteoclasts (MNCs) with three or more nuclei at 100 magnification were counted as osteoclasts. RAW 264.7 cells were treated with RANKL-treated cells as normal (nor).
대조군의 경우 정상군에 비해 TRAP 양성 다핵형 파골세포가 다수 생성되었으나, 택란 추출물을 함께 처리한 실험군의 경우 택란 추출물 농도에 의존적으로 TRAP 양성 다핵형 파골세포 형성이 억제되었다(도 2A).In the control group, more TRAP-positive multinuclear osteoclasts were produced than in the normal group, but in the experimental group treated with the taxane extract, TRAP-positive multinuclear osteoclast formation was suppressed depending on the concentration of the taxane extract (FIG. 2A).
TRAP 양성 다핵형 파골세포를 파골세포로 간주하고 계수한 결과, TRAP 양성 다핵형 세포 수 역시 택란 추출물 농도 의존적으로 감소하였다(도 2B).TRAP-positive multinucleated osteoclasts were regarded as osteoclasts and counted. As a result, the number of TRAP-positive multinucleated osteoclasts also decreased depending on the concentration of taxane extract (FIG. 2B).
4-Nitrophenyl phosphate disodium salt hexahydrate(sigma aldrich, MO, USA) 4.93 mg, 0.5 M acetate 850 μL 및 tartrate acid solution 150 μL를 섞어 만든 시약 50 μL와 세포를 배양한 배지 50 μL를 새로운 96-well plate에 투입하였다.50 μL of 4-Nitrophenyl phosphate disodium salt hexahydrate (sigma aldrich, MO, USA) 4.93 mg, 0.5 M acetate 850 μL and
37 °C에서 60분 동안 반응시킨 후, 0.5M NaOH를 50 μL를 투입하여 반응을 종료 시키고, 405nm에서 흡광도를 측정함으로써 TRAP 효소 활성(TRAP activity)을 평가하였다.After reacting at 37 ° C for 60 minutes, the reaction was terminated by adding 50 μL of 0.5 M NaOH, and the absorbance was measured at 405 nm to evaluate the TRAP activity.
측정 결과, 택란 추출물을 함께 처리한 실험군에서는 택란 추출물 농도에 의존적으로 TRAP 효소 활성이 감소하였다(도 2C).As a result, in the experimental group treated with the talan extract, TRAP enzyme activity was reduced depending on the talan extract concentration (Fig. 2C).
상기 결과는 택란 추출물은 파골세포의 분화능을 억제하는 효과가 우수함을 시사한다.The results suggest that the taxlan extract has an excellent effect of inhibiting the differentiation capacity of osteoclasts.
실시예 3 : 파골세포의 골 흡수능 평가Example 3 Evaluation of Bone Absorption Capacity of Osteoclasts
택란 추출물이 파골세포의 골 흡수능에 미치는 영향을 알아보기 위해, 상기 제조예 2의 세포를 안정화한 후 RANKL을 처리하여 파골세포로 분화를 유도하고 파골세포가 생성한 pit를 측정하여 파골세포의 골 흡수능을 분석하였다.In order to determine the effect of the talan extract on osteoclasts of osteoclasts, the cells of Preparation Example 2 were stabilized and then treated with RANKL to induce differentiation into osteoclasts and to determine the pit generated by osteoclasts Absorption capacity was analyzed.
상기 RAW 264.7 세포를 osteo assay strip well plate(Coring incorporated, New York, USA)에서 24시간 동안 안정화하였다. RANKL 100 ng/mL을 첨가한 배양액으로 교환하고 택란 추출물 0, 1, 10, 100 μg/mL을 각각 처리한 후 5일 동안 배양하였다. The RAW 264.7 cells were stabilized for 24 hours in osteo assay strip well plates (Coring incorporated, New York, USA).
배양된 세포들은 4% NaClO를 사용하여 제거한 후 현미경을 통해 파골세포에 의하여 형성된 흡수 구멍(resorption pit)을 관찰하고, 파골세포에서 의하여 형성된 흡수 구멍의 크기(Pit area)와 전체 크기(Total area)의 비율을 측정하여 파골세포의 골 흡수능을 분석하였다.The cultured cells were removed using 4% NaClO, and the microscope observed the absorption pit formed by the osteoclast, and the size and total area of the absorption hole formed by the osteoclast. The bone absorption capacity of osteoclasts was analyzed by measuring the ratio of.
관찰 결과, 정상군에 비해 대조군에서 흡수 구멍이 유의하게 증가하였으며, 택란 추출물을 처리한 실험군에서는 택란 추출물 농도에 의존적으로 흡수 구멍의 형성이 감소되었다. As a result, the absorption pores were significantly increased in the control group compared to the normal group, and the formation of the absorption pores was decreased in the experimental group treated with the taklan extract depending on the concentration of the taxan extract.
특히, 100 μg/mL의 농도로 처리한 실험군에서 흡수 구멍의 형성이 유의하게 감소하였다(p<0.05)(도 3).In particular, the formation of absorption holes was significantly reduced (p <0.05) in the experimental group treated at a concentration of 100 μg / mL (Fig. 3).
상기 결과는 택란 추출물에 파골세포의 골 흡수능을 억제하는 효과가 있음을 시사한다.The results suggest that there is an effect of inhibiting the bone resorption capacity of osteoclasts to the taxlan extract.
실시예 4 : NFATc1 및 c-Fos 단백질 발현 억제 활성 평가Example 4: Evaluation of NFATc1 and c-Fos Protein Expression Inhibition Activity
택란 추출물이 파골세포 분화의 주된 기전인 NFATc1(nuclear factor of activated T cells 1) 및 c-Fos 단백질 발현에 미치는 영향을 웨스턴 블롯(western blot)을 통해 분석하였다.Western blot analysis of the effects of taxane extract on the major mechanism of osteoclast differentiation on NFATc1 (nuclear factor of activated T cells 1) and c-Fos protein expression was analyzed.
보다 구체적으로, 제조예 2의 RAW 264.7 세포에 RANKL 100 ng/mL을 처리한 후 택란 추출물 0, 1, 10, 100 μg/ml을 각각 처리한 뒤 1일 동안 배양하였다. More specifically, after treating
배양된 세포들은 protease inhibitor와 phosphatase inhibitor가 들어있는 RIPA buffer(1 M Tris (pH 7.4), 3 M NaCl, NP-40, 10% Na deoxycholate, 10% SDS)를 이용하여 용해시키고 단백질을 추출하였다.Cultured cells were lysed and extracted with RIPA buffer (1 M Tris (pH 7.4), 3 M NaCl, NP-40, 10% Na deoxycholate, 10% SDS) containing protease and phosphatase inhibitors.
SDS-PAGE and Western blotting을 실시하여 세포에서 단백질을 분리하고, 분리된 단백질을 nitrocellulose transfer membrane에 옮겼다.SDS-PAGE and Western blotting was performed to separate proteins from the cells, and the separated proteins were transferred to nitrocellulose transfer membrane.
TBST(0.05% Tween-20 in Tris-buffered saline, pH 7.4)에 녹인 5% 탈지유를 이용하여 막에 있는 비특이적 결합부위를 모두 블로킹하였다.All nonspecific binding sites on the membrane were blocked using 5% skim milk dissolved in TBST (0.05% Tween-20 in Tris-buffered saline, pH 7.4).
NFATc1 및 c-Fos를 1차 항체로서 각각 항-NFAT(Santacruz, CA, USA) 및 항-c-fos(Cell Signaling, Danvers, MA, USA)에 반응시켰다.NFATc1 and c-Fos were reacted with anti-NFAT (Santacruz, CA, USA) and anti-c-fos (Cell Signaling, Danvers, MA, USA) as primary antibodies, respectively.
PBST로 5회 세정하고 호스라디시 페록시다제(hoseradish peroxidase: HRP)가 결합된 2차 항체와 반응시킨 후 ECL Advance(Amersham Pharmacia Biotech, NY, USA)로 발색시켜 분석하였다.After washing five times with PBST and reacted with a second antibody bound to the horseradish peroxidase (HRP) it was analyzed by color development with ECL Advance (Amersham Pharmacia Biotech, NY, USA).
분석 결과 NFATc1 단백질의 발현은 대조군에서 정상군에 비해 유의하게 증가하였으며, 택란 추출물을 함께 처리한 실험군에서는 택란 추출물 농도 의존적으로 NFATc1의 단백질 발현이 감소하였다.As a result, the expression of NFATc1 protein was significantly increased in the control group compared to the normal group, and in the experimental group treated with taxane extract, NFATc1 protein expression was decreased depending on the concentration of taxan extract.
특히, 택란 추출물 100 μg/mL을 처리한 실험군에서 NFATc1 단백질 발현이 유의하게 감소하였다(p<0.05)(도 4).In particular, NFATc1 protein expression was significantly reduced (p <0.05) in the experimental group treated with 100 μg / mL of lanthanum extract (Fig. 4).
또한, c-Fos 단백질의 발현은 대조군에서 정상군에 비해 유의하게 증가하였으며, 택란 추출물을 1 μg/mL 처리한 실험군에서는 대조군과 비슷한 경향을 보였으나, 택란 추출물 10, 100 μg/mL을 처리한 실험군의 경우 택란 추출물 농도에 의존적으로 c-Fos의 단백질 발현량이 감소하였다.In addition, the expression of c-Fos protein was significantly increased in the control group compared to the normal group, and in the experimental group treated with 1 μg / mL of the taklan extract, the experimental group showed similar tendency as the control group. In the experimental group, the protein expression level of c-Fos was decreased depending on the concentration of taxane extract.
특히, 택란 추출물 100 μg/mL을 처리한 실험군에서 c-Fos 단백질 발현이 유의하게 감소하였다(P<0.05)(도 5).In particular, c-Fos protein expression was significantly reduced (P <0.05) in the experimental group treated with 100 μg / mL of lanthanum extract (Fig. 5).
실시예 5 : RANK 신호 경로 억제 활성 평가Example 5 Evaluation of RANK Signaling Pathway Inhibitory Activity
택란 추출물이 파골세포 분화의 주된 기전인 TRAP, NFATc1, c-Fos, CTK(Cathepsin K), MMP-9(matrix metalloproteinase-9) 및 CAII(Carbonic anhydrase II)의 mRNA 발현에 미치는 영향을 실시간 정량 중합효소 연쇄반응(Real-time quantitative PCR)을 통해 분석하였다.Real-time quantitative polymerization of the effects of talan extract on the mRNA expression of TRAP, NFATc1, c-Fos, CTK (Cathepsin K), matrix metalloproteinase-9 (MMP-9) and carbonic anhydrase II (CAII) Analyzes were carried out by enzyme chain reaction (Real-time quantitative PCR).
구체적으로, 상기 제조예 2에서 제조한 RAW 264.7 세포에 RANKL 100 ng/mL을 처리하고 택란 추출물 0, 1, 10, 100 μg/mL를 각각 처리한 후 4일 동안 배양하였다. Specifically, the RAW 264.7 cells prepared in Preparation Example 2 treated with
배양된 세포에 Trizol 용액(Invitrogen, USA)을 처리하여 전체 RNA(total RNA)를 추출하였다. The cultured cells were treated with Trizol solution (Invitrogen, USA) to extract the total RNA (total RNA).
추출한 2 μg 의 RNA를 제조의 지시에 따라 reverse transcriptase를 사용하여 cDNA(complementary DNA)로 합성하였다. 합성한 cDNA는 KAPA PCR kit(Kapa Biosystems)를 사용하여 real-time PCR을 수행하였다.2 μg of extracted RNA was synthesized into cDNA (complementary DNA) using reverse transcriptase according to the preparation instructions. The synthesized cDNA was performed using real-time PCR using a KAPA PCR kit (Kapa Biosystems).
GAPDH(Glyceraldehyde 3-phosphate dehydrogenase)를 이용하여 mRNA 농도를 표준화(normalization) 하였다. MRNA concentrations were normalized using GAPDH (Glyceraldehyde 3-phosphate dehydrogenase).
Image J software(Ver. 1.46, National Institutes of Health)를 사용하여 각 band density의 데이터 분석을 진행하였으며, 실험에 사용된 프라이머 서열은 하기 표 1과 같다.Data analysis of each band density was performed using Image J software (Ver. 1.46, National Institutes of Health), and the primer sequences used in the experiment are shown in Table 1 below.
그 결과, c-Fos 및 TRAP의 mRNA 발현이 정상군에 비해 유의하게 증가하였으며, 택란 추출물을 1 μg/mL 처리한 실험군에서는 대조군과 비슷한 경향을 보였다.As a result, mRNA expression of c-Fos and TRAP was significantly increased compared to the normal group, and the experimental group treated with 1 μg / mL of the taklan extract showed a similar tendency to the control group.
반면, 택란 추출물 10, 100 μg/mL을 처리한 실험군의 경우 택란 추출물 농도에 의존적으로 TRAP의 mRNA 발현량이 감소하였다.On the other hand, in the experimental group treated with 10, 100 μg / mL of the talan extract, the mRNA expression level of TRAP decreased depending on the talan extract concentration.
특히, 택란 추출물 100 μg/mL을 처리한 실험군에서 c-Fos 및 TRAP의 mRNA 발현량이 유의하게 감소하였다(P<0.01).In particular, mRNA expression levels of c-Fos and TRAP were significantly decreased in the experimental group treated with 100 μg / mL of taxane extract (P <0.01).
또한, 대조군에서 NFATc1, RANK, CAII 및 CTK의 mRNA 발현이 정상군에 비해 유의하게 증가하였으며, 택란 추출물을 함께 처리한 실험군에서는 택란 추출물 농도에 의존적으로 RANK, CAII 및 CTK의 mRNA 발현이 감소하였다.In addition, mRNA expression of NFATc1, RANK, CAII, and CTK was significantly increased in the control group compared to the normal group, and mRNA expression of RANK, CAII, and CTK was decreased in the experimental group treated with the taklan extract, depending on the concentration of the taklan extract.
특히, 택란 추출물 10, 100 μg/mL을 처리한 실험군에서 NFATc1, RANK, CAII 및 CTK mRNA 발현이 유의하게 감소하였다(p<0.01).In particular, NFATc1, RANK, CAII and CTK mRNA expression was significantly decreased in the experimental group treated with 10, 100 μg / mL of the thylan extract (p <0.01).
한편, MMP-9의 mRNA 발현의 경우, 대조군에서는 정상군에 비해 MMP-9의 mRNA 발현량이 유의하게 증가하였으나, 대조군과 택란 추출물을 처리한 실험군 간에는 유의한 차이가 없었다(도 6).Meanwhile, in the case of mRNA expression of MMP-9, the mRNA expression level of MMP-9 was significantly increased in the control group compared to the normal group, but there was no significant difference between the control group and the experimental group treated with taxane extract (FIG. 6).
상기 결과는 택란 추출물이 파골세포의 분화와 관련된 유전자의 발현을 억제하여 우수한 파골세포 분화 억제 활성을 가지고, 골 질환을 효과적으로 완화 또는 개선시킬 수 있음을 시사한다.The results suggest that the taxane extract has excellent osteoclast differentiation inhibitory activity by inhibiting the expression of genes related to osteoclast differentiation and can effectively alleviate or improve bone diseases.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다.The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the invention is indicated by the following claims, and it should be construed that all changes or modifications derived from the meaning and scope of the claims and their equivalents are included in the scope of the invention.
Claims (8)
RANK 신호 경로(RANK signaling pathway)를 억제하는 골 질환의 예방 또는 치료용 약학적 조성물.The method of claim 1,
Pharmaceutical composition for the prevention or treatment of bone diseases that inhibit the RANK signaling pathway.
c-Fos 또는 NFATc1의 발현을 하향 조절하는 골 질환의 예방 또는 치료용 약학적 조성물.The method of claim 2,
A pharmaceutical composition for preventing or treating bone diseases which down-regulates the expression of c-Fos or NFATc1.
파골세포의 분화를 억제하는 골 질환의 예방 또는 치료용 약학적 조성물.The method of claim 3,
A pharmaceutical composition for preventing or treating bone diseases that inhibits the differentiation of osteoclasts.
상기 추출물은 물, 알코올, 에틸아세테이트, 아세톤, 핵산, 디클로로메탄 또는 이들의 혼합 용매로 추출된 골 질환의 예방 또는 치료용 약학적 조성물.The method of claim 1,
The extract is a water, alcohol, ethyl acetate, acetone, nucleic acids, dichloromethane or a pharmaceutical composition for the prevention or treatment of bone diseases extracted with a mixed solvent thereof.
상기 골 질환은 골다공증, 골 형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군에서 하나 이상 선택된 골 질환의 예방 또는 치료용 약학적 조성물.The method of claim 1,
The bone disease is a pharmaceutical composition for the prevention or treatment of at least one bone disease selected from the group consisting of osteoporosis, bone dysplasia, osteomalacia, bone loss, fractures, bone defects and hip reduction.
상기 골 질환은 골다공증, 골 형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군에서 하나 이상 선택된 골 질환의 예방 또는 개선용 건강기능식품.The method of claim 7, wherein
The bone disease is a health functional food for the prevention or improvement of one or more bone diseases selected from the group consisting of osteoporosis, bone dysplasia, osteomalacia, bone loss, fractures, bone defects and hip reduction.
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