KR102161111B1 - Pharmaceutical composition for preventing or treating osteoporosis containing linalool as an active ingredient - Google Patents
Pharmaceutical composition for preventing or treating osteoporosis containing linalool as an active ingredient Download PDFInfo
- Publication number
- KR102161111B1 KR102161111B1 KR1020180140312A KR20180140312A KR102161111B1 KR 102161111 B1 KR102161111 B1 KR 102161111B1 KR 1020180140312 A KR1020180140312 A KR 1020180140312A KR 20180140312 A KR20180140312 A KR 20180140312A KR 102161111 B1 KR102161111 B1 KR 102161111B1
- Authority
- KR
- South Korea
- Prior art keywords
- bone
- linarool
- formula
- pharmaceutical composition
- osteoporosis
- Prior art date
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- A—HUMAN NECESSITIES
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Abstract
본 발명은 리나로올을 유효성분으로 함유하는 골다공증의 예방 또는 치료용 약학적 조성물에 관한 것으로, 본 발명에 따른 약학적 조성물은 조골세포 분화 마커 유전자인 Dlx5, Runx2, Id1, OC의 발현량을 증가시킴으로써, 조골세포의 분화를 촉진하는 효과가 있어 골다공증의 예방 또는 치료용 의약품 또는 건강식품으로 널리 이용될 수 있다.
또한, 파골세포를 표적으로 하기보다는 조골세포의 활성을 증가시킴으로써 골형성을 촉진 시켜 근본적으로 골다공증을 치료할 수 있으며, 2차 골절 예방효과를 나타낼 수 있는 장점이 있다.The present invention relates to a pharmaceutical composition for the prevention or treatment of osteoporosis containing linarool as an active ingredient, and the pharmaceutical composition according to the present invention contains the expression levels of osteoblast differentiation marker genes Dlx5, Runx2, Id1, OC. By increasing it, it has the effect of promoting the differentiation of osteoblasts, so it can be widely used as a pharmaceutical or health food for preventing or treating osteoporosis.
In addition, it is possible to fundamentally treat osteoporosis by promoting bone formation by increasing the activity of osteoblasts rather than targeting osteoclasts, and has the advantage of showing a secondary fracture prevention effect.
Description
본 발명은 리나로올을 유효성분으로 함유하는 골다공증의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating osteoporosis, containing linarool as an active ingredient.
최근 각종 산업재해 및 교통사고가 증가하고 고령화 사회로 접어들면서 골다공증 및 그에 따른 골절등에 의한 근골격계 질환이 증가하고 있다. 이와 같은 골질환등의 예방과 치료를 위해 골 재생 능력유도를 위한 다양한 형태의 뼈이식제와 조골세포의 활성향상 및 파골세포의 활성을 저하시키기 위한 새로운 형태의 관련질환 치료제들이 개발되고 있다. 또한, 골종양, 골결손이 심한 부위를 채울 수 있는 신생골을 능동적으로 유도하기 위하여 줄기세포와 조골세포를 이용하여 다양한 연구들이 시도되고 있다.Recently, as various industrial accidents and traffic accidents increase and entering an aging society, diseases of the musculoskeletal system due to osteoporosis and resulting fractures are increasing. For the prevention and treatment of such bone diseases, various types of bone graft agents for inducing bone regeneration ability and new types of related disease treatments for improving the activity of osteoblasts and reducing the activity of osteoclasts are being developed. In addition, various studies have been attempted using stem cells and osteoblasts to actively induce new bones that can fill areas with severe bone tumors and bone defects.
골의 재형성 과정은 오래된 골이 주기적으로 새로운 골로 전환되는 과정으로, 이 과정은 증식, 분화 및 세포외기질의 석회화유도 등의 단계를 거쳐 진행된다. 일반적으로 성인의 골 형성과 흡수 과정은 중간엽줄기세포 유래의 조골세포와 조혈모세포 유래의 파골세포의 상호작용에 의해 균형을 이루면서 골의 건강을 유지하는데, 조골세포의 활성도가 낮아져 골 형성이 감소 되거나 파골세포의 활성도가 강해져 골 흡수가 증가 되는 등의 조골세포와 파골세포 간의 활성 불균형이 일어나게 되면 조직 내 화학조성에는 큰 변화가 없지만 골 질량이 감소하여 골다공증(osteoporosis)과 같은 골 대사질환이 유발될 수 있다.Bone remodeling is a process in which old bones are periodically converted into new bones, and this process proceeds through steps such as proliferation, differentiation, and induction of calcification of the extracellular matrix. In general, the process of bone formation and resorption in adults is balanced by the interaction of osteoblasts derived from mesenchymal stem cells and osteoclasts derived from hematopoietic stem cells to maintain bone health, but bone formation decreases due to low osteoblast activity. If there is an active imbalance between osteoblasts and osteoclasts, such as increased bone resorption due to increased activity of osteoclasts or increased bone resorption, there is no significant change in the chemical composition in the tissue, but bone mass decreases, causing bone metabolic diseases such as osteoporosis. Can be.
골다공증은 유전적 요인이나 식이, 생활 방식과 같은 환경적 요인에 의해서도 영향을 받는 복합적인 질병으로, 특히 여성의 경우 폐경기에 이르면 호르몬의 변화에 의해 골 감소가 급격히 진행된다.Osteoporosis is a complex disease that is also affected by genetic factors, diet, and environmental factors such as lifestyle, and especially in women, bone loss rapidly progresses due to hormonal changes when menopause.
현재 시판되고 있는 골다공증 치료제는 비타민 D, 여성호르몬제, 비스포스포네이트제제, 선택적 에스트로겐 수용체 조절제, 칼시토닌 제제 등이 있는데 대부분 파골세포의 활성을 감소시켜 골 흡수를 조절함으로써 뼈의 소실을 막아주는 방식에 의하고 있다. 그러나 파골세포의 활성억제를 통한 골다공증 치료법들은 근본적으로 골다공증을 치료할 수 있는 치료법이 아니기 때문에 완치에 한계가 있으며 실질적인 골밀도 증가 및 골 강화가 이루어질 수 있는 조골세포 활성의 증가가 필수적으로 요구된다.Currently marketed osteoporosis treatments include vitamin D, female hormones, bisphosphonates, selective estrogen receptor modulators, and calcitonin agents, and most of them are based on a method that prevents bone loss by reducing the activity of osteoclasts to regulate bone resorption. . However, because osteoporosis treatments through inhibition of osteoclast activity are not fundamentally curable treatments for osteoporosis, there is a limit to cure, and an increase in osteoblast activity that can substantially increase bone density and strengthen bone is required.
또한, 골다공증은 약물의 단기 투여만으로는 치료할 수 없고 약물의 장기 투여가 필수적인 질환이므로, 약물을 장기 투여할 때에도 부작용이 없으면서 우수한 약효를 갖는 새로운 물질들의 개발이 요구되고 있다.In addition, since osteoporosis cannot be cured by only short-term administration of drugs, and long-term administration of drugs is essential, development of new substances having no side effects even when long-term administration of drugs and having excellent efficacy is required.
이에 따라, 최근에는 기존 치료법의 부작용 최소화와 골 소실을 최소화하면서 골 형성을 촉진할 수 있는 한약재 및 식품 등의 천연물 유래 활성성분을 이용한 대체요법 연구들이 활발히 진행되고 있다.Accordingly, in recent years, studies on alternative therapies using active ingredients derived from natural products such as herbal medicinal herbs and foods that can promote bone formation while minimizing side effects and bone loss of existing treatments have been actively conducted.
한편, 리나로올은 라벤더와 고수풀을 비롯한 많은 꽃과 향신료에서 발견되는 자연 발생 테르펜으로, 꽃향기를 발산하며 스트레스를 줄이기 위해 가장 널리 사용되는 물질 중 하나이다. 허브, 향신료, 나무, 감귤루의 열매 등의 식물에 의해 천연적으로 생합성되며, 이중 95 % 이상이 방향제 및 착취제로 화장품, 비누, 향수에 사용되고, 단 1 % 만이 식품 및 음료에 향과 맛을 내기 위해 사용되고 있다.On the other hand, linarool is a naturally occurring terpene found in many flowers and spices, including lavender and coriander, and is one of the most widely used substances to reduce stress by emitting floral fragrance. It is naturally biosynthesized by plants such as herbs, spices, trees, and citrus fruits, and more than 95% of them are used in cosmetics, soaps and perfumes as fragrances and deodorants, and only 1% of them give flavor and taste to foods and beverages. It is being used to pay.
또한, 리나로올 성분의 질병 치료와 관련된 연구로서 리나로올의 혈관신생 억제효능이 보고된 바 있으며, 한국등록특허 제10-1189763호에서는 리나로올의 중추신경계 장애 치료효과가 개시된 바 있다.In addition, as a study related to the treatment of diseases of the linarool component, the angiogenesis inhibitory effect of linarool has been reported, and in Korean Patent No. 10-1189763, the effect of linarool in treating central nervous system disorders has been disclosed.
그러나 리나로올이 조골세포의 증식 및 분화에 미치는 영향에 대한 연구결과는 아직 보고된 바 없다.However, no research results have been reported on the effect of linarool on the proliferation and differentiation of osteoblasts.
본 발명자들은 근본적으로 골다공증을 치료하기 위해 실질적인 골밀도 증가 및 골 강화를 위해 조골세포의 활성을 증가시키고, 장기간 복용하여도 부작용이 적은 새로운 약학적 조성물을 개발하기 위해 노력하던 중, 리나로올이 조골세포의 증식 및 분화를 촉진함을 확인함으로써 본 발명을 완성하였다.The inventors of the present invention were trying to develop a new pharmaceutical composition that essentially increases the activity of osteoblasts to substantially increase bone density and strengthen bone to treat osteoporosis, and that has less side effects even when taken for a long time. The present invention was completed by confirming that it promotes cell proliferation and differentiation.
따라서, 본 발명의 목적은 골다공증 예방 및 치료 효능이 우수하고 장기간 복용하여도 부작용이 적은 약학적 조성물 및 건강기능식품을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a pharmaceutical composition and a health functional food having excellent efficacy in preventing and treating osteoporosis and having fewer side effects even when taken for a long time.
상기 목적을 달성하기 위해, 본 발명은 하기 화학식 1로 표시되는 화합물을 유효성분으로 함유하는 골다공증의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of osteoporosis containing a compound represented by the following formula (1) as an active ingredient.
상기 약학적 조성물은 조골세포 분화를 촉진시키는 것을 특징으로 할 수 있다.The pharmaceutical composition may be characterized by promoting osteoblast differentiation.
상기 화학식 1로 표시되는 화합물은 Runx2(runt-related transcription factor 2), Id1(inhibitor of DNA binding 1), Dlx5(distal-less homeobox 5) 및 OC(osteocalcin) 중 어느 하나 이상의 조골세포 분화 마커 유전자의 발현량을 증가시키는 것을 특징으로 할 수 있다.The compound represented by Formula 1 is of any one or more of osteoblast differentiation marker genes of Runx2 (runt-related transcription factor 2), Id1 (inhibitor of DNA binding 1), Dlx5 (distal-less homeobox 5) and OC (osteocalcin). It may be characterized by increasing the expression level.
상기 화학식 1로 표시되는 화합물의 농도는 0.0001 내지 5 μM 인 것을 특징으로 할 수 있다.The concentration of the compound represented by Formula 1 may be 0.0001 to 5 μM.
또한, 본 발명은 하기 화학식 1로 표시되는 화합물을 유효성분으로 함유하는 골다공증의 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving osteoporosis containing a compound represented by the following formula (1) as an active ingredient.
[화학식 1][Formula 1]
본 발명에 따른 약학적 조성물은 조골세포 분화 마커 유전자인 Dlx5, Runx2, Id1, OC의 발현량을 증가시킴으로써, 조골세포의 분화를 촉진하는 효과가 있어 골다공증의 예방 또는 치료용 의약품 또는 건강식품으로 널리 이용될 수 있다.The pharmaceutical composition according to the present invention has the effect of promoting the differentiation of osteoblasts by increasing the expression levels of the osteoblast differentiation marker genes Dlx5, Runx2, Id1, and OC, so it is widely used as a pharmaceutical or health food for the prevention or treatment of osteoporosis. Can be used.
또한, 파골세포를 표적으로 하기보다는 조골세포의 활성을 증가시킴으로써 골형성을 촉진 시켜 근본적으로 골다공증을 치료할 수 있으며, 2차 골절 예방효과를 나타낼 수 있는 장점이 있다.In addition, it is possible to fundamentally treat osteoporosis by promoting bone formation by increasing the activity of osteoblasts rather than targeting osteoclasts, and has the advantage of showing a secondary fracture prevention effect.
도 1은 리나로올 농도에 따른 세포의 생존율을 확인한 MTT 실험 결과이다.
도 2는 리나로올을 1 μM 농도로 처리 후, 0, 2, 4일간 배양한 MC3T3-E1 세포에서 조골세포 분화 유전자 발현을 확인한 결과이다.
도 3은 리나로올, 아스코르브산과 베타-글리세로포스페이트 혼합물을 각각 처리한 MC3T3-E1 세포와 이들을 모두 혼합하여 처리한 MC3T3-E1 세포에서 조골세포 분화 유전자 발현을 비교한 결과이다.
도 4는 리나로올, 아스코르브산과 베타-글리세로포스페이트 혼합물을 각각 처리한 MC3T3-E1 세포와 이들을 모두 혼합하여 처리한 MC3T3-E1 세포에서의 ALP 염색 결과이다.
도 5는 리나로올, 아스코르브산과 베타-글리세로포스페이트 혼합물을 각각 처리한 MC3T3-E1 세포와 이들을 모두 혼합하여 처리한 MC3T3-E1 세포에서의 ARS 염색 결과이다.1 is a result of an MTT experiment confirming the viability of cells according to linarool concentration.
Figure 2 is a result of confirming the osteoblast differentiation gene expression in MC3T3-E1 cells cultured for 0, 2, and 4 days after treatment with linarool at a concentration of 1 μM.
3 is a result of comparing osteoblast differentiation gene expression in MC3T3-E1 cells treated with linarool, ascorbic acid, and beta-glycerophosphate mixtures, and MC3T3-E1 cells treated by mixing all of them.
4 is a result of ALP staining in MC3T3-E1 cells treated with linarool, ascorbic acid, and beta-glycerophosphate mixture, and MC3T3-E1 cells treated by mixing all of them.
5 is a result of ARS staining in MC3T3-E1 cells treated with linarool, ascorbic acid, and beta-glycerophosphate mixture, and MC3T3-E1 cells treated by mixing all of them.
이하, 본 발명을 상세히 설명한다. 본 명세서 및 청구범위에 사용되는 용어나 단어는 통상적이거나 사전적인 의미로 한정해서 해석되어서는 아니되며, 발명자는 그 자신의 발명을 가장 최선의 방법으로 설명하기 위해 용어의 개념을 적절하게 정의할 수 있다는 원칙에 입각하여 본 발명의 기술적 사상에 부합하는 의미와 개념으로 해석되어야만 한다.Hereinafter, the present invention will be described in detail. The terms or words used in the present specification and claims should not be construed as being limited to their usual or dictionary meanings, and the inventor may appropriately define the concept of terms in order to describe his own invention in the best way. It should be interpreted as a meaning and concept consistent with the technical idea of the present invention based on the principle that there is.
본 발명은 골다공증의 예방 또는 치료용 약학적 조성물 및 건강기능식품에 관한 것이다.The present invention relates to a pharmaceutical composition and health functional food for the prevention or treatment of osteoporosis.
본 명세서에서 용어 골다공증은 뼈의 양이 감소하고 질적인 변화로 인하여 뼈의 강도가 약해진 상태를 의미하고, 골다공증의 예방, 개선 및 치료라 함은 골 밀도 저하, 골 손실로 인한 각종 질병을 모두 포함하는 것으로 해석된다.In the present specification, the term osteoporosis refers to a condition in which the amount of bone is decreased and the strength of the bone is weakened due to qualitative changes, and prevention, improvement and treatment of osteoporosis include all diseases caused by bone loss and bone loss. Is interpreted as doing.
본 발명은 하기 화학식 1로 표시되는 화합물을 유효성분으로 함유하는 골다공증의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating osteoporosis containing a compound represented by the following Formula 1 as an active ingredient.
[화학식 1][Formula 1]
상기 화학식 1로 표시되는 화합물은 리나로올(Linalool)로 명명될 수 있고, C10H18O 분자식과 154 g/mol의 분자량을 갖는다.The compound represented by Formula 1 may be named linalool, and C 10 H 18 O It has a molecular formula and a molecular weight of 154 g/mol.
상기 화학식 1로 표시되는 화합물은 약학적으로 허용 가능한 염의 형태로 사용될 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 아세트산, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 다이하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Rate, sebacate, fumarate, maleate, butine-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 디클로로메탄, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다.The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc. and adding an organic or inorganic acid May be prepared by filtration and drying, or may be prepared by distilling off a solvent and an excess of acid under reduced pressure and then drying to crystallize under an organic solvent.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
상기 화학식 1로 표시되는 화합물인 리나로올은 공지된 방법에 의해 천연물로부터 추출된 것이나 합성된 것을 사용할 수 있으며, 그 제조방법이나 기원은 한정되지 않는다.Linarool, a compound represented by Chemical Formula 1, may be extracted from natural products or synthesized by a known method, and its preparation method or origin is not limited.
리나로올은 리나로올을 주성분으로 하는 정유를 알코올칼리로 비누화하고, 중성까지 세정한 유분을 감압증류하는 방법으로 제조될 수 있다.Linarool can be prepared by saponifying essential oil containing linarool as a main component with alcoholic potassium, and distilling the oil washed to neutrality under reduced pressure.
또한, 정유 중에 함유된 리나로올에 상당하는 붕산을 넣고 감압하에서 천천히 가열하여 생성되는 물을 제거하면 리나로올은 붕산에스테르가 되므로, 미반응물을 감압하에서 증류 제거한 후 붕산에스테르를 수증기 또는 알칼리로 분해하고 유리하는 유분을 세정 후 증류하는 방법에 의해 제조될 수 있다.In addition, if boric acid equivalent to the linarool contained in the refinery is added and heated slowly under reduced pressure to remove the water produced, linarool becomes a boric acid ester, so the unreacted material is distilled off under reduced pressure and then the boric acid ester is converted to steam or alkali. It can be prepared by a method of distilling after washing the decomposed and liberated oil.
상기 약학적 조성물은 조골세포 분화를 촉진시키는 것을 특징으로 할 수 있다.The pharmaceutical composition may be characterized by promoting osteoblast differentiation.
조골세포의 분화를 촉진시키는 화합물은 골다공증 및 골절 등과 같은 질환 및 증상의 예방 또는 치료에 사용될 수 있을 뿐만 아니라, 골 강화를 목적으로 하는 치주질환 치료에도 사용될 수 있으며(Zhang et al., ShanghaiKou Qiang Yi Xue 7(2), pp99-103, 1998; Cahill et al, Biol Blood Marrow Transplant 10(10), pp709-717, 2004), 화상으로 비롯되는 골 성장 장애 치료에 유용하게 사용될 수 있다는 연구도 보고된바 있다(Klein et al.,Osteoporos Int. 16(6), pp631-635, 2005).Compounds that promote the differentiation of osteoblasts can be used not only to prevent or treat diseases and symptoms such as osteoporosis and fractures, but also to treat periodontal diseases for the purpose of strengthening bone (Zhang et al., ShanghaiKou Qiang Yi) Xue 7(2), pp99-103, 1998; Cahill et al, Biol Blood Marrow Transplant 10(10), pp709-717, 2004), also reported that it can be useful for treating bone growth disorders caused by burns. (Klein et al., Osteoporos Int. 16(6), pp631-635, 2005).
상기 약학적 조성물은 조골세포 등의 부족으로 인한 골 형성에 문제가 있는 질환에 제한 없이 사용될 수 있으며, 구체적으로 에스트로겐의 부족으로 인한 인터루킨-1(IL-1)에 의한 골 파괴와 염증성 질환 등이 포함될 수 있고, 과도한 파골 세포의 골 흡수에 의한 골다공증, 뼈전이암 병소(bone metastatic lesion), 원발성으로 뼈에 생성된 종양, 류마티스성 또는 퇴행성 관절염, 치주질환, 염증성 치조골 흡수질환, 염증성 뼈 흡수 질환 및 파제트병(Paget's disease) 등과 같은 병리학적 골 질환으로 골 파괴를 촉진하는 질환이 포함될 수 있다.The pharmaceutical composition can be used without limitation for diseases having problems with bone formation due to lack of osteoblasts, etc., specifically, bone destruction and inflammatory diseases caused by interleukin-1 (IL-1) due to lack of estrogen. Osteoporosis due to excessive bone resorption of osteoclasts, bone metastatic lesions, primary tumors in bone, rheumatoid or degenerative arthritis, periodontal disease, inflammatory bone resorption disease, inflammatory bone resorption disease And diseases that promote bone destruction with pathological bone diseases such as Paget's disease.
상기 화학식 1로 표시되는 화합물은 상기 화학식 1로 표시되는 화합물은 Runx2(runt-related transcription factor 2), Id1(inhibitor of DNA binding 1), Dlx5(distal-less homeobox 5) 및 OC(osteocalcin) 중 어느 하나 이상의 조골세포 분화 마커 유전자의 발현량을 증가시키는 것을 특징으로 할 수 있다.In the compound represented by Formula 1, the compound represented by Formula 1 is any of Runx2 (runt-related transcription factor 2), Id1 (inhibitor of DNA binding 1), Dlx5 (distal-less homeobox 5), and OC (osteocalcin). It may be characterized by increasing the expression level of one or more osteoblast differentiation marker genes.
조골세포 분화는 호르몬, 뼈형성 단백질(Bone Morphogenetic Proteins, BMPs)과 같은 사이토카인, Runx2(runt-related transcription factor 2), Id1(inhibitor of DNA binding 1), Dlx5(distal-less homeobox 5), OC(osteocalcin), ALP(alkaline phosphatase)과 같은 다양한 전사인자에 의해서 조절된다. 그 중에서도 Id1, Dlx5, Runx2는 조골세포 분화 초기에 발현되는 필수적인 유전자로 이들 유전자의 발현은 조골세포 분화가 가속화됨을 의미한다.Osteoblast differentiation involves hormones, cytokines such as Bone Morphogenetic Proteins (BMPs), Runx2 (runt-related transcription factor 2), Id1 (inhibitor of DNA binding 1), Dlx5 (distal-less homeobox 5), OC It is regulated by various transcription factors such as (osteocalcin) and ALP (alkaline phosphatase). Among them, Id1, Dlx5, and Runx2 are essential genes that are expressed in the early stages of osteoblast differentiation. The expression of these genes means that osteoblast differentiation is accelerated.
구체적으로, Runx2(runt-related transcription factor 2)는 조골세포 분화에 있어 중요한 조절자로 많이 알려져 있으며, 다분화능세포 또는 조골전구세포에서 ALP(alkaline phosphatase), OC(osteocalcin) 그리고 뼈 시알로프로틴(bone sialoprotein)과 같은 유전자를 조절함으로써 조골세포 분화를 촉진하는 유전자이다.Specifically, Runx2 (runt-related transcription factor 2) is widely known as an important regulator in osteoblast differentiation, and in multipotent cells or osteoblasts, ALP (alkaline phosphatase), OC (osteocalcin), and bone sialoprotein (bone sialoprotein), which promotes osteoblast differentiation by regulating genes.
Id1(inhibitor of DNA binding 1)은 조골세포에서 세포의 성장과 분화 사이의 균형에 영향을 미치는 전사인자이고, 조골세포 특이적 분화에 있어서 초기 단계에 중요한 역할을 하는 것으로 알려져 있다. 뿐만 아니라 근원세포, 중간엽 줄기세포에서 조골세포 분화로 전환될 때 Id1(inhibitor of DNA binding 1) 유전자 발현의 조절에 따라 분화가 촉진된다. Id1 (inhibitor of DNA binding 1) is a transcription factor that affects the balance between growth and differentiation of cells in osteoblasts, and is known to play an important role in the early stages in osteoblast-specific differentiation. In addition, when the myoblast and mesenchymal stem cells are converted to osteoblast differentiation, differentiation is promoted by regulating the expression of the Id1 (inhibitor of DNA binding 1) gene.
Dlx5(distal-less homeobox 5)는 뼈에 의해 유도되며 Runx2(runt-related transcription factor 2)의 프로모터에 직접적으로 결합하여 전사를 조절하고, 조골세포 분화의 후기 표지 유전자인 OC(osteocalcin)의 유전자 발현을 조절함으로써 조골세포 분화를 조절한다.Dlx5 (distal-less homeobox 5) is induced by bone and directly binds to the promoter of Runx2 (runt-related transcription factor 2) to regulate transcription, and expression of the osteocalcin (OC) gene, a late marker gene for osteoblast differentiation. By regulating osteoblast differentiation.
상기 화학식 1로 표시되는 화합물의 농도는 0.0001 내지 5 μM 인 것을 특징으로 할 수 있다.The concentration of the compound represented by Formula 1 may be 0.0001 to 5 μM.
보다 상세하게는, 상기 화학식 1로 표시되는 화합물의 농도는 0.0001 내지 5 μM 일 수 있고, 바람직하게는 0.0001 내지 2 μM 일 수 있으며, 보다 바람직하게는 0.0001 내지 1 μM일 수 있다.More specifically, the concentration of the compound represented by Formula 1 may be 0.0001 to 5 μM, preferably 0.0001 to 2 μM, and more preferably 0.0001 to 1 μM.
만일, 상기 화학식 1로 표시되는 화합물의 농도가 상기 기재된 범위 미만인 경우 약학적인 효과가 미미하게 나타날 수 있고, 상기 기재된 범위를 초과할 경우 세포독성이 나타날 수 있는 문제점이 있다.If the concentration of the compound represented by Formula 1 is less than the above-described range, the pharmaceutical effect may be insignificant, and if the concentration exceeds the above-described range, cytotoxicity may occur.
상기 약학적 조성물은 임상 투여시에 경구 또는 비경구로 투여가 가능하며, 일반적인 의약품 제제의 형태로 사용될 수 있다.The pharmaceutical composition may be administered orally or parenterally during clinical administration, and may be used in the form of a general pharmaceutical formulation.
상기 약학적 조성물은 산제, 과립제, 정제, 경질 캡슐제, 연질 캐슐제 또는 주사제의 형태로 제형화되는 것을 특징으로 할 수 있다.The pharmaceutical composition may be characterized in that it is formulated in the form of a powder, granule, tablet, hard capsule, soft capsule or injection.
보다 상세하게는, 각각 통상적인 방법에 따라 산제, 과립제, 정제, 캡슐, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 멸균 주사용액, 사전 충전식 주사 용액제의 형태 또는 동결건조된 형태로 제형화할 수 있으나, 이에 제한되는 것은 아니다.More specifically, oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, sterile injection solutions, pre-filled injection solutions, or freeze-dried It may be formulated in a form, but is not limited thereto.
제형화할 경우에는 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조될 수 있다.In the case of formulation, it can be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 유효 성분에 적어도 하나 이상의 부형제, 예컨대, 전분, 칼슘 카르보네이트, 수크로오스, 락토오스, 젤라틴 등을 혼합하여 제조할 수 있다. 또한, 단순한 부형제 이외에도 마그네슘 스테아레이트, 탈크와 같은 윤활제도 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. in the active ingredient. It can be prepared by mixing. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used.
경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 통상적으로 사용되는 단순 희석제인 물, 액체 파라핀 이외에 다양한 부형제, 예컨대 습윤제, 감미제, 방향제, 보존제 등이 함께 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함된다.Liquid formulations for oral administration include suspensions, liquid solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., may be included in addition to water and liquid paraffin, which are commonly used simple diluents. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories, and the like.
본 발명의 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 증상의 정도, 약물 형태, 투여 경로 및 기간에 따라 적절하게 선택될 수 있다.A preferred dosage of the pharmaceutical composition of the present invention may be appropriately selected according to the condition and weight of the patient, the degree of symptoms, the form of the drug, the route and duration of administration.
또한, 본 발명은 하기 화학식 1로 표시되는 화합물을 유효성분으로 함유하는 골다공증의 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving osteoporosis containing a compound represented by the following formula (1) as an active ingredient.
[화학식 1][Formula 1]
상기 화학식 1로 표시되는 화합물은 리나로올(Linalool)로 명명될 수 있고, C10H18O 분자식과 154 g/mol의 분자량을 갖는다.The compound represented by Formula 1 may be named linalool, and C 10 H 18 O It has a molecular formula and a molecular weight of 154 g/mol.
상기 건강기능식품은 조골세포 분화를 촉진시키는 것을 특징으로 할 수 있다.The health functional food may be characterized by promoting osteoblast differentiation.
상기 화학식 1로 표시되는 화합물은 상기 화학식 1로 표시되는 화합물은 Runx2(runt-related transcription factor 2), Id1(inhibitor of DNA binding 1), Dlx5(distal-less homeobox 5) 및 OC(osteocalcin) 중 어느 하나 이상의 조골세포 분화 마커 유전자의 발현량을 증가시키는 것을 특징으로 할 수 있다.In the compound represented by Formula 1, the compound represented by Formula 1 is any of Runx2 (runt-related transcription factor 2), Id1 (inhibitor of DNA binding 1), Dlx5 (distal-less homeobox 5), and OC (osteocalcin). It may be characterized by increasing the expression level of one or more osteoblast differentiation marker genes.
상기 화학식 1로 표시되는 화합물의 농도는 0.0001 내지 5 μM 인 것을 특징으로 할 수 있다.The concentration of the compound represented by Formula 1 may be 0.0001 to 5 μM.
보다 상세하게는, 상기 화학식 1로 표시되는 화합물의 농도는 0.0001 내지 5 μM 일 수 있고, 바람직하게는 0.0001 내지 2 μM 일 수 있으며, 보다 바람직하게는 0.0001 내지 1 μM일 수 있다.More specifically, the concentration of the compound represented by Formula 1 may be 0.0001 to 5 μM, preferably 0.0001 to 2 μM, and more preferably 0.0001 to 1 μM.
만일, 상기 화학식 1로 표시되는 화합물의 농도가 상기 기재된 범위 미만인 경우 약학적인 효과가 미미하게 나타날 수 있고, 상기 기재된 범위를 초과할 경우 세포독성이 나타날 수 있는 문제점이 있다.If the concentration of the compound represented by Formula 1 is less than the above-described range, the pharmaceutical effect may be insignificant, and if the concentration exceeds the above-described range, cytotoxicity may occur.
상기 건강기능식품은, 비제한적으로 각종 음료, 껌, 차, 과자, 비타민 복합체, 건강 보조식품 등의 형태로 제조될 수 있다.The health functional food may be prepared in the form of, but not limited to, various beverages, gum, tea, confectionery, vitamin complexes, health supplements, and the like.
또한, 상기 건강기능식품은 골다공증 개선을 목적으로 건강식품에 첨가되는 경우도 포함하며, 식품의 종류에 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.In addition, the health functional food may be added to health food for the purpose of improving osteoporosis, and there is no particular limitation on the type of food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages and vitamin complexes, and it includes all health foods in the usual sense.
상기 건강기능식품의 바람직한 섭취량은 섭취자의 상태 및 체중, 증상의 정도, 식품 형태, 섭취 기간에 따라 다르며 적절하게 선택될 수 있다.The preferred intake amount of the health functional food depends on the condition and weight of the eater, the degree of symptoms, the food type, and the intake period, and may be appropriately selected.
골의 형성과정에 조골세포의 분화는 유전형질의 발현에 의해 조절되며, 배양방법에 따라 고유의 특성을 가진다. 골세포의 분화 및 골 형성에 관여하는 중요한 신호전달체계는 대표적으로 변화 성장 인자-β(transforming growth factor-β: TGF-β)와 뼈형성단백질(bone morphogenetic protein: BMP), 윈트/베타-카테닌(Wnt/β-catenin), 섬유아세포 증식인자(fibroblast growth factor: FGF), 헤지호그(hedgehog), 노치(notch) 등이 알려져 있다.The differentiation of osteoblasts in the process of bone formation is regulated by the expression of genotypes, and has unique characteristics depending on the culture method. Important signaling systems involved in bone cell differentiation and bone formation are typically transforming growth factor-β (TGF-β), bone morphogenetic protein (BMP), and wint/beta-catenin. (Wnt/β-catenin), fibroblast growth factor (FGF), hedgehog, and notch are known.
이러한 신호전달체계는 골세포 분화과정 동안 Runx2(Runt-related transcription factor 2) 및 Dlx5(Distalless-related homeobox 5) 등과 같은 골 형성과 관련한 다양한 전사인자의 발현과 활성화를 유도하며, ALP(alkaline phosphatase), Id1(inhibitor of DNA binding 1), OC(Osteocalcin) 등의 골 분화 관련 유전자를 발현시킨다. 이러한 조골세포에서의 분화 유도 물질로는 아스코르브산(ascorbic acid, AA), 베타-글리세로포스페이트(β-glycerophosphate,β-GP), 덱사메타손(dexamethasone) 등이 알려져 있다.This signaling system induces the expression and activation of various transcription factors related to bone formation such as Runx2 (Runt-related transcription factor 2) and Dlx5 (Distalless-related homeobox 5) during the bone cell differentiation process.Alkaline phosphatase (ALP) , Id1 (inhibitor of DNA binding 1), OC (Osteocalcin) to express bone differentiation related genes. Ascorbic acid (AA), beta-glycerophosphate (β-GP), dexamethasone, and the like are known as substances that induce differentiation in osteoblasts.
본 발명에서는 골조직에 존재하는 조골세포와 유사한 MC3T3-E1 전조골세포(preosteoblasts)를 이용하여 리나로올이 조골세포의 증식 및 분화에 미치는 영향을 알아보기 위한 실험을 진행하였으며, 그 결과 리나로올은 조골세포의 증식 및 분화에 긍정적인 효과를 나타냄을 확인할 수 있었다.In the present invention, an experiment was conducted to investigate the effect of linarool on the proliferation and differentiation of osteoblasts using MC3T3-E1 preosteoblasts similar to osteoblasts present in bone tissue. Was confirmed to have a positive effect on the proliferation and differentiation of osteoblasts.
이하, 본 발명을 구체적으로 설명하기 위해 실시예 및 실험예를 들어 상세하게 설명하기로 한다. 그러나 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 아래에서 상술하는 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해서 제공되는 것이다.Hereinafter, examples and experimental examples will be described in detail in order to describe the present invention in detail. However, the embodiments according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the embodiments described below. Embodiments of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.
<실험예 1> MTT 세포독성 실험<Experimental Example 1> MTT cytotoxicity test
(1) 재료준비 및 세포배양(1) Material preparation and cell culture
본 실험에서 사용된 리나로올(Linalool)은 Sigmal aldrich사에서 구입하였고, 마우스 유래 MC3T3-E1 세포는 ATCC (American Type Culture Collection, Manassas, VA, USA)에서 구입하여 사용하였다.Linalool used in this experiment was purchased from Sigmal aldrich, and mouse-derived MC3T3-E1 cells were purchased from ATCC (American Type Culture Collection, Manassas, VA, USA) and used.
MC3T3-E1 세포 배양에 사용된 알파-최소필수배지(α-MEM), 소태아혈청(fetal bovine serum, FBS), 항생물질(antibiotics), 트립신-EDTA는 GibcoBRL(GibxoBRL, Grandisland, NY, USA)로부터 구입하였고, 세포독성 검사에 사용된 3-(4,5-디메틸티아졸-2-일)-2,5-디페닐테트라졸리움 브로마이드(MTT) 시약은 Sigma사 (chem, co, St.Louis. Mo. USA)로부터 구입하였다.Alpha-minimum essential medium (α-MEM) used in MC3T3-E1 cell culture, fetal bovine serum (FBS), antibiotics, trypsin-EDTA, GibcoBRL (GibxoBRL, Grandisland, NY, USA) 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent purchased from Sigma (chem, co, St.Louis) used for cytotoxicity test Mo. USA).
MC3T3-E1 세포를 α-MEM을 사용하여 배양하고, 접시의 바닥에 붙어 있는 MC3T3-E1 세포를 FBS 2 μL를 이용하여 워싱해주고, 트립신(Trypsine) 500 μL를 이용하여 떨어트려 주었다.MC3T3-E1 cells were cultured using α-MEM, and MC3T3-E1 cells attached to the bottom of the dish were washed with 2 μL of FBS, and dropped with 500 μL of Trypsine.
새로운 α-MEM을 이용하여 세포들을 e-튜브(e-tube)에 넣은 후 원심분리(Hano, science)하고, 원심분리가 끝나면 상층액을 제거하고 15 μL 코니칼 튜브(conical tube)에 옮겨 닮았다.Using new α-MEM, cells were placed in an e-tube and then centrifuged (Hano, science).After centrifugation was completed, the supernatant was removed and transferred to a 15 μL conical tube. .
혈구계(hemocytometer)와 커버 글래스(cover glass)를 이용하여 세포 수를 구하고, 조직 배양 검사 플레이트(Tissue Culture Test plate) 48-well에 α-MEM을 200 μL 넣어 주었다.The number of cells was calculated using a hemocytometer and a cover glass, and 200 μL of α-MEM was added to a 48-well tissue culture test plate.
측정된 세포를 48-well에 넣어 준 다음 인큐베이터 (Model3154, FormaScientific, USA)에 보관하였다.The measured cells were placed in a 48-well and then stored in an incubator (Model3154, Forma Scientific, USA).
(2) MTT 분석(2) MTT analysis
세포의 생존능력 및 독성을 평가하기 위하여 흡광을 이용한 MTT 분석을 실시하였다. 테트라졸리움 염인 MTT는 살아있는 세포에 의해서만 분해되며, 수용성인 MTT를 불용성 침전물인 보라색의 포마잔(Formazan)으로 환원시키는데 여기에는 미토콘드리아 효소인 석시네이트 디하이드로제네이즈(succinate dehydrogenase)를 필요로 한다. 또한 세포수와 생성된 포마잔 사이에 양적인 관계가 설정된다면 약물의 감수성을 결정짓는데도 이용될 수 있다.In order to evaluate the viability and toxicity of cells, MTT analysis using absorption was performed. MTT, a tetrazolium salt, is only degraded by living cells, and reduces water-soluble MTT to purple formazan, an insoluble precipitate, which requires succinate dehydrogenase, a mitochondrial enzyme. It can also be used to determine the sensitivity of a drug if a quantitative relationship is established between the number of cells and the formazan produced.
먼저, MC3T3-E1 세포를 48-well에 각각 분주하여 24시간 인큐베이터에 보관하였다.First, MC3T3-E1 cells were each dispensed into 48-wells and stored in an incubator for 24 hours.
리나로올과 디메틸설폭사이드(DMSO)를 희석하여, 각각의 well에 첨가한 뒤 인큐베이터에서 1시간 보관하였다. 보라색으로 염색된 배양액을 제거해주고 FBS를 이용하여 워싱해주었다. 각 well에 DMSO 400 μL를 첨가해주었고, UV/visible spectrophotometer (Uvikon 922, Kontron, Italy) 570 nm에서 흡광도를 측정하였다.Linarool and dimethyl sulfoxide (DMSO) were diluted, added to each well, and stored in an incubator for 1 hour. The purple dyed culture medium was removed and washed with FBS. 400 μL of DMSO was added to each well, and absorbance was measured at 570 nm with a UV/visible spectrophotometer (Uvikon 922, Kontron, Italy).
(3) 실험결과(3) Experiment result
MTT 분석결과를 도 1에 나타내었다. 나타낸 바와 같이, 리나로올 5 μM 농도에서 활성도가 급격히 낮아지는 것을 확인할 수 있었다.The MTT analysis results are shown in FIG. 1. As shown, it was confirmed that the activity was rapidly lowered at a concentration of 5 μM of linarool.
<실험예 2> 리나로올 처리에 따른 조골세포 분화마커의 발현 분석<Experimental Example 2> Expression analysis of osteoblast differentiation markers according to linarool treatment
(1) 실험방법(1) Experiment method
1) RNA 추출 및 cDNA 합성1) RNA extraction and cDNA synthesis
RNA를 추출하기 위해 트리졸(Trizol) 용액(Bioscience technology)을 이용하였다. 스크랩퍼로 세포를 모아주고 클로로폼(chloroform)을 각각 60 μL 씩 넣어준 다음 볼텍싱(vortexing)을 15초간 해주었다. Trizol solution (Bioscience technology) was used to extract RNA. The cells were collected with a scraper, chloroform was added to each of 60 μL, and then vortexing was performed for 15 seconds.
이어서, 원심분리 (14500 rpm, 4℃, 15 min)를 해주고 RNA가 있는 상층액 부분을 옮겨 이소프로필(Isopropyl) 150 μL를 처리하고 상온에서 30분간 반응시켰다. 30분 후 원심분리 (14500 rpm, 4℃, 10 min)를 해주었고, 상층액을 제거하고 70% 에탄올을 200 μL씩 넣고 워싱하였다. Subsequently, centrifugation (14500 rpm, 4° C., 15 min) was performed, the supernatant portion containing RNA was transferred, and 150 μL of isopropyl was treated, followed by reaction at room temperature for 30 minutes. After 30 minutes, centrifugation (14500 rpm, 4° C., 10 min) was performed, the supernatant was removed, and 200 μL of 70% ethanol was added and washed.
워싱 후, 원심분리 (13000 rpm, 4℃, 10 min)를 한 뒤 상층액을 제거하고 건조 시켰다. 3차 증류수를 20 μL씩 넣고 4 ℃에서 30 분간 반응시켰고, 30 분 후 RNA를 정량하였다. 이 후에 흡광도를 측정하고 25 μL에 맞추어 RNA, 3차 증류수, emeraldAmp GT PCR Master Mix (Takara Bio Inc, Japan)를 25 μL에 맞추어 넣어 주고, 흡광도를 측정하였다.After washing, centrifugation (13000 rpm, 4°C, 10 min) was performed, and the supernatant was removed and dried. 20 μL of distilled water was added each, and reacted at 4° C. for 30 minutes, and RNA was quantified after 30 minutes. After that, absorbance was measured, RNA, tertiary distilled water, and emeraldAmp GT PCR Master Mix (Takara Bio Inc, Japan) were added to 25 μL, and absorbance was measured.
2) 실시간 중합효소 연쇄반응(RT-PCR, Real-time polymerase chain reaction)2) Real-time polymerase chain reaction (RT-PCR)
PCR 버퍼, 프라이머 (β-actin, Runx2, Id1, OC, Dlx5), 3차 증류수를 준비하고 혼합물을 만들었다. PCR 튜브를 준비하고, 혼합물 19 μL과 cDNA 1 μL을 넣어주었다. 튜브를 볼텍싱(vortexing)하였고, 원심분리한 다음 PCR 장비 (Mygenie96, Bioneer, USA)에 넣고 장비를 작동시켰다. 프라이머 서열 및 작동 조건을 표 1 및 표2에 나타내었다. 이 후, 1 % 아가로스 겔(Agarose gel)을 이용하여 전기영동을 하였고 UV를 이용하여 결과를 측정하였다.PCR buffer, primers (β-actin, Runx2, Id1, OC, Dlx5), and tertiary distilled water were prepared to prepare a mixture. A PCR tube was prepared, and 19 μL of the mixture and 1 μL of cDNA were added. The tube was vortexed, centrifuged, and then put into a PCR equipment (Mygenie96, Bioneer, USA) and the equipment was operated. Primer sequences and operating conditions are shown in Tables 1 and 2. After that, electrophoresis was performed using 1% agarose gel, and the result was measured using UV.
DenaturationPre-
Denaturation
ExtensionPost-
Extension
(2) 실험결과(2) Experiment result
1) 리나로올 처리시간에 따른 조골세포 분화 유전자 발현1) Expression of osteoblast differentiation gene according to linarool treatment time
리나로올 1 μM 농도를 처리한 뒤, 0, 2, 4일 동안 배양된 각각의 샘플에 대해 RT-PCR을 통해 유전자 발현을 확인한 결과, 4일차일 때 유전자 발현이 가장 높게 나타났다. 결과적으로, 리나로올 처리시간에 의존적으로 조골세포 분화 유전자 발현이 나타나는 것을 확인할 수 있었다(도 2 참조).After treatment with a concentration of 1 μM linarool, gene expression was confirmed through RT-PCR for each sample cultured for 0, 2, and 4 days, and the gene expression was highest on the 4th day. As a result, it was confirmed that the osteoblast differentiation gene expression appeared depending on the linarool treatment time (see FIG. 2).
2) 조건처리에 따른 조골세포 분화 유전자 발현2) Expression of osteoblast differentiation gene according to condition treatment
조골세포 분화를 유도하는 물질로 아스코르브산(ascorbic acid, AA)과 베타-글리세로포스페이트(β-Glycerophosphate,β-GP)를 사용하여, 아스코르브산과 베타-글리세로포스페이트 혼합물, 리나로올을 각각 단독으로 처리한 것과 이들을 모두 혼합하여 처리한 것의 유전자 발현정도를 비교하였다.Ascorbic acid (AA) and beta-glycerophosphate (β-GP) are used as substances that induce osteoblast differentiation, and ascorbic acid, beta-glycerophosphate mixture, and linarool are used alone. The gene expression levels were compared between those treated with and those treated by mixing them all.
이 때, 리나로올 1 μM 농도로 4일 동안 배양된 세포를 사용하였다.At this time, cells cultured for 4 days at a concentration of 1 μM linarool were used.
비교 결과, Id1, Runx2는 리나로올만 첨가했을 때 가장 진하게 나왔고, Dlx5는 아스코르브산, 베타-글리세로포스페이트, 리나로올을 모두 혼합하여 처리하였을 때 가장 진하게 나오는 것을 확인할 수 있었다(도 3참조).As a result of comparison, it was confirmed that Id1 and Runx2 were the most dark when only linarool was added, and Dlx5 was the most concentrated when ascorbic acid, beta-glycerophosphate, and linarool were all mixed and treated (see FIG. ).
<실험예 3> ALP(Alkaline phosphatas) 염색 실험<Experimental Example 3> ALP (Alkaline phosphatas) staining experiment
(1) 실험방법(1) Experiment method
24 well에 MC3T3-E1 세포를 분주하고, 대조군(Control), 아스코르브산(Ascorbic acid, AA, Sigma)과 베타-글리세로포스페이트(β-glycerophosphate,β-GP, Sigma) 혼합물, 리나로올, 아스코르브산과 베타-글리세로포스페이트 및 리나로올 혼합물을 각각의 well에 첨가하였다. Dispense MC3T3-E1 cells into 24 wells, control, ascorbic acid (AA, Sigma) and beta-glycerophosphate (β-GP, Sigma) mixture, linarool, ascorb A mixture of acid, beta-glycerophosphate and linarool was added to each well.
이 때, 리나로올 1 μM 농도로 4일 동안 배양된 세포를 사용하였다.At this time, cells cultured for 4 days at a concentration of 1 μM linarool were used.
이후, 실온에 보관하였다가 증류수로 세척해 주고, 준비된 BCIP/NBT (sigma aldrich)를 첨가하여 약 15분간 실온에 방치 한 후, 다시 증류수로 세척하고 염색정도를 확인하였다.Thereafter, it was stored at room temperature, washed with distilled water, prepared BCIP/NBT (sigma aldrich) was added and left at room temperature for about 15 minutes, and then washed again with distilled water and the degree of dyeing was checked.
(2) 실험결과(2) Experiment result
상기 실험의 결과를 도 4에 나타내었다. 나타낸 바와 같이, 리나로올 처리 well에서 염색된 결과를 나타내어 리나로올이 ALP 발현을 증가시킴을 알 수 있었으며, 세포의 증식단계에서 여러 층의 골을 형성하는 초기에 도움이 될 것으로 예상되었다.The results of the experiment are shown in FIG. 4. As shown, the staining results in the linarool-treated wells were shown, indicating that linarool increased ALP expression, and was expected to be helpful in the early stages of forming multiple layers of bone in the cell proliferation stage.
또한, 아스코르브산, 베타-글리세로포스페이트, 리나로올을 모두 혼합하여 처리하였을 때 가장 진하게 염색되어 가장 높은 활성도를 나타내는 것을 확인할 수 있었다.In addition, when all of ascorbic acid, beta-glycerophosphate, and linarool were mixed and treated, it was confirmed that the darkest dyeing showed the highest activity.
<실험예 4> 알리자린 레드 에스 염색(Alizarin red s staining) 분석<Experimental Example 4> Alizarin red s staining analysis
(1) 실험방법(1) Experiment method
조골세포의 분화가 진행되면서 칼슘(calcium)이 세포외 기질에 침착되어 석회화가 진행되는데, 이를 알아보기 위해 각각의 well에 대조군(Control), 아스코르브산과 베타-글리세로포스페이트 혼합물, 리나로올, 아스코르브산과 베타-글리세로포스페이트 및 리나로올 혼합물 순으로 첨가하여 ARS 염색을 진행하였다.As osteoblast differentiation progresses, calcium is deposited on the extracellular matrix and calcification proceeds.To check this, control, ascorbic acid and beta-glycerophosphate mixture, linarool, and ascorb in each well. ARS staining was performed by adding an acid, beta-glycerophosphate, and linarool mixture in order.
이 때, 리나로올 1 μM 농도로 21일 동안 배양된 세포를 사용하였다.At this time, cells cultured for 21 days at a concentration of 1 μM linarool were used.
10 % 포름알데히드(Merck KGaA, Darmstadt, Germany)를 well 안에 첨가하고, 15분간 방치하여 세포들을 고정시켜 주었다. 이후, 3차 증류수로 두 번 워싱 해주었다. 2 % ARS standard(alizarin red solution) 200 μL을 각 well에 넣어주었고 호일에 싸서 가볍게 흔들어 주었다. 15 분후 3차 증류수로 세척하고, 결과를 확인하였다.10% formaldehyde (Merck KGaA, Darmstadt, Germany) was added to the well and allowed to stand for 15 minutes to fix the cells. Afterwards, it was washed twice with 3rd distilled water. 200 μL of 2% ARS standard (alizarin red solution) was put into each well, wrapped in foil and shaken lightly. After 15 minutes, it was washed with third distilled water, and the result was confirmed.
(2) 실험결과(2) Experiment result
석회화 결절 형성능은 조골세포의 분화에 중요한 바이오 마커로 알리자린 레드 에스 염색으로 확인할 수 있다. 알리자린은 무기질화된 세포 기질의 칼슘을 염색하므로 석회화 결절 형성 정도와 염색 정도가 비례한다. The ability to form calcified nodules can be confirmed by Alizarin Red S staining as an important biomarker for the differentiation of osteoblasts. Alizarin stains calcium in the mineralized cell matrix, so the degree of calcified nodule formation and the degree of staining are proportional.
도 5에 나타낸 바와 같이, 아스코르브산과 베타-글리세로포스페이트 혼합물을 처리했을 때 보다 아스코르브산과 베타-글리세로포스페이트 및 리나로올 혼합물을 처리했을 때 더 진한 염색이 나타남을 확인할 수 있었다.As shown in Figure 5, it was confirmed that darker staining appeared when the ascorbic acid and beta-glycerophosphate and linarool mixture were treated than when the ascorbic acid and beta-glycerophosphate mixture was treated.
결과적으로, 리나로올이 조골세포 분화에 긍정적인 효과를 줄 수 있음을 알 수 있다.As a result, it can be seen that linarool can have a positive effect on osteoblast differentiation.
한편, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.Meanwhile, the compound represented by Formula 1 according to the present invention can be formulated in various forms depending on the purpose. The following illustrates some formulation methods in which the compound represented by Formula 1 according to the present invention is contained as an active ingredient, and the present invention is not limited thereto.
<제제예> <Preparation Example>
1-1. 산제의 제조1-1. Preparation of powder
화학식 1의 화합물 500 ㎎ 500 mg of the compound of formula 1
유당 100 ㎎ 100 mg lactose
탈크 10 ㎎
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다. The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
1-2. 정제의 제조1-2. Manufacture of tablets
화학식 1의 화합물 500 ㎎ 500 mg of the compound of formula 1
옥수수전분 100 ㎎ Corn starch 100 mg
유당 100 ㎎ 100 mg lactose
스테아린산 마그네슘 2 ㎎ 2 mg of magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다. After mixing the above ingredients, tablets are prepared by tableting according to a conventional tablet preparation method.
1-3. 캅셀제의 제조1-3. Preparation of capsules
화학식 1의 화합물 500 ㎎ 500 mg of the compound of formula 1
옥수수전분 100 ㎎ Corn starch 100 mg
유당 100 ㎎ 100 mg lactose
스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다. According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare a capsule.
1-4. 주사제의 제조1-4. Preparation of injections
화학식 1의 화합물 500 ㎎500 mg of the compound of formula 1
주사용 멸균 증류수 적량 Suitable amount of sterile distilled water for injection
pH 조절제 적량proper amount of pH adjuster
통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다. It is prepared with the above ingredients per ampoule (2 ml) according to a conventional injection preparation method.
1-5. 액제의 제조1-5. Preparation of liquid
화학식 1의 화합물 100 ㎎ 100 mg of the compound of formula 1
이성화당 10 g 10 g of isomerized sugar
만니톨 5 g 5 g of mannitol
정제수 적량Purified water appropriate amount
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색 병에 충진하여 멸균시켜 액체를 제조한다.According to the usual preparation method of liquid preparation, add and dissolve each component in purified water, add lemon scent, mix the above ingredients, add purified water, add purified water, adjust the total to 100 ml, and fill in a brown bottle. The liquid is prepared by sterilization.
Claims (5)
[화학식 1]
In vitro (in vitro), osteoblast differentiation promoting method comprising the step of treating osteoblasts with a compound represented by the following formula (1).
[Formula 1]
상기 화학식 1로 표시되는 화합물은 Runx2(runt-related transcription factor 2), Id1(inhibitor of DNA binding 1), Dlx5(distal-less homeobox 5) 및 OC(osteocalcin) 중 어느 하나 이상의 조골세포 분화 마커 유전자의 발현량을 증가시키는 것을 특징으로 하는 조골세포 분화 촉진 방법.
The method of claim 1,
The compound represented by Formula 1 is of any one or more of osteoblast differentiation marker genes among Runx2 (runt-related transcription factor 2), Id1 (inhibitor of DNA binding 1), Dlx5 (distal-less homeobox 5), and OC (osteocalcin). Osteoblast differentiation promoting method, characterized in that to increase the expression level.
상기 화학식 1로 표시되는 화합물의 농도는 0.0001 내지 5μM 인 것을 특징으로 하는 조골세포 분화 촉진 방법.
The method of claim 1,
The method for promoting osteoblast differentiation, characterized in that the concentration of the compound represented by Formula 1 is 0.0001 to 5 μM.
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