어린이를 위한 최고의 복지,키 성장

뉴메드의 ‘황기추출물’ 이 올바른 성장을 도와줍니다.

뉴메드의 키 성장 원료 황기추출물 등 복합물 HT042 이야기

뉴메드행복한 세상을 만드는 바이오벤처

뉴메드는 천연물을 기반으로 한 기능성원료 전문연구 기업입니다.

2003년 경희대학교 한의과대학 출신들의 뜻이 모여 설립됐습니다.

천연물로부터 부가가치 높은 신약/건강기능식품 원료를 만들어냅니다.

식약처로부터 기능성원료로 인정받은 황기추출물 등 복합물(HT042)은

2000년대 초반 시작한 어린이 키 성장 연구의 결실입니다.

성장지연으로 고통받는 지구촌의 어린이를 돕는다는 사명을 실천하고 있습니다.

ww

w.n

eum

ed.c

o.kr

ww

w.n

eum

ed.c

o.kr2017’s

2016’s

2015’s

2014’s

2013’s

2008’s

2007’s

2006’s

2005’s

2004’s

2003’s

2012’s

2011’s

2010’s

2009’s

050402

1209

0801

04

04

12

06

12

0403

1004

0504

09

11

11080503

12

중소기업 대상 수상한국보건산업진흥원장상 수상서울시우수기업브랜드 Hi Seoul 브랜드 선정

벤처활성화 유공포상 중소기업청장 표창 수상한국 호간성(간 기능 개선) 10만불 중국 수출

HT042 어린이 키 성장 개별 인정형 건강기능식품 원료 인정HP426 간 기능 개선 개별 인정형 건강기능식품 원료 인정

HT008 관절 기능 개선 수입원료 개별 인정형건강기능식품 원료 인정

교육과학기술부 프론티어 사업 우수 결과물 선정

혈관성 치매 치료 천연물신약 HP012기술이전

이노비즈 기업 인증

연 매출 29억 원 달성, 수출 70만불 달성

기업부설연구소 한의과학기술연구소(KISTEM) 인증벤처기업인증

공장설립, 제조허가 취득주식회사 뉴메드 설립

뇌신경세포 보호 활성 조성물 미국, 일본, 중국 특허 획득성장 촉진용 조성물 특허 기술이전

HT008 관절 기능 개선 개별 인정형 건강기능식품 원료 인정

대기업 투자유치 및 공동연구 협약

HT008-1 기억력개선 개별 인정형 건강기능식품 원료 인정제약회사 투자 유치 및 공동연구 협약바이오 창투사 투자 유치ISO9001:2008 인증

연 매출 120억 달성

전세계 어린이의 25%는

성장지연으로 고통받고 있습니다.

스턴팅 차일드(Stunting Child),

태아부터 생후 2년까지 1,000일동안의 영양부족이나

감염 등으로 인해 성장이 지연된 어린이를 말합니다.

전세계 어린이 1억 6천만명이 넘으며, 5세 미만 어린이 4명 중

1명은 stunting(성장지연)을 겪고 있습니다.

(Source: de Onis et al., 2013)

<20.0%

20.0%-29.9%

30.0%-29.9%

≥40.0%

Data not available

5세 미만 성장지연 어린이(stunting child)의 세계 분포 현황

성장지연 어린이는 성장촉진

기능물질이 필요합니다.

성장지연 예방에는 영양 공급이 중요하지만, 성장지연 어린이는 성장촉진 기능물질이 필요합니다.

황기추출물은 어린이 키성장에 도움을 주는 성장촉진 기능물질 입니다.

뉴메드는 성장촉진 기능물질 개발 뿐 아니라 성장지연 예방을 위한 영양 등 프로그램도 연구하고 있습니다.

키는 어떻게 클까요?

키 성장에는 성장인자가 중요합니다.

성장인자가 성장판을

자극하여 키가 큽니다.

뇌하수체 전엽에서 분비되는 성장호르몬은 간과 성장판에서 성장인자 IGF-1을 합성합니다.

생성된 성장인자 IGF-1은 성장단백질 IGFBP-3와 결합하여 성장판으로 이동한 후 성장판 연골세포의 수와

크기를 증가시킵니다.

아이들의 긴뼈 양 끝부분에는 성장판이라는 부위가 있습니다.

성장인자는 성장판에서 연골세포를 자극해

연골세포의 수와 크기를 증가시킵니다.

성장판 연골세포의 수와 크기가 증가하는 속도를 빠르게 하면

키의 성장속도가 빨라집니다.

성장호르몬신체 전반을 통해 성장을

촉진하도록 뇌하수체 전엽에서 분비되는 호르몬

성장인자IGF-1

성장호르몬이 간에서 전환된 주요 성장조절물질

성장단백질IGFBP-3

성장인자를 성장판까지 운반하는 활성물질

성장단백질이 성장인자를 더 많이 더 확실하게

뼈의 성장판까지 이동시켜 줌

성장 단백질은 성장인자를 운반하는활성물질입니다.

성장판팔, 다리 뼈에서 길이 성장이 일어나는 부분

13세 여자열린 성장판, 성장이 지속됨

25세 여자닫힌 성장판, 성장이 멈춤

뉴메드는 국내 최초로 초정밀 뼈 성장속도

측정기술을 구축하여 키 성장 연구의 기반을

마련하였습니다.

2000년대 초반 뉴메드는 테트라사이클린 침착을 이용한 초정밀 뼈 성장속도 측정기술을 구축하였습니다.

테트라사이클린을 흰쥐에 주입하면, 테트라사이클린은 성장판에서 연골세포의 수와 크기가 증가한 후 골화가 일어

나는 부위의 칼슘과 함께 침착하여 형광을 나타냅니다.

48시간 간격으로 테트라사이클린을 주입하였을 때 나타나는 2개의 형광띠 사이의 간격을 측정하면 뼈 성장 속도를

마이크로미터 단위로 정밀하게 측정하여 단기간 내에 성장한 뼈 길이를 확인할 수 있습니다.

이 방법을 2002년 유럽소아과학회지에 게재하였으며, 2003년에는 건강기능식품 가이드라인으로 실렸습니다.

이 방법을 이용하여 15년간 수 십 여종의 천연물을 스크리닝 하였고, 효능이 우수한 소재를 확보했습니다.

Resting Zone

Proliferating Zone

Hypertrophic Zone

METAPHYSIS

GROWTH PLATE

(출처: Hansson, 1968; Leem, 2002)

황기추출물,

국내 최초로 식약처에서

어린이 키성장 기능성을

인정받았습니다.

경희대 한의과학대학에서 시작된 15년간의 연구가 결실을 맺었습니다.

한의학에서 찾아낸 황기, 가시오갈피, 한속단의 키 성장 효과를 밝혔습니다.

황기추출물 등 복합물은 천연물 신소재 연구개발기업 뉴메드가 개발한

국내 최초∙유일의 어린이 키 성장 기능성 개별인정 원료입니다.

원료명: 황기추출물 등 복합물 HT042

개별인정번호 2014-40

기능성: 어린이 키성장에 도움을 줄 수 있음

섭취량: 1,500mg/day

원물: 황기, 가시오갈피, 한속단

“17.2% 더 컸네”, 두 번에 걸친 어린이 인체적용시험에서 키 성장 기능성을 입증했습니다.

키 성장에 필요한 성장단백질, 황기추출물 섭취로 증가합니다.

키가 작은 학령기 어린이를 대상으로 한 무작위 이중맹검 인체적용시험에서 황기추출물을 섭취한 어린이들이

17.2% 추가 성장하였습니다.

학령기전 어린이를 대상으로 피험자수와 섭취기간을 늘려 실시한 다기관 무작위 이중맹검 인체적용시험에서도

동일하게 추가 성장함을 재입증 하였습니다.

만 7~12세 어린이가 12주간 섭취하였을 때, 성장단백질 IGFBP-3가 유의미하게 증가합니다. 성장단백질은 뼈 신

장의 핵심요소인 성장인자가 오랫동안 제대로 기능할 수 있도록 도와줍니다.

2.5

3500

1.5

3300

0.5

3100

2900

2

3400

1

3200

0

3000

2800

0-4 weeks

Placebo

IGFB

P-3(

ng/m

l)

4-8 weeks 8-12 weeks

HT042

HT042 group

섭취 후

Control group

섭취 전

만 7세 – 12세 어린이가 12 주간 섭취 하였을 때

17.2% 증가

만 7세 – 12세 어린이가 12 주간 섭취 하였을 때

성장단백질 IGFBP-3 증가* IGFBP-3 성장호르몬 분비지표

(출처: 인체적용시험 보고서, 2009)

(출처: 인체적용시험 보고서, 2009)

뼈 길이 성장속도를 빠르게 합니다.

테트라사이클린 성장속도 측정법을 통해 황기추출물이 발육기 흰쥐의 뼈 길이 성장속도를 증가시키는 것을

확인하였습니다.

황기추출물은 발육기 흰쥐의 성장판 연골세포 수와 크기를 증가시켜 성장판 증식부와 비대부를 두껍게 합니다.

2주간에 걸친 컴퓨터 단층촬영(microCT)에서도 황기추출물은 발육기 흰쥐의 정강뼈 길이를 대조군보다 더 증가시

켰습니다.

황기추출물 투여군 뼈길이 성장속도 증가

황기추출물 투여군 연골세포 증식 증가

컴퓨터 단층촬영(micro CT)으로 황기추출물 투여군 뼈 길이 증가 확인

rhGH

rhGH

HT042

HT042

300

200

100

0

250

150

50

ControlControl

Control

ControlHT042 HT042성장판

증식부 두께(출처: Journal of Medicinal Food, 2010)

(출처: Journal of Medicinal Food, 2010)

(출처: eCAM, 2017)

성장판 비대부 두께11.2% 증가 12.4% 증가

300

200

100

0

250

150

50

성장판을 자극하는 성장인자의 생성이 증가합니다.

성장 뿐 아니라 뼈를 튼튼하게 합니다.

황기추출물은 발육기 흰쥐의 간, 혈중, 성장판에서 성장인자 IGF-1을 증가시키고, 성장판에서 뼈 형성 단백질

BMP-2을 증가시킵니다.

컴퓨터 단층촬영(microCT)을 통해 황기추출물이 골밀도를 증가시키고 골미세구조를 개선시키는 것을 확인했습니다.

황기추출물 투여군 간에서 성장인자 IGF-1 발현 증가

황기추출물 투여군 혈중에서 성장인자 IGF-1 농도 증가

컴퓨터 단층촬영(micro CT)으로 황기추출물 투여군 골밀도, 골미세구조 개선 확인

황기추출물 투여군 성장판에서 성장인자 IGF-1과 뼈 형성단백질 BMP-2 발현 증가

1000

0

1500

500

Control

Control

Control

Control

RZ

PZ

HZ

RZ

PZ

HZ

HT042

HT042

HT042

HT042

IGF-1

BMP-2rhGH

rhGH

rhGH

rhGH

(출처: Journal of Medicinal Food, 2010, Phytotherapy Research, 2012. eCAM, 2017)

(출처: eCAM, 2017)

Seru

m IG

F-1

conc

entr

atio

n(n

g/m

l)

황기추출물은 성조숙증을 일으키지 않습니다.

여자 어린이는 성 성숙이 일어나면 에스트로겐이 분비되어 생리가 시작되고, 에스트로겐은 성장판을

닫히게 합니다.

황기추출물은 에스트로겐 유사작용과 에스트로겐 분비촉진작용이 없어 성조숙증을 일으키지 않습니다.

난소절제술(OVX)을 통해 황기추출물 및 구성원료들의 에스트로겐 유사작용이 없음을 확인

미성숙 쥐 자궁비대 실험을 통해 황기추출물의

에스트로겐 분비촉진 작용이 없음을 확인

150

30

200

40

0

0

250

50

60

70

50

10

100

20

Sham

Control

HT04217-estradiol

HT042

황기 한속단OVX control

17-estradiol

가시오갈피

Uter

ine

wei

ght (

mg)

Uter

ine

wei

ght (

mg)

*대조군: 17-estradiol (에스트로겐)(출처: Phytotherapy Research, 2012)

(출처: Phytotherapy Research, 2012)

(출처:한국경제, 2012)

정상 아동

성조숙증 아동

황기추출물은 안전합니다.

2회에 걸친 어린이 인체적용시험을 통해 안전성을 확인하였습니다.

공인기관에서 실시한 단 회 투여 독성시험과 13주 반복투여 독성시험에서 이상반응이나 독성이

나타나지 않았습니다.

황기는 동의보감 등에서 전통적으로 어린이에 사용해온 안전한 원료입니다.

황기추출물의 연구결과

뉴메드와 산학협력연구팀은 3건의 키성장 관련 특허를 보유하고 있고 SCI 및 KCI급 논문 8편을 발표했습니다.

“키성장에 특별한 개별 기능을 인정…”

특허등록 10-0997215

“랫드의 100μm 성장, 24시간만에 확인 …”

유럽소아과학회지 (Eur J Pediatr (2002) 161: 406-407)

“어린이 대상 인체적용시험에서 유의 효과 확인…”

인체적용시험보고서, 2008, 2017

RESEARCH LETTER

Kanghyun Leem Æ Sun-Young Park Æ Dong-Hwan LeeHocheol Kim

Lovastatin increases longitudinal bone growth and bone morphogeneticprotein-2 levels in the growth plate of Sprague-Dawley rats

Received: 9 July 2001 /Accepted: 25 February 2002 / Published online: 30 April 2002� Springer-Verlag 2002

Lovastatin increases longitudinal bone growth and bonemorphogenetic protein-2 levels in the growth plate ofSprague-Dawley rats and may have implications for thetreatment of children.

Lovastatin is a drug widely used to reduce cholesterollevels in blood. It is known to act via the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase. Recently, Mundy et al. [5] showed that lo-vastatin increases bone morphogenetic protein-2 (BMP-2) levels in human MG-63 osteoblasts, and suggestedthat it could be used to treat the loss of bone mass inrodents. There was, however, no study on longitudinalbone growth. Keller et al. [3] reported that the longitu-dinal growth rate of the lower leg was reduced in pre-mature infants. Accordingly, we set out to investigatewhether lovastatin increases longitudinal bone growth inthe growth plate of the adolescent male rat.

Male Sprague-Dawley rats of 3 weeks of age wereused in the experiment. The experimental procedureswere performed in accordance with the animal careguidelines of the NIH and the Korean Academy ofMedical Sciences. Animals were housed under con-trolled temperature (20±2�C) and lighting (07:00–19:00 h) conditions, with food and water made availablead libitum. Rats were divided into two groups (n=5 ineach group): the control group and the lovastatin-ad-ministrated group. Animals of the lovastatin-adminis-trated group were injected intraperitoneally with

5 mg/kg lovastatin for every 5 consecutive daysaccording to [5], while those of the control group weregiven equivalent injections of normal saline. The oralintakes and body weights of both groups were measuredbut did not show any statistical difference (data notshown). On the 3rd and 5th days after administration,all animals were injected intraperitoneally with10 mg/kg tetracycline for measurement of bone growth.On the 6th day, animals of each group were totallyanaesthetised with ether and sacrificed 1 h after anintraperitoneal injection of 5-bromo-2¢-deoxyuridine(BrdU, 30 mg/kg) to determine the incorporation intonewly synthesised DNA. The proximal tibia wereexcised, fixed for 24 h in 4% paraformaldehyde, anddecalcified by immersion in 10% EDTA for 24 h. Eachsample was sectioned longitudinally (section width40 lm). Bone growth was calculated by measuring thegap between successive bands formed by the injectedtetracycline using a fluorescence microscope [2]. Ex-pressed BMP-2 and incorporated BrdU were detected byavidin-biotin-peroxidase complex-linked immunohisto-chemistry [1,4]. The proliferating ratio of chondrocytesin growth plates for 1 h was measured by calculatinglabelling indices of BrdU positive chondrocytes [6].

The longitudinal bone growth rate for 48 h in normaladolescent rats was 489.0±70.1 lm and lovastatin wasshown to promote bone growth, increasing the rate to780.5±72.8 lm (Fig. 1A) (P<0.05). The labelling indexfor proliferating chondrocytes of the lovastatin-admin-istrated group was 32.5±5.7% compared to the controlgroup (19.0±7.8%, P<0.05). Both the number ofBMP-2-positive cells and the intensity of BMP-2 ex-pression in proliferating, maturing, and hypertrophicchondrocytes of growth plates were increased in the lo-vastatin-administrated group (Fig. 1C) compared withthe control group (Fig. 1B).

The increase in body length is mostly due to thegrowth of longitudinal bones and their growth is a re-flection of the proliferation and differentiation ofchondrocytes in the growth plates. Interestingly, lo-vastatin increased longitudinal bone growth significantly

Eur J Pediatr (2002) 161: 406–407DOI 10.1007/s00431-002-0955-3

K. LeemDepartment of Herbal Pharmacology,College of Pharmacy, Woosuk University,Chonbuk, South Korea

S-Y. Park Æ D-H. Lee Æ H. Kim (&)Department of Herbal Pharmacology,Graduate School of East-West Medical Science,Kyung Hee University, 1 Hoegi-Dong,Dongdaemoon-Ku, Seoul 130-701, South KoreaE-mail: heavenok@dreamwiz.comTel.: +82-2-9610419Fax: +82-2-9640325

The Herbal Formula HT042 Induces Longitudinal Bone Growthin Adolescent Female Rats

Mi-Yeon Kim,1,2 Youngmi Park,1 Naba Raj Pandit,1 Jiyoung Kim,1 Mikyung Song,1

Juyeon Park,2 Ho-Young Choi,1 and Hocheol Kim1,2

1Department of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University;and 2Korea Institute of Science and Technology for Eastern Medicine, NeuMed Inc., Seoul, Republic of Korea

ABSTRACT The effect of HT042, a blend of three herbal extracts, on longitudinal bone growth was investigated in short-

and long-term rat models. In the short-term model, we divided female Sprague-Dawley rats (3 weeks old) into six groups,

according to treatment: vehicle, HT042 (100mg=kg), Phlomis umbrosa (100mg=kg), Astragalus membranaceus (100mg=kg),and Eleutherococcus senticosus (100mg=kg) were administered twice daily, and recombinant human growth hormone (rhGH)

(1 IU) was subcutaneously injected once daily. Treatments were maintained for 4 days in each case. On day 3, tetracycline

(20mg=kg) was injected intraperitoneally (20mg=kg) to form the fluorescent band on the growth plates. On days 2–4, 5-

bromo-20-deoxyuridine (BrdU) (50mg=kg) was injected intraperitoneally to label proliferating cells. On day 5, the tibias were

dissected and fixed in 30% sucrose. Dehydrated bone was sectioned at a thickness of 40 mm and observed. The bone growth in

groups administered HT042 and rhGH was significantly increased to 433.50 ± 21.61 and 434.49 ± 15.21mm=day, respectively,from 410.03 ± 17.4 mm=day (control). The height of the growth plates in the HT042 and rhGH groups was also significantly

increased to 556.5 ± 21.1 and 544.2 ± 21.1 mm (P< .05), respectively, from 518.1 ± 4.1 mm (normal). The number of BrdU-

positive cells in chondrocytes of the HT042 and rhGH groups was increased to 389 ± 36 and 627 ± 39 cells=mm2 (P< .001),

respectively, from 264 ± 17 cells=mm2 (control). Insulin-like growth factor-1 and bone morphogenetic protein-2 in the HT042

group were highly expressed in the growth plate. In the long-term rat model, the body weight, nose–tail length, and nose–anus

length were measured by microknemometry for 4 weeks. The body weight of the rhGH group was significantly increased. The

nose–anus length of the HT042 and rhGH groups was significantly greater at 18.5 ± 0.3 and 18.7 ± 0.3 cm compared to

18.2 ± 0.2 cm (control).

KEY WORDS: � Astragalus membranaceus � 5-bromo-20-deoxyuridine � chondrocyte � Eleutherococcus senticosus� growth plate � HT042 � longitudinal bone growth � Phlomis umbrosa � recombinant human growth hormone

INTRODUCTION

Growth retardation in children can be caused bygenetic, nutritional, metabolic, and=or endocrine fac-

tors. Malnutrition, metabolic acidosis, and growth hormone(GH) deficiencies are conditions that can interfere with achild’s ability to reach normal stature.1 GH replacementtherapy is often used to treat children with short stature, butmany investigators have examined the possible efficacy oftraditional medicinal herbs. For thousands of years, tradi-tional medicinal herbs had been used to treat children withgrowth retardation, and the results have been recorded in thetraditional Korean medicinal book, Dongeuibogam. Variousherbal medicines for children had been recommended suchas, among others, Panax ginseng, Astragalus membrana-ceus, Atractylodes macrocephala, Glycyrrhiza glabra,

Angelica sinensis, Poria cocos, and Eleutherococcus senti-cosus. Furthermore, some herbs were reported to facilitatebone growth. A. membranaceus was reported to acceleratethe proliferation and promotion of bone marrow stromalcells2 and to induce GH in pituitary cell culture.3 E. senti-cosus was reported to promote the longitudinal bone growthin adolescent male rats4 and to increase bone mineral densityof the mouse tibia.5

Bone growth is a result of endochondral cell proliferationin growth plates and conversion of chondrocytes into newbone.6 To track these cells, cell labeling techniques using5-bromo-20-deoxyuridine (BrdU) were developed. BrdU is athymidine analog that incorporates into DNA of dividingcells during the S-phase of the cell cycle.7

For this bone growth study based on medicinal herbs weselected three herbs—the root of A. membranaceus, the stemof E. senticosus, and the root of Phlomis umbrosa—fromDongeuibogam and designated the formula HT042. Thebone growth effect of HT042 was investigated in adolescentfemale Sprague-Dawley rats. We measured the bone growthof tibia and BrdU-positive cells on chondrocytes in the

Manuscript received 18 January 2010. Revision accepted 20 July 2010.

Address correspondence to: Hocheol Kim, Department of Herbal Pharmacology, Collegeof Oriental Medicine, Kyung Hee University, 1 Hoegidong, Dongdaemoongu, Seoul 130-701, Republic of Korea, E-mail: hckim@khu.ac.kr

JOURNAL OF MEDICINAL FOODJ Med Food 13 (6) 2010, 1376–1384# Mary Ann Liebert, Inc. and Korean Society of Food Science and NutritionDOI: 10.1089=jmf.2010.1007

1376

Skeletal Growth and IGF Levels in Rats afterHT042 Treatment

Mi-Yeon Kim,1,2 Ji Young Kim,1 Dongwook Lim,1 Donghun Lee,2 Yoonjung Kim,2Gyu Tae Chang,3 Ho-Young Choi1 and Hocheol Kim1,2*1Department of Herbal Pharmacology, College of Oriental Medicine, Kyung HeeUniversity, Hoegi-dong, Dongdaemun-gu, Seoul 130-701,Republic of Korea2Korea Institute of Science and Technology for Eastern Medicine (KISTEM), NeuMed Inc., Seoul 130-701, Republic of Korea3Department of Pediatrics, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea

HT042, a new herbal prescription consisting of Astragalus membranaceus, Phlomis umbrosa and Eleutherococcussenticosus, is used in traditional Koreanmedicine to stimulate growth in children. This study was conducted to inves-tigate the effects of HT042 on skeletal growth, insulin-like growth factor-1 (IGF-1) and insulin-like growth factorbinding protein-3 (IGFBP-3) levels, and oestrogenic activity in female rats. Female Sprague–Dawley rats weredivided into control, recombinant human growth hormone (rhGH; 20mg/kg/day), and HT042 (100mg/kg/day)groups and treated for 3weeks. Axial skeletal growth, femur length, and growth plate length were measured every3weeks. The serum IGF-1 and IGFBP-3 levels were analysed. Moreover, the oestrogenic activity of the herbalextracts in the immature and ovariectomized rats was tested. The nose–anus, nose–tail, femur and growth-platelengths were increased significantly in the HT042 group. Both IGF-1 and IGFBP-3 were highly expressed in thehypertrophic zone of the growth plate. The serum IGF-1 levels were increased. Moreover, HT042 had no utero-trophic effects in the rats. Consequently, HT042 promoted longitudinal bone growth by stimulating cell proliferationin the epiphyseal plate and inducing the expression of IGF-1without an oestrogenic response. HT042may be helpfulin stimulating growth in children with short stature. Copyright © 2012 John Wiley & Sons, Ltd.

Keywords: HT042; herbal extract; skeletal growth; IGF-1; uterotrophic assay.

INTRODUCTION

It is widely recognized that the growth of children is acommon marker of their health (Kurokawa et al.,2008) and that growth is regulated by the interactionof genetic and acquired factors with environmentalinfluences (Weedon et al., 2007), especially socioeco-nomic conditions and nutritional status (Steckel, 2008).Growth retardation in children has a multifactorial ori-gin. Factors that contribute to growth retardation includeprotein–calorie malnutrition, metabolic acidosis and pe-ripheral resistance to growth hormone (GH) in the targetorgans, as well as anaemia, renal osteodystrophy anduremia itself altering the growth hormone/insulin-likegrowth factor-1 (GH/IGF-1) axis (Dunkel, 2009).The current methods for increasing final height include

GH treatment alone or together with the gonadotropin-releasing hormone (GnRH) analogue treatment(Leschek et al., 2004). However, excessive GH treatmentmay hasten growth velocity and rapid progressionthrough puberty, and the combination of GH and GnRHagonists often decreases bone mineral density (BMD;Yanovski et al., 2003). In addition,GH administration pre-vents protein degradation in many diseases. Long-termtreatment with GH increases lean body weight, muscleand lipid weights. Short-term treatment with GHincreases plasma insulin and IGF-1 concentrations and

decreases protein concentrations in urine. Moreover, theadministration of GH is limited by its poor absorptionfrom the gastrointestinal tract. Regarding the economicsof the GH treatment, biosynthetic GH is expensive andin addition the short- and long-term benefits for the indi-vidual are uncertain (Bryant et al., 2007).

During bone growth, several indices and hormone (e.g.IGF-1, insulin-like growth factor binding protein-3(IGFBP-3)) levels change. IGF-1 plays essential roles ingrowth as a growth-promoting polypeptide. In serum,mostIGF-1 (70–80%) forms a 150-kD complex by bindingwith IGFBP-3. IGFBP-3 acts as a regulator of growth-dependent IGF-1 signalling through the enhancement ofIGF-1 stability in serum or repression of IGF-1 binding tothe IGF-1 receptor (Binoux and Hossenlopp, 1988; Baret al., 1990). In the liver, circulating IGF-1 and IGFBP-3are synthesized by hepatocytes in a GH-dependent manner(Richman et al., 2001; Roith et al., 2001). In addition,IGF-1 is expressed in all non-hepatic tissues, where it actsin a paracrine/autocrine fashion (Yakar et al., 2002).

In addition, oestrogens also play a pivotal role inthe regulation of normal skeletal growth and maturationin both boys and girls (Cutler, 1997). In both genders,oestrogen deficiency leads to the absence of a pubertalgrowth spurt. When oestrogenic materials enter thebody via the intake of phytoestrogen and endocrine dis-ruptors, sexual maturation is promoted (Kato et al.,2003). Based on these clinical observations, aromataseinhibition has been proposed as a potential approachfor growth enhancement in children with short stature(Cernich et al., 2004; Dunkel, 2006).

Many ongoing studies are attempting to elucidate al-ternative therapeutic medicines (Ra et al., 2004). Korean

* Correspondence to: Hocheol Kim, Department of Herbal Pharmacology,College of Oriental Medicine, Kyung Hee University, 1 Hoegidong,Dongdaemoongu, Seoul 130-701, Republic of Korea.E-mail: hckim@khu.ac.kr

PHYTOTHERAPY RESEARCHPhytother. Res. 26: 1771–1778 (2012)Published online 3 March 2012 in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/ptr.4642

Copyright © 2012 John Wiley & Sons, Ltd.

Received 30 September 2011Revised 17 January 2012

Accepted 26 January 2012

Molecules 2013, 18, 13271-13282; doi:10.3390/molecules181113271

molecules ISSN 1420-3049

www.mdpi.com/journal/molecules Communication

Effect of HT042, Herbal Formula, on Longitudinal Bone Growth in Spontaneous Dwarf Rats

Ji Young Kim 1, MiKyung Song 1, Donghun Lee 1, Jungbin Song 1, Sang Woug Park 2, Juyeon Park 2, Seungjoon Park 3, Ho-Young Choi 1 and Hocheol Kim 1,*

1 Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Korea

2 Korea Institute of Science and Technology for Eastern Medicine (KISTEM), NeuMed Inc., Seoul 130-701, Korea

3 Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea

* Author to whom correspondence should be addressed; E-Mail: hckim@khu.ac.kr; Tel.: +82-2-961-0419; Fax: +82-2-964-0325.

Received: 23 September 2013; in revised form: 15 October 2013 / Accepted: 16 October 2013 / Published: 28 October 2013

Abstract: HT042 is a new herbal prescription consisting of Astragalus membranaceus, Phlomis umbrosa and Eleutherococcus senticosus, which are used in Korean medicine to stimulate growth in children. We investigated the effects of HT042 on the body weight, longitudinal bone growth, and bone length in spontaneous dwarf rats (SDR). Male and female SDRs were divided into three groups: the control group (DW, 10 mL/kg/day), the recombinant human GH group (rhGH; 500 µg/kg/day), and the HT042 (100 mg/kg/day) group. Each group received the respective treatments for 10 days. Body weight was measured on day 10 of treatment. On day 8, tetracycline (20 mg/kg) was injected intraperitoneally into all individuals to form a fluorescent band on the newly synthesized bone. On day 10, femur and tibia lengths were measured using PIXImus. Body weight, longitudinal bone growth, and bone length were not affected in the HT042 group. In contrast, the rhGH group showed significantly increased body weight, longitudinal bone growth, and bone length. In conclusion, HT042 does not act through a GH-like effect to promote longitudinal bone growth.

Keywords: HT042; herbal extract; longitudinal bone growth; spontaneous dwarf rat

OPEN ACCESS molecules

Article

Effects of Phlomis umbrosa Root on LongitudinalBone Growth Rate in Adolescent Female RatsDonghun Lee, Young-Sik Kim, Jungbin Song, Hyun Soo Kim, Hyun Jung Lee, Hailing Guo andHocheol Kim *

Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Korea;allstart2925@naver.com (D.L.); yjbsik@naver.com (Y.-S.K.); jbsong0527@gmail.com (J.S.);lovelyradix@hanmail.net (H.S.K.); lhjung91@hanmail.net (H.J.L.); guohailing1026@gmail.com (H.G.)* Correspondence: hckim@khu.ac.kr; Tel.: +82-2-961-0419; Fax: +82-2-964-0325

Academic Editor: Derek J. McPheeReceived: 2 March 2016; Accepted: 31 March 2016; Published: 7 April 2016

Abstract: This study aimed to investigate the effects of Phlomis umbrosa root on bone growth andgrowth mediators in rats. Female adolescent rats were administered P. umbrosa extract, recombinanthuman growth hormone or vehicle for 10 days. Tetracycline was injected intraperitoneally to producea glowing fluorescence band on the newly formed bone on day 8, and 5-bromo-21-deoxyuridinewas injected to label proliferating chondrocytes on days 8–10. To assess possible endocrine orautocrine/paracrine mechanisms, we evaluated insulin-like growth factor-1 (IGF-1), insulin-likegrowth factor binding protein-3 (IGFBP-3) or bone morphogenetic protein-2 (BMP-2) in responseto P. umbrosa administration in either growth plate or serum. Oral administration of P. umbrosasignificantly increased longitudinal bone growth rate, height of hypertrophic zone and chondrocyteproliferation of the proximal tibial growth plate. P. umbrosa also increased serum IGFBP-3 levels andupregulated the expressions of IGF-1 and BMP-2 in growth plate. In conclusion, P. umbrosa increaseslongitudinal bone growth rate by stimulating proliferation and hypertrophy of chondrocyte with theincrement of circulating IGFBP-3. Regarding the immunohistochemical study, the effect of P. umbrosamay also be attributable to upregulation of local IGF-1 and BMP-2 expressions in the growth plate,which can be considered as a GH dependent autocrine/paracrine pathway.

Keywords: Phlomis umbrosa; bone growth rate; IGF-1; growth plate

1. Introduction

Short stature is defined as the height of an individual more than two standard deviation score(SDS) below the average height for an age, sex, and population group [1]. Short children might havea high frequency of psychosocial problems such as lower self-esteem, social immaturity, or beingbullied [2–5]. People with shorter height are reported to have a lower health-related quality of lifeeven if they do not fit into the definition of short stature [6]. People with shorter height also havehigher morbidity of coronary heart diseases, perhaps because of the smaller diameter of their bloodvessels [7,8].

Short stature caused by certain diseases, including growth hormone (GH) deficiency, accountsfor 20% of all short children, but the remaining 80% are not determined, so-called idiopathic shortstature (ISS) [1]. In case of GH deficiency, average increase in final height attributable to GH therapy isabout 30 cm compared with predicted adult height [9,10]. In the case of ISS, the US FDA approved GHtherapy in ISS children shorter than ´2.25 SDS in 2003 based on the evidence derived from two clinicalstudies [11,12], nevertheless, the average increase in final height attributable to GH therapy in childrenwith ISS is just 3.5–7.5 cm (4–7 years) [11,13–16]. In this case of ISS, the effect remains controversialbecause the estimated cost of GH therapy for adult height gain is about 10,000–20,000 dollars/cm [1,15].

Molecules 2016, 21, 461; doi:10.3390/molecules21040461 www.mdpi.com/journal/molecules

大韓本草學會誌 제32권 제1호(2017년 1월)Kor. J. Herbol. 2017；32(1)：63-68

ISSN 1229-1765(Print), ISSN 2288-7199(Online)http://dx.doi.org/10.6116/kjh.2017.32.1.63.

Sprague-Dawley계 흰쥐를 이용한 HT042의 14일 반복 경구투여 독성연구

송정빈1#, 이동헌1#, 김영식1, 이승경1, 배진숙2, 김호철1*

1 : 경희대학교 한의과대학 본초학교실, 2 : ㈜켐온 비임상연구센터

A 14-day Repeated Dose Oral Toxicity Study of HT042 in Sprague-Dawley Rats

Jungbin Song1#, Donghun Lee1#, Young-Sik Kim1, Seunggyeong Lee1,

Jin-Sook Bae2, Hocheol Kim1*

1 : Dept. of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University

2 : Nonclinical Research Institute, Chemon Inc.

ABSTRACT

Objectives : HT042 is a combination of three herbal extracts from the roots of Astragalus membranaceus, the stems

of Eleutherococcus senticosus and the roots of Phlomis umbrosa, which has been demonstrated to increase longitudinal

bone growth rate. The aim of this study was to assess the safety of HT042 after repeated oral administration.

Methods : A 14-day repeated oral dose toxicity study was conducted using male and female Sprague–Dawley rats.

HT042 was administered orally at repeated doses of 500, 1,000 and 2,000 ㎎/㎏/day for 14 days. Clinical signs and

mortality were observed daily, whereas body weight and food consumption were recorded weekly throughout the

experiment. At the end of the study, blood was taken from the posterior vena cava for hematology and serum

biochemistry. All organs of the body surface, subcutis, head, thoracic cavity, and abdominal cavity were observed

grossly. Then, the internal organs were removed and weighed.

Results : No death occurred and no significant changes in clinical sign, body weight, food consumption and serum

biochemistry parameters were observed in male and female rats over the study period. Although there were some

alterations in hematologic and necropsy findings, and organ weights, these changes were not considered toxicologically

significant.

Conclusions : These results suggest that the 14-day repeated administration of HT042 does not produce any significant

oral toxicity at doses of up to 2,000 ㎎/㎏/day in male and female rats under the present experimental conditions.1)

Key words : HT042, Astragalus membranaceus, Eleutherococcus senticosus, Phlomis umbrosa, toxicity

Ⅰ. 서 론

HT042는 황기, 자오가 및 한속단 추출물 복합물로 골길이

성장을 촉진하는 물질이다1-3). 황기(黃芪)는 콩과(Fabaceae)에

속한 다년생 초본 황기 Astragalus membranaceus의 뿌리로

益衛固表, 利水消腫, 托毒, 生肌의 효능으로 사용되며, 자오가

(刺五加)는 두릅나무과(Araliaceae)에 속한 낙엽관목 가시오

갈피 Eleutherococcus senticosus의 뿌리 및 줄기로 補腎强腰,

*Corresponding author : Hocheol Kim, Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedaero, Dongdaemun-gu, Seoul 02447, Republic of Korea. ·Tel：+82-2-961-0419 ·E-mail : hckim@khu.ac.kr#First author : Jungbin Song, Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedaero, Dongdaemun-gu, Seoul 02447, Republic of Korea. ·Tel：+82-2-961-0419 ·E-mail : jbsong@khu.ac.kr#First author : Donghun Lee, Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedaero, Dongdaemun-gu, Seoul 02447, Republic of Korea. ·Tel：+82-2-961-0419 ·E-mail : allstart2925@naver.com ·Received：14 November 2016 ·Revised：6 January 2017 ·Accepted：15 January 2017

Phytomedicine 32 (2017) 59–67

Contents lists available at ScienceDirect

Phytomedicine

journal homepage: www.elsevier.com/locate/phymed

Original Article

Safety evaluation of Astragalus extract mixture HT042 and its

constituent herbs in Sprague–Dawley rats

Jungbin Song a , Donghun Lee a , Byoungjae Min b , Jin-Sook Bae c , Gyu Tae Chang d , Hocheol Kim a , ∗

a Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, South Korea b Korea Institute of Science and Technology for Eastern Medicine (KISTEM), NeuMed Inc., 88 Imun-ro, Dongdaemun-gu, Seoul 02440, South Korea c Nonclinical Research Institute, Chemon Inc., 240 Nampyeong-ro, Yangji-myeon, Cheoin-gu, Yongin-si, Gyeonggi-do 17162, South Korea d Department of Pediatrics of Korean Medicine, Kyung Hee University Hospital at Gangdong, 892 Dongnam-ro, Gangdong-gu, Seoul 05278, South Korea

a r t i c l e i n f o

Article history: Received 23 October 2016 Revised 20 March 2017 Accepted 27 March 2017

Keywords: Astragalus extract mixture HT042 Astragalus membranaceus Eleutherococcus senticosus Phlomis umbrosa Toxicity

a b s t r a c t

Background: Astragalus extract mixture HT042 is a combination of three standardized extracts from As- tragalus membranaceus root, Eleutherococcus senticosus stem, and Phlomis umbrosa root, which has proven to stimulate children’s height growth. Purpose: The aim of this study was to demonstrate the safety of HT042 and its three constituent herbs when administered orally. Methods: Acute and sub-chronic oral toxicity studies were conducted using male and female Sprague–Dawley rats. In the acute toxicity study, HT042 and each of the herbs was administered at single doses of up to 50 0 0 mg/kg. In the 13-week sub-chronic toxicity study, HT042 was administered at repeated doses of up to 40 0 0 mg/kg/day. Results: In the acute toxicity study of HT042 and each of the herbs, no deaths occurred and there was no indication of toxicity, on the basis of clinical signs, body weight, and necropsy findings. In the sub- chronic toxicity study of HT042, there were no deaths and no changes in clinical signs or the findings of ophthalmic examinations. Although there were some treatment-related changes in other findings, these alterations were not considered toxicologically significant because they remained within normal ranges or recovered during the recovery period. Conclusion: The oral approximate lethal doses of HT042 and each of the herbs were > 50 0 0 mg/kg, and the no-observed-adverse-effect level of HT042 was 40 0 0 mg/kg/day in male and female rats.

© 2017 Elsevier GmbH. All rights reserved.

Introduction

Astragalus extract mixture HT042 is a combination of three standardized herbal extracts from Astragalus membranaceus root, Eleutherococcus senticosus stem, and Phlomis umbrosa root. It has been developed to promote height growth in children with short stature.

HT042 was found to stimulate height growth in a 3-month, placebo-controlled trial, and this was further confirmed in a 6- month trial involving 140 children with mild short stature (data not published). In preclinical studies, HT042 has been shown to increase longitudinal bone growth rate through chondrocyte prolif- eration and hypertrophy in growth plates ( Kim et al., 2010, 2012 ).

Abbreviations: RBC, red blood cell; ALT, alanine aminotransferase; ICH, Interna- tional Council for Harmonisation.

∗ Corresponding author. E-mail address: hckim@khu.ac.kr (H. Kim).

The mechanism underlying HT042’s activity involves the stimula- tion of growth hormone secretion ( Kim et al., 2013 ), which is pre- sumed to lead to the systemic production of insulin-like growth factor-1 and local production of bone morphogenetic protein-2 and insulin-like growth factor-1 in growth plates ( Kim et al., 2010, 2012 ).

HT042 is considered safe because each of its constituent herbs has been widely consumed for a long time and has not shown significant adverse effects (Editorial Board of Zhong Hua Ben Cao, 1999) . Nonetheless, even if the herbs are non-toxic when con- sumed individually, their combination could result in toxic effects owing to herb–herb interactions ( Che et al., 2013 ). In addition, al- though a daily intake of 1500 mg has been proven safe and well- tolerated in both 3- and 6-month clinical trials, children may in- gest excessive amounts over long periods. Furthermore, unlike the other two herbs, the systemic toxicity profile of P. umbrosa in an- imals is not well-established yet. To ensure the safety as an agent

http://dx.doi.org/10.1016/j.phymed.2017.03.005 0944-7113/© 2017 Elsevier GmbH. All rights reserved.

Research ArticleAstragalus Extract Mixture HT042 Improves BoneGrowth, Mass, and Microarchitecture in Prepubertal FemaleRats: A Microcomputed Tomographic Study

Jungbin Song,1 Sung Hyun Lee,2 Donghun Lee,1 and Hocheol Kim1

1Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu,Seoul 02447, Republic of Korea2Korea Institute of Science and Technology for Eastern Medicine (KISTEM), NeuMed Inc., 88 Imun-ro, Dongdaemun-gu,Seoul 02440, Republic of Korea

Correspondence should be addressed to Hocheol Kim; hckim@khu.ac.kr

Received 13 March 2017; Accepted 13 April 2017; Published 10 May 2017

Academic Editor: Ki-Wan Oh

Copyright © 2017 Jungbin Song et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Astragalus extract mixture HT042 is a standardized multiherbal mixture comprising Astragalus membranaceus, Eleutherococcussenticosus, and Phlomis umbrosa, which has proven to promote children’s height growth. The aim of this study was to investigatethe effects of HT042 on longitudinal bone growth, bone mass, and bone microstructure in growing rats using a high-resolutionmicrocomputed tomography system. Four-week-old female rats were fed an HT042-containing diet for 2 weeks. Tibial length wasmeasured at baseline and weekly in vivo. At the end of the study, volumetric bone mineral density (vBMD) and microarchitecturalparameters were estimated in the trabecular and cortical bone of the tibia. Tibial length gain was significantly increased by HT042compared to that reported with the control diet. In the proximal tibial metaphysis, HT042-treated rats had significantly highertrabecular vBMD, bone volume fraction, and trabecular number and lower trabecular separation, trabecular pattern factor, andstructuremodel index values than control rats did. Total cross-sectional area and bone area of the cortical bone in the tibial diaphysisalso increased. These findings suggest that HT042 increases longitudinal bone growth rate, improves trabecular bone mass, andenhances the microarchitecture of trabecular and cortical bone during growth.

1. Introduction

One of the main functions of bone is to provide structuralsupport for the body. During childhood, bones grow in size,accruemass, and change their architecture to develop a strongstructure for load bearing [1]. The percentile location of anindividual’s bone traits, such as bone mineral density andtrabecular and cortical morphology, all of which determinebone strength, is likely established during childhood [2–5].Therefore, the optimization of bone strength during child-hood is important for lifelong bone health.

Several studies have demonstrated that short-staturedchildren have impaired bone health. Low bone mineralcontent (BMC) and bone mineral density (BMD) at severalskeletal sites are reported in short children [6–9]. Shortchildren exhibit increased bone resorption [6] and have

impaired bone structure and bone strength [10]. Growth hor-mone (GH) treatment has been reported to increase height,normalize BMD, and improve bone structure and strength inshort children [6, 9, 10]. In addition to well-established effectson growth plate cartilage, GH exerts anabolic effects on boneand stimulates new bone formation, which results in greaterbone mass and improved skeletal structure [11, 12].

Astragalus extract mixture HT042 is a standardizedmultiherbal mixture consisting of Astragalus membranaceus,Eleutherococcus senticosus, and Phlomis umbrosa. HT042was found to increase height growth rate in children withmild short stature in a 12-week placebo-controlled trial,which was confirmed by another 24-week trial (data notpublished). HT042 has been shown to induce longitudinalbone growth by stimulation of chondrocyte proliferationand hypertrophy in growth plates [13, 14]. The mechanism

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2017, Article ID 5219418, 7 pageshttps://doi.org/10.1155/2017/5219418

Research ArticleAstragalus Extract Mixture HT042 Increases Longitudinal BoneGrowth Rate by Upregulating Circulatory IGF-1 in Rats

Donghun Lee,1 Sung Hyun Lee,2 Yoon Hee Lee,2 Jungbin Song,1 and Hocheol Kim1

1Department of Herbal Pharmacology, Kyung Hee University College of Korean Medicine, Seoul 02447, Republic of Korea2Korea Institute of Science and Technology for Eastern Medicine (KISTEM), NeuMed Inc., Seoul 02440, Republic of Korea

Correspondence should be addressed to Hocheol Kim; hckim@khu.ac.kr

Received 22 February 2017; Revised 1 May 2017; Accepted 22 May 2017; Published 20 June 2017

Academic Editor: I-Min Liu

Copyright © 2017 Donghun Lee et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Astragalus extract mixture HT042 is a standardized ingredient of health functional food approved by Korean FDA with a claimof “height growth of children.” HT042 stimulates bone growth rate and increases local IGF-1 expression in growth plate of ratswhich can be considered as direct stimulation of GH and its paracrine/autocrine actions. However, it remains unclear whetherHT042 stimulates circulatory IGF-1 which also plays a major role to stimulate bone growth. To determine the effects on circulatoryIGF-1, IGF-1 and IGFBP-3 expressions and phosphorylation of JAK2/STAT5 were evaluated in the liver after 10 days of HT042administration. HT042 upregulated liver IGF-1 and IGFBP-3 mRNA expression, IGF-1 protein expression, and phosphorylationof JAK2/STAT5. HT042 also increased bone growth rate and proliferative zonal height in growth plate. In conclusion, HT042stimulates bone growth rate via increment of proliferative rate by upregulation of liver IGF-1 and IGFBP-3 mRNA followed by IGF-1 protein expression through phosphorylation of JAK2/STAT5, which can be regarded as normal functioning of GH-dependentendocrine pathway.

1. Introduction

Longitudinal bone growth is the result of chondrocyte pro-liferation and ensuing hypertrophy in growth plates, calledendochondral ossification which is mainly controlled bya system of growth hormone- (GH-) insulin-like growthfactor-1 (IGF-1) axis [1]. Mammalian growth plate consists ofthree principal zones: resting, proliferative, and hypertrophiczones. In resting zone, GH begins its actions by directstimulation of resting stem-like chondrocytes to start pro-liferation. The following cell replication in proliferative zoneand terminal differentiation and enlargement in hypertrophiczone are both primarily caused by circulatory IGF-1 [2, 3] andlocally expressed IGF-1 [4].

Circulatory IGF-1 is biosynthesized in the liver as anendocrine hormone in the ternary form bound to IGFbinding protein-3 (IGFBP-3) and acid labile subunit (ALS),while IGF-1 is also expressed by nonliver tissues includinggrowth plate, where it works in a paracrine/autocrine fashion

[5]. For better understanding of the endocrine versus theparacrine/autocrine roles of IGF-1 in bone growth, previ-ous studies have been used to examine the relative con-tribution to longitudinal bone growth. It has been widelyreported that longitudinal growth is mainly mediated byparacrine/autocrine actions of IGF-1 based on the Yakar et al.study that liver IGF-1 deficient mice developed normally inspite a 75% reduction in serum IGF-1 levels due to compen-satory serumGHand nonhepatic IGF-1 [6, 7]. But, years later,the same team revealed that circulatory IGF-1 is importantfor maintaining normal growth by the study that liver IGF-1and ALS double knockout mice were much smaller becausethere was a decrease in not only IGF-1 production but alsocirculatory IGF-1 stability that originated from compensatorynonliver sources because of the absence of protective ALSprotein [3].This suggests that circulatory IGF-1 plays a majorrole in longitudinal bone growth rate.

Almost 80% of circulatory IGF-1 is produced by liver inhumans and rodents. It is well established that circulatory

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2017, Article ID 6935802, 8 pageshttps://doi.org/10.1155/2017/6935802

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