Journal of Nutrition and Health (J Nutr Health) 2016; 49(1): 1 ~ 7 http://dx.doi.org/10.4163/jnh.2016.49.1.1 pissn 2288-3886 / eissn 2288-3959 Review 비타민 D: 호르몬같은영양소 * 신미영 권인숙 안동대학교생활과학대학식품영양학과 Vitamin D: Hormone-like nutrient* Shin, Mee-Young Kwun, In-Sook Department of Food Science and Nutrition, Andong National University, Andong 36729, Korea ABSTRACT Purpose: The aim of this review is to comprehensively summarize the definition of vitamin D as a nutrient as well as a hormone-like molecule and its new function in prevention of various chronic diseases. Methods: The review was written by the method for systematic reivew writing. Literatures from the various sources, including research articles, book chapters, proceedings and electronic materials as appropriate, were screened first and then reviewed and analyzed for the review. Results: Vitamin D was originally considered as the essential nutrient as a vital carbon compound and was first discovered among children with osteomalacia, also known as ricket disease, characterized by poorly calcified bones which were easily bent rather than broken. Since that time, vitamin D has been known as the key nutrient to improve bone health. However, recently emerging study findings have shown that vitamin D acts as the hormone-like nutrient since it is synthesized like a hormone when our body needs and this particular vitamin also acts like a cell signaling ligand which regulates gene expression of various proteins. So far positive effects of vitamin D have been suggested for the action of anticancer, antiimmune function, and anti-cardiovascular disease, as well as antidiabetic function, etc. In this review, the definition for vitamin D as a nutrient vitamin as well as a hormone-like molecule, cell signaling mechanism of vitamin D, and finally the potential role for the prevention of chronic diseases are discussed. Conclusion: Vitamin D is now being considered as a vital nutrient as a vitamin and as a potential substance for prevention of several chronic diseases. KEY WORDS: vitamin D, bone health, hormone, chronic disease 서론 1920년대에인체의영양소결핍을치료하는연구자와의사들은아동들의뼈가충분히칼슘화가일어나지않아서골연화증 (osteomalacia, 또는 ricket이라고불리는구루병 ) 이있는아동들에게서비타민 D가부족하다는것을알게되었다. 1 따라서발견당시부터비타민 D는뼈건강과밀접한관계가있는것으로잘알려져있으며, 오늘날까지뼈의건강을증진시키는강화식품용영양소중에대표적인것으로알려져있다. 골연화증 (osteomalacia) 은칼슘이나비타민 D의부족으로골 ( 뼈 ) 이잘경화 ( 무기질화또는칼슘화, mineralization, calcification) 되지못하여골이휘는현상으로 (osteomalacia), 주로자라나는아동들에게서 많이나타나는증상이다. 이와비슷하게생각되는골다공증 (osteoporosis) 은역시뼈에칼슘이부족한경우는같으나, 주로중년기이후성인에게많이나타나는현상이며. 이는기존의뼈조직에서칼슘이빠져나와, 뼈에칼슘이부족해지고따라서뼈가작은충격에도쉽게잘부러지는현상을말한다 (osteoporosis). 2 이제까지비타민 D는지용성비타민 (vitamin: carboncontaining amine chemicals) 종류에속하는필수영양소로알려져왔지만, 실은이특수비타민은신체가필요하면체내에서합성되기도하고, 식품을통해섭취한비타민 D 형태도체내에서다시신체가필요로하는형태로변환되어야하며, 비타민 D가기능을하고자하는조직세포에까지혈류를타고운반되어가서세포에신호전달을해줌으 Received: February 1, 2016 / Accepted: February 11, 2016 *This work was supported by a grant of 2015 ANU Research Fund of Andong National University. To whom correspondence should be addressed. tel: +82-54-820-5917, e-mail: iskwun@andong.ac.kr 2016 The Korean Nutrition Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
2 / 호르몬같은영양소비타민 D 로써비로소조직의세포가비타민 D로서기능을활용하는점등, 기존의영양소비타민 D로서만알고있던것과는다른여러특성을나타내고있다. 3 이러한비타민의새로운특성들이근래에여러면에서활발히연구보고되고있으며, 따라서비타민 D에대한새롭고흥미로운기능들이많이알려지고있다. 뼈를튼튼하게한다는기존의기본적기능외에항암기능, 항염증성기능, 당뇨병및심혈관계질병예방기능등이보고되고있다. 따라서비타민 D는지금가지영양학분야에서뼈건강과관련이있는영양소로주로알려져왔는데, 근래에비타민 D의새로운기능들이보고되면서비타민 D는영양학자들뿐만아니라기초생물과학연구자및임상관련전문가들의관심도많이받고있다. 아래에비타민 D의영양소으로서의기능과더불어호르몬물질같은작용에대해서설명하였다. 연구방법 체계적총설작성방법활용본논문은비타민 D에대해체계적총설 (systematic review) 작성방법에근거해서작성하였다. 4 그작성단계는다음의 5 단계를사용하였다. 1) 1단계 : 비타민 D의영양소및호르몬으로서의기능에대한근거및내용에대해서전체적윤곽을계획했다 (frameing the question). 2) 2단계 : 해당되는자료및문헌을검색하고확인하였다 (identifying relevant work). 3) 3단계 : 선정된문헌들에대한연구적가치및질을평가, 분석하였다 (assessing the quality of studies). 4) 4단계 : 분석된내용, 즉본총설의데이터를글또는도식으로정리하였다 (summarizing the evidence). 5) 5단계 : 본총설에서피력하고자했던내용에대해서편입견없이분석된데이터에대한객관적해석과결론을유추하였다 (interpreting the findings). 즉간결히정리하면, 총설주제에대한선정, 문헌검색, 문헌선정및선정자료의분석순서로작성하였다. 상세문헌고찰및분석방법문헌검색과분석은기간은 2015년 9월 1일부터 10월 31 일까지행하였으며, 문헌의자료는국외 database로서는 Pubmed, Google Scholar, Google 등을활용하였으며, 국내 database로서는 KISS, DBPIA, RISS, NDSL 등을활용하였다. 문헌검색의검색어는 비타민 D 및관련용어로하였으며, 문헌검색의대상은학술지논문, 저서등을주로하였다. 20년이상오래된논문은되도록배제하였고, 총약 100편이상의선정논문중에서심화된연구내용검토를통해서약 22편의논문및데이타베이스를대상으로총 설을작성하였다. 결과및고찰 비타민의정의및체내합성비타민의정의 원래비타민 (vitamin) 의어원은 우리몸에꼭필요한물질이지만체내에서만들어지지않으므로식품으로부터섭취해야하고, 우리몸이꼭필요로하는 (vital) 탄소를함유하는화합물 (carbone-containing chemicals) 형태의물질 이라는뜻에서유래되었다. 5,6 이러한용어정의면에서만본다면비타민 D는영양소의한종류인비타민범주에속하지만, 한편으로는기존의비타민의속성에약간어긋나는특성을가지고있다. 즉, 대부분의비타민은체내에서합성이되지않아주로식품으로부터공급을받아야하지만, 비타민 D는체내합성이가능하다는점이다. 3 비타민 D는태양빛이있으면우리몸에서콜레스테롤의일종인 7-dehydrocholesterol을이용하여피하조직에서만들수있다 (Fig. 1). 비타민 D 급원식품을살펴보면주로생선, 난황등에들어있으며, 다양한식품에골고루함 Fig. 1. Vitamin D synthesis using sunlight and cholestrol in body. Vitamin D precursor (or called as pro-vitamin D3) is first synthesiszed at skin tissue (skin cells) using sunlight (ultraviolet B, UVB), then this synthesized vitamin D precursor is secreted outside skin cells and carried to the liver through blood vessel and after then in the liver it is transformed to 25(OH)D (cholecalcitriol). Once synthesized, 25(OH)D is secreted outside liver cell and transferred to the kidney and there 25(OH)D is synthesized to 1,25(OH) 2 D as the final form of active vitamin D. This active form of 1,25(OH) 2 D is now secreted outside kidney cells and carried to the various tissue where vitamin D activity is needed. Our body only can use vitamin D as the active vitamin D type as 1,25(OH) 2 D. Abbreviations: UVB - ultraviolet B; vitamin D precursor - previtamin D3 or provitamin D3; 25(OH)D - cholecalcitrol; 1,25(OH) 2D 1,25-dihydrooxycholecalciferol or calcitriol; active vitamin D 1,25(OH) 2 D (Image was revised by the authors. Source: Reference 8).
Journal of Nutrition and Health (J Nutr Health) 2016; 49(1): 1 ~ 7 / 3 유되어있기보다는, 함유되어있는식품종류가다소제한적이다. 이러한점을보완하고자우리몸은어쩌면비타민 D를합성할수있도록되어있으며, 따라서외부로부터의섭취에크게신경을쓰지않아도몸이필요로할때공급을받을수있도록되어있는셈이다. 3,7 일반적으로영양소중에는우리몸이꼭필요로하지만체내합성은되지않아서꼭외부환경인식품으로부터섭취해야하는영양소들은비교적다양한식품들에골고루함유되어있는편이며, 따라서일상적인식생활에서특정영양소가쉽게결핍되지않도록하는영양소도있기는하다 ( 무기질인인의경우가이에해당됨 ). 비타민 D는특이하게식품으로부터섭취를한비타민 D 형태그대로우리몸에서쓰이는것이아니라, 다양한조직세포들 ( 피부세포, 간세포, 신장세포등 ) 이활성형비타민 D를만드는과정에참여해서우리몸이사용하는점도다른비타민들과는다른점이다. 아래에서비타민 D의체내합성에대해서좀더상세히설명하고자한다. 비타민 D의체내합성신체는비타민 D를합성할수있는데, 햇빛을쬐게되면우리몸의피부조직세포는체내의 cholesterol로부터만든 7-dehydrocholesterol이란물질을햇빛의자외선 (ultraviolet) 을이용하여비타민 D 3 로변환시킨다 (Fig. 2). 7- dehydrocholesterol 은햇빛에의해서비타민 D 3 로되기때문에 provitamin D 3 또는비타민 D 전구체 (vitamin D precursor) 라고불리기도한다 (pro-, 접두어 이전의 뜻 ). 피부조직에서비타민 D가합성되는부위는표피세포층이기보다는피부표피층바로밑하층구조를이루고있는피하조직의진피세포층이다. 3 피하조직세포에서합성된 vitamin D 3 는피부세포밖으 로분비되어, 혈관을타고간으로가서간세포안에존재하는미토콘드리아 (mitochondria: 세포안의소기관으로서주로에너지생성을담당함 ) 및마이크로좀 (microsome: 세포내소포체의일부가분리되어서만들어진세포소기관로서운반체의기능을하거나, 스테로이드같은물질을합성함 ) 에있는효소에의해서 25(OH)D 물질로합성된다. 그런다음다시간세포밖으로분비되어혈관을통해신장으로가서신장세포에서 1,25(OH)D로합성된다음, 신장세포밖으로분비되면혈관을통해온몸의각조직세포에가서신체가원하는비타민 D의생리적기능및대사를행하게된다. 신장세포가합성하는마지막단계의비타민 D 의형태, 즉 1,25 (OH) 2 D 형태가되어야만우리몸의세포가활용할수있는비타민 D의형태라하여이를 활성형비타민 D 라고한다 (Fig. 1, 2). 8 Fig. 3에는버섯식품에들어있는비타민 D의형태나또는우리신체가합성한비타민 D의종류들을제시하였다. 우리몸은신체내에서콜레스테롤로부터만들어지거나식품으로부터섭취되는비타민 D가일단우리몸에들어오면일련의과정을거쳐서비타민 D의기능을하게되므 Fig. 2. The structure of cholesterol and 7-dehydrocholesterol (provitamin D3) (Image was redrawn and revised. Source: References 3 and 8). Fig. 3. Types of vitamin D. Vitamin D2 is abundantly present in mushroom, while D3 (25-hydroxy-cholecalciferol) is synthesized to cholesterol at skin. Vitamin D3 is synthesized by adding one OH (hydroxyl) group to the provitamin D at the liver, and then again one more OH group added at the kidney, which finally 1,25-dihydroxycholecalciferol (calcitriol, active form of vitamin D) is synthesized. Our body can utilize vitamin D2 from mushroom etc. to the active form of vitamin D (calcitriol) (Image was redrawn and revised. Source: References 3 and 8).
4 / 호르몬같은영양소비타민 D 로햇빛을많이쬐던가, 비타민 D의식이섭취가부족하지않도록신경쓰는것이중요하다. 호르몬의정의와기능호르몬이란우리몸에서세포에신호를전달해서세포가이에대한반응을보이도록하는일종의세포신호전달물질 (messenger molecules for cell signaling) 단백질이다. 호르몬은세포가만들어서분비하게되므로, 유전정보를가지는 DNA의염기서열로부터 RNA, 그리고단백질로합성되는과정을거치면서만들어지게되고, 일단신체의어느특정조직세포에서만들어지면그조직세포들로부터분비되어서혈관을통해이동해서다른조직세포인목적세포 (target cells) 에가서작동하게된다. 8 이러한특성이호르몬에대한설명이라면, 비타민 D의경우는비록단백질호르몬은아니지만체내의피부조직, 간조직을거쳐최종적으로신장세포에서 활성형비타민 D 가만들어지고, 분비되어서혈관을통해몸의각필요조직세포에가서세포에신호를주게되고, 이과정이호르몬과유사하다고볼수있다. 따라서근래에는비타민 D를꼭영양소비타민이라는범주에국한하지않고, 호르몬같은영양소로보기도한다. Fig. 4에호르몬이만들어져서분비되어목적세포까지가게되는내용을제시하였다. 비타민 D의호르몬으로서의기능 : 체내세포내합성및세포신호전달기능신체내세포에의한합성과정비타민 D의체내에서의합성과정에대해서는앞부분에서이미충분히설명을하였다. Fig. 5에서는체내에서만들어진활성형비타민 D가세포내로이동하여 DNA 상에서유전자발현을도와주는과정을보여주고있다. 비타민 D의세포신호전달및단백질발현조절기능혈액중의활성형비타민 D의세포신호전달기능, 즉세포내유전자와단백질발현및세포내에서의기능에대해서 Fig. 6에서좀더상세히나타내었다. 9 신장세포에서합성된 활성형비타민 D (1,25[OH] 2 Vit D) 는혈액중으로분비되면, 혈액중에비타민 D를결합시키는단백질 (vitamin D-binding protein, VBP) 과결합하여세포막을통과하여세포내로이동하게된다. 이때비타민 D의신호전달작용을받게되는세포를호르몬의정의에의해서호르몬작용 Fig. 4. Hormone and hormonal cell signaling. Hormone is the cell signaling protein which is synthesized by the particular endocrine cells. Once hormone is synthesized, then it is secreted outside cells and then travels in blood stream to the hormone target cells. At the target cells, hormone do act as hormonal cell signaling. Vitamin D acts like hormon (hormone-like nutrient), because it is finally synthesized by the kidney cells as the active form of vitamin D (1,25(OH)2 vitamin D, calcitriol), then secreted into the blood stream and carried to various target cells which it works as hormonal cell signaling molecule (Image was revised. Source: Reference 8). Fig. 5. Vitamin D synthesis in our body and the pathway to affect on gene expression. Vitamin D, whether it is acquired from the diet or synthesized in our body, is finally syntheized to the active form of 1,25(OH)2D and carried to the target cells via blood vessels. In the cells, vitamin D affects on vitamin D-dependent gene expression and therefore finally protein expression. For example, when our body needs the protein which assists Ca absorption or promotes bone health, then vitamin D can signal these informations. Then vitamin D helps to upregulate those particular genes and proteins expression. When vitamin D stimulates upregulation of gene expression as shown in figure, vitamin D needs to complex with RXR (retinoid X receptor protein) and VDR (vitamin D receptor protein). Therefore nutrient retinol is critical for vitamin D action. Abbreiviation: CYP27A1, cytochrome P450, family 27, subfamily A, polypeptide 1; CYP27B1, cytochrome P450, family 27, subfamily B, polypeptide 1; RXR, retinoid X receptor; VDR, vitamin D (1,25-dihydroxyvitamin D3) receptor; 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D (Image was revised. Source: Reference 9).
Journal of Nutrition and Health (J Nutr Health) 2016; 49(1): 1 ~ 7 / 5 의목적세포 (target cell) 라고할수있다. 세포내의세포질에는비타민 D를감지하는비타민 D 수용체 (vitamin D receptor, VDR) 단백질이있으며, 세포내로들어온비타민 D는비타민 D 결합단백질 (vitamin D binding protein, DBP) 에서떨어져서비타민 D 수용체 (vitamin D receptor, VDR) 단백질에결합하게된다. 9 이렇게결합된비타민 D- VDP 복합단백질은 DNA 상의특정한유전정보를가진부분 ( 나중에합성될단백질의정보를가지고있는 DNA 염기서열부분 ) 에결합하게되고, 이러한결합에의해서 RNA 합성및최종적으로단백질합성까지영향을주므로서비타민 D에의해서발현이조절된단백질들이세포밖으로분비다. 10-12 Fig. 6에서보는바와같이, 비타민 D가뼈건강에좋다고하는것도사실은비타민 D의세포내신호전달관점에서보면, 비타민 D가뼈에칼슘을많이축척하기위해서소화관에서 Ca의흡수를높일수있는데, 이를위해서는소화관에서 Ca의흡수를높일수있는단백질의유전자를많이전사 (transcription, mrna를만드는것 ) 시키고, 이에해당되는단백질이많이만들어져서소화관으로부터 Ca이많이흡수되면뼈건강이증진될수있는것이다. 6,13 비타민 D의영양소로서의기능 : 뼈건강촉진기전이제까지비타민 D의영양소및호르몬으로서의특성에대해서설명하였는데, 여기에서는잠시비타민 D의뼈형성촉진기능에대해서설명하고자한다. 비타민 D는 ( 활성형비타민 D인 1,25(OH) 2 vitamin D, calcitriol이라고함 ) 혈액중의 Ca 농도를높일수가있으며, 이렇게높아진혈액 Ca의여유분은뼈조직으로가서하이드록시아파타이트 (hydroxyapatite, 인화합물의일종 ) 을형성하여뼈조직에침착함으로서뼈의경화를도와준다. 13 비타민 D가혈액중의 Ca의농도를높이는경우는두가지방법이있는데하나는소장에서의 Ca의흡수를높여서혈액중에 Ca 농도를높이는경우로서이경우에는혈액중의여분의 Ca 이뼈로저장되어뼈의칼슘화를촉진시킬수있다. 15 또다른경우는예외적으로혈액중의 Ca 농도는일정수준이하로내려가면근육세포나기타조직세포에서 Ca 이필요한세포대사기능이방해를받음으로, 이를방지하기위해우리신체는일정한수준의 Ca을뼈로부터용출시켜서혈액의 Ca 수준으로정상으로유지하려고한다. 이때비타민 D는뼈에저장되어있는 Ca을혈액으로용출시켜혈중의 Ca 농도는증가시키나, 뼈의칼슘침착을저하 Fig. 6. Cell signaling and the regulation of protein expression by vitamin D. Active vitamin D (1,25[OH]2 Vit D), which is synthesized by kidney cells and secreted into the blood vessels, combines with vitamin D-binding protein (DBP) in the blood, and then move into the cells which are the target cells of vitamin D. Within the cytosol, vitamin D receptor protein (VDR) can recognize this vitamin D-DBP complex and once vitamin D-DBP complex is detached, then vitamin D combines at this time with VDR to get into the nucleus. Within the nucleus, vitamin D-VDR-RXR complex combines with a particular vitamin D-dependent DNA elements and regulates the vitamin D- dependent gene expression (transcription). Abbreviation: DBP, vitamin D binding protein; 1,25[OH]2 Vit D), active vitamin D; VDR, vitamin D receptor; RXR, retinoid X receptor; DNA, deoxyribonucleic acid; RNA, ribonucleic acid; +/- gene transcription, up-/down-regulation (Image was revised. Source: Reference 6).
6 / 호르몬 같은 영양소 비타민 D 시켜 뼈의 무기질화를 저하시키는 이중적인 면을 가지고 있는 다양한 생리적 기능이 있다는 연구 결과들이 많이 보 있다. 따라서 평소 식사 일광을 통한 비타민 D의 합성을 잘 고되고 있다 (Fig. 7). 근래에 보고된 비타민 D의 기능에는 하고, 혈액 중의 Ca 농도가 낮아지지 않도록 Ca 식품도 잘 암세포의 증식을 저하시키고, 암세포의 사멸을 촉진하거 섭취하면, 혈액 중의 Ca 농도가 낮아지는 경우를 피할 수 나 암세포를 위한 신생혈관을 형성을 저해함으로서 암을 있어서 비타민 D의 뼈의 칼슘화 촉진 기능 쪽으로 혜택을 볼 수 있다.5,15,16 예방할 수 있는 항암기능7,9,15,17 면역기능에 관여하는 단 백질 합성을 촉진시켜서 염증 및 염증 관련 질병을 예방할 수 있는 기능 및 항세균성 기능,18,19 고혈압 등 심혈관계 질 비타민 D의 호르몬으로서의 새로운 기능들 병을 예방할 수 있는 단백질들의 합성을 촉진시켜서 심혈 지금까지의 내용을 정리하면 비타민 D는 식이와 체내 관계 질병 및 고혈압 예방을 할 수 있는 기능,6,20 그리고 항 합성으로 우리 몸에 들어와 신장 조직에서 최종적으로 활 당뇨병성 기능21 등에 대한 연구결과들이 보고되고 있다 성형 비타민 D의 형태가 되어서 혈액을 통해 운반되어, 필 된다. 대체로 비타민 D가 관여하는 유전자 발현 및 이에 따 (Fig. 7).22 이러한 비타민 D의 기능은 호르몬으로서의 역 할처럼 세포 내에서 세포가 만드는 단백질 합성을 조절할 수 있는 세포신호전달 기능에 근거한다. 이들 각각의 구체 른 단백질 합성을 촉진시킴으로써, 우리 몸의 생리적 기능 적인 기전에 대해서는 다음 총설에서 더 상세히 논의하고 에 관여한다는 내용이다. 이와 같이 비타민과 호르몬의 특 자 한다. 요한 조직 세포 안으로 들어가서 세포 내 신호전달을 하게 성을 동시에 가지고 있는 비타민 D가 1) 소장 내에서 Ca의 지금까지 본 총설에서는 비타민 D가 이제까지의 고유의 흡수를 도와주는 단백질 합성을 촉진시키고, 2) 조골 세포 기능이었던 뼈 건강 촉진의 기능이 있는 영양소로서의 기 (osteoblast, 골 형성 세포)와 파골 세포 (osteoclast, 골용해 세포)의 세포 분화와 기능을 조절함으로써 뼈 건강을 촉진 시키는 작용 이외에, 근래에 와서는 만성 질병을 예방할 수 비타민 D에 대한 정의, 비타민 D의 체내 합성과정, 호르몬 능 뿐만 아니라, 새로이 비타민 및 호르몬으로서의 기능, 물질로서의 체내 합성 배경과 세포신호전달의 내용, 그리 Fig 7. The nutrient and hormone-like roles of vitamin D. Traditionally, vitamin D is well known as the nutrient which promotes bone health by stimulating Ca absorption by upregulating the protein expresstion and synthesis for Ca absorption and osteoblast differentiation etc (as nutrient). In these days, numerous studies show that vitamin D is also having various functions of anticancer through up-regulating the proteins for preventing cancer cell proliferation, anti-cardiovascular and anti-diabetic function, which are not considered only as the nutrient but cell signaling molecule (hormone-like nutrient). Abbreviations: VDR, vitamine D receptor protein; RXR, retinoid X receptor; RNA POL II, RNA polymerase II; VDRE, vitamin D response element (Image was revised. Source: Reference 22).
Journal of Nutrition and Health (J Nutr Health) 2016; 49(1): 1 ~ 7 / 7 고근래새로이소개되고있는비타민 D의생리활성기능에대해서간략히설명하였다. 기존의신체가꼭필요로하는영양소물질로만알고있었던비타민 D가여러만성질병들, 즉암, 면역, 심혈관계및당뇨병예방및치료에대해서도긍정적인기능을가지고있다는사실은비타민 D의새로운기능들이며, 따라서식이및체내합성을통해비타민 D의기능을신체가잘활용하여좋은건강상태를유지할수있음을의미한다. References 1. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, Bassford T, Beresford SA, Black HR, Blanchette P, Bonds DE, Brunner RL, Brzyski RG, Caan B, Cauley JA, Chlebowski RT, Cummings SR, Granek I, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Johnson KC, Judd H, Kotchen JM, Kuller LH, Langer RD, Lasser NL, Limacher MC, Ludlam S, Manson JE, Margolis KL, McGowan J, Ockene JK, O Sullivan MJ, Phillips L, Prentice RL, Sarto GE, Stefanick ML, Van Horn L, Wactawski- Wende J, Whitlock E, Anderson GL, Assaf AR, Barad D; Women s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354(7): 669-683. 2. Anderson PH, Atkins GJ. The skeleton as an intracrine organ for vitamin D metabolism. Mol Aspects Med 2008; 29(6): 397-406. 3. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005; 289(1): F8-F28. 4. Khan KS, Kunz R, Kleijnen J, Antes G. Five steps to conducting a systematic review. J R Soc Med 2003; 96(3): 118-121. 5. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266-281. 6. Reddy Vanga S, Good M, Howard PA, Vacek JL. Role of vitamin D in cardiovascular health. Am J Cardiol 2010; 106(6): 798-805. 7. Davis CD, Milner JA. Nutrigenomics, vitamin D and cancer prevention. J Nutrigenet Nutrigenomics 2011; 4(1): 1-11. 8. Vitamin D and your health: breaking old rules, raising new hopes [Internet]. Boston (MA): Harvard Health Publications; 2009 Jun 9 [cited 2015 Nov 10]. Available from: http://www.health.harvard. edu/newsweek/vitamin-d-and-your-health.htm. 9. Ahn J, Albanes D, Berndt SI, Peters U, Chatterjee N, Freedman ND, Abnet CC, Huang WY, Kibel AS, Crawford ED, Weinstein SJ, Chanock SJ, Schatzkin A, Hayes RB; Prostate, Lung, Colorectal and Ovarian Trial Project Team. Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk. Carcinogenesis 2009; 30(5): 769-776. 10. Haussler MR, Haussler CA, Whitfield GK, Hsieh JC, Thompson PD, Barthel TK, Bartik L, Egan JB, Wu Y, Kubicek JL, Lowmiller CL, Moffet EW, Forster RE, Jurutka PW. The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the Fountain of Youth to mediate healthful aging. J Steroid Biochem Mol Biol 2010; 121(1-2): 88-97. 11. Joshi S, Pantalena LC, Liu XK, Gaffen SL, Liu H, Rohowsky- Kochan C, Ichiyama K, Yoshimura A, Steinman L, Christakos S, Youssef S. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17a. Mol Cell Biol 2011; 31(17): 3653-3669. 12. Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, Collins JF, Haussler MR, Ghishan FK. 1alpha,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 2005; 289(6): G1036-G1042. 13. Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, Hsieh JC, Jurutka PW. Molecular mechanisms of vitamin D action. Calcif Tissue Int 2013; 92(2): 77-98. 14. Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 2010; 61: 91-104. 15. Bikle D. Extrarenal synthesis of 1,25-dihydroxyvitamin D and its health implications. In: Holick MF, editor. Vitamin D: physiology, molecular biology, and clinical applications. 2nd edition. New York (NY): Humana; 2010. p. 277-295. 16. Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM. Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A 1992; 89(17): 8097-8101. 17. Murillo G, Matusiak D, Benya RV, Mehta RG. Chemopreventive efficacy of 25-hydroxyvitamin D3 in colon cancer. J Steroid Biochem Mol Biol 2007; 103(3-5): 763-767. 18. Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008; 8(9):685-698. 19. Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 2008; 4(2): 80-90. 20. Artaza JN, Mehrotra R, Norris KC. Vitamin D and the cardiovascular system. Clin J Am Soc Nephrol 2009; 4(9): 1515-1522. 21. Grundmann M, von Versen-Höynck F. Vitamin D - roles in women's reproductive health? Reprod Biol Endocrinol 2011; 9: 146. 22. UCLA Orthopaedic Surgery (US). Vitamin D and human health [Internet]. Los Angeles (CA): UCLA Heath; [cited 2015 Dec 10]. Available from: http://ortho.ucla.edu/body.cfm?id=205.