[보고서]골모세포 분화 유도 및 파골세포 분화 억제를 동시에 유발하는 펩타이드를 이용한 골질환 치료 효과

민병무

골모세포 분화 유도 및 파골세포 분화 억제를 동시에 유발하는 펩타이드를 이용한 골질환 치료 효과
Modulation of osteoblast and osteoclast differentiation using functional peptides for regeneration of bone disorders 원문보기

보고서 정보
주관연구기관	서울대학교 Seoul National University
연구책임자	민병무
참여연구자	강현기 , 김정우 , 박신아 , 박초연 , 장다현 , 정성윤 , 조승빈
보고서유형	최종보고서
발행국가	대한민국
언어	한국어
발행년월	2018-12
과제시작연도	2017
주관부처	보건복지부 [Ministry of Health & Welfare(MW)(MW)
등록번호	TRKO202200008639
과제고유번호	1465024069
사업명	질환극복기술개발
DB 구축일자	2022-09-24
키워드	기능성 펩타이드.골모세포 및 파골세포의 분화.전임상 동물모델.골질환.생체적용.Functional peptides.Osteoblast and osteoclast differentiation.Preclinical animal models.Bone disorders.Clinical application.

초록 ▼

연구의 목적 및 내용
골기질단백질 유래 기능성 펩타이드의 골모세포 및 파골세포의 분화와 관련된 기초연구를 통하여 최적의 골질환 치료용 펩타이드를 발굴하고, 이를 이용한 골재생기전의 전임상적용을 위한 각종 골조직 결손 질환모델에서 골재생능을 검증하고자 함. 또한 궁극적으로 기능성 펩타이드를 악안면부위를 포함한 골질환 환자의 치료에 효율적으로 활용할 수 있는 기반을 마련하고자 함.

연구개발성과
1. 골모세포 분화 촉진 및 파골세포 분화 억제를 동시에 유발하는 후보물질인 기능성 펩타이드 발굴과 최적화 및 그의 분자기전 규명
● 골모세포 분화 유도 및 파골세포 분화 억제를 동시에 유발하는 기능성 펩타이드 발굴과 최저 기능단위 규명을 통한 최적화 및 후보물질 기능 규명을 위해 사람 성체줄기세포의 확보와 골모세포로의 분화 조건 확립과 파골세포 분화 유도조건을 확립하였음.
● 기능성 펩타이드에 따른 골모세포 및 파골세포 분화능 비교 및 특성을 분석하였음.
● 펩타이드에 의한 골모세포 및 파골세포의 분화관련 신호전달경로를 규명함.
2. 골형성능 최적화를 위한 지지체(scaffold) 선별 및 전임상 동물모델 이식 수술법 확립
● 기능성 펩타이드 기반 융합 나노지지체를 선별하고, 전임상 동물모델 이식수술법을 확립하였음.
● 기능성 펩타이드의 in vivo 골형성능을 규명하고, 분자기전을 규명하였음.
3. 질환모델에서의 이식술 개발, 펩타이드 치료효과 평가 및 유효성 분석
● 전신적 골조직 질환 동물모델 (난소절제술 모델 및 collagen-induced arthritis model 모델)에서 골다공증의 골소실 회복효과 및 류마티스성 관절염의 예방 및 치료효과를 규명하여 생체적용 연구를 시행하였음.
● 국소적 골조직 질환 동물모델 (Burr-hole 골절모델 및 임플란트 모델)에서 골재생과 골유착 효과를 규명하여 생체적용 연구를 시행하였음.

연구개발성과의 활용계획(기대효과)
● 골모세포 분화를 촉진시켜 골형성을 촉진시키고, 동시에 파골세포 분화를 억제시켜 골흡수를 억제시킴으로서 골다공증 치료제 개발 및 다른 골질환 치료를 위한 골재생 원천기술 확보.
● 여러 골질환 치료제 개발의 기초를 마련하여 대국민 보건을 크게 증진시킬 뿐만 아니라 자신감 회복, 사회관계의 활성화, 일할 수 있는 능력회복 등 삶의 질 향상에 이바지할 것임.
● 본 연구개발과정에서 획득한 기술과 산물을 바탕으로 국내.외 특허 획득 및 학문 후속세대 양성
● 기술이전을 통하여 골다공증 치료제 개발 및 이를 산업화로 연결시킴으로써 해외수출에 따른 막대한 경제적 성과 및 많은 양질의 일자리 창출 효과가 기대됨.

(출처 : 요약문 12p)

Abstract ▼

Purpose&Contents
The purpose of this research is to develop the optimal therapeutic bioactive peptide originated from bone matrix protein through basic researches related to the differentiation of osteoblasts and osteoclasts. Additionally, it is to identify their bone regeneration potentials in different bone tissue defective models for the preclinical trial applications of bone regeneration mechanisms. Moreover, the establishment of clinical methodologies for the effective applications to the patients with bone diseases including oral and maxillofacial regions using functional peptides is our final goal.

Results
1. Identification and optimization of a functional bioactive peptide, a candidate substance that simultaneously induces osteoblast differentiation and osteoclast differentiation inhibition, and identification of its molecular mechanism
● The bioactive functional peptide which simultaneously induces osteoblast differentiation and osteoclast differentiation inhibition is excavated, and the minimal core functional peptide is identified and optimized. To characterize the functional active peptide, human adult stem cells were established, and conditions for differentiation into osteoblasts and conditions for inducing osteoclast differentiation were established.
● The effects of functional peptide on the differentiation of osteoblasts and osteoclasts were studied and characterized.
● Identification of signaling pathways associated with osteoblasts and osteoclast differentiation by functional bioactive peptide.
2. Selection of scaffold for optimization of bone formation and establishment of transplantation procedures in preclinical animal models
● Functional peptide-based fusion nano-scaffolds were screened, and transplantation procedures in preclinical animal models were established.
● The effect of bioactive functional peptide on bone formation was elucidated, and its molecular mechanism was further elucidated in vivo.
3. Development of transplantation in disease models, evaluation of efficacy of peptide treatment, and validation analysis
● We investigated the effect of bioactive functional peptide on osteoporosis treatment and the prevention and treatment of rheumatoid arthritis in animal models of systemic bone diseases (ovariectomy model and collagen-induced arthritis model model).
● We investigated the effect of bioactive functional peptide on bone regeneration and osseointegration in animal models of local bone diseases (burr-hole fracture model and implant model).

Expected Contribution
● Mass productions of highly functional peptides that both stimulate osteoblast differentiation and suppress osteoclast differentiation, simultaneously, and securement of technological root sources through identifications of signal pathways and development of functional peptides.
● Establishment of the basis for the development of therapeutics related to bone diseases, and further improvement on the qualities of human life through the recovery of health conditions, confidence, social interactions, and working abilities.
● Acquisitions of domestic and international patents and training of future researchers through techniques and products obtained during the developmental process of this research.
● Contributions for the development of peptide therapeutics and fostering proteomics industries through technology transfers.

(source : SUMMARY 13p)

목차 Contents

표지 ... 1
보고서요약 ... 2
제 출 문 ... 10
보고서 요약서 ... 11
국문 요약문 ... 12
SUMMARY ... 13
Table of Contents ... 14
목차 ... 15
1. 연구개발과제의 개요 ... 16
1-1. 연구개발 목적 ... 16
1-2. 연구개발의 필요성 ... 16
1-3. 연구개발 범위 ... 19
2. 국내외 기술개발 현황 ... 23
2-1. 국내외 관련분야의 환경 변화 ... 23
3. 연구수행 내용 및 결과 ... 27
4. 목표달성도 및 관련분야 기여도 ... 63
4-1. 목표달성도 ... 63
4-2. 관련분야 기여도 ... 64
5. 연구결과의 활용계획 ... 65
6. 연구과정에서 수집한 해외과학기술정보 ... 65
7. 연구개발성과의 보안등급 ... 66
8. 국가과학기술종합정보시스템에 등록한 연구시설·장비 현황 ... 66
9. 연구개발과제 수행에 따른 연구실 등의 안전조치 이행실적 ... 66
10. 연구개발과제의 대표적 연구실적 ... 67
11. 기타사항 ... 67
12. 참고문헌 ... 68
끝페이지 ... 71

표/그림 (30)

표 연간 골다공증 내원 환자 수 및 총 진료비 (2009~2013) (출처: 대한민국 통계청)
표 골다공증 외래 다빈도 상병 급여 현황 (2009~2013) (출처: 대한민국 통계청)
표 치료용 펩타이드의 장점 및 펩타이드 의약품 세계시장 규모
표 연구수행 기관, 개발 내용 및 연구개발성과의 활용현황
표 펩타이드 작용에 대한 모식도
표 사람 비트로넥틴에서 개발한 기능성 펩타이드 RVYFFKGKQYWE (VnP-16)의 최소 기능단위 규명. VnP-16 펩타이드의 N-말단 및 C-말단으로부터 순차적으로 하나씩의 아미노산잔기가 제거된 synthetic 펩타이드의 아미노산잔기 서열 (좌측). VnP-16 펩타이드의 N-말단 및 C-말단으로부터 순차적으로 하나씩의 아미노산잔기가 제거된 합성 펩타이드가 사람 피부유래 줄기세포로부터 분화시킨 골모세포의 세포부착능을 측정한 결과 RVYFFKGKQYWE (VnP-16) 펩타이드가 가장 높은 골모세포 세포부착능을 보여 최소 기능단위 임을 규명하였음 (우측)
표 사람 골기질단백질 비트로넥틴으로부터 개발한 기능성 펩타이드 VnP-16의 세포특이성 평가 및 치주인대세포에 대한 기능 평가. (A) 사람 정상 피부각화세포(NHEKs), 사람 정상 구강각화세포(NHOKs), 사람 정상 피부섬유모세포(NHDFs), 사람 정상 구강섬유모세포(NHOFs), PC-12 세포, MC3T3-E1, CV-1 세포 및 NIH/3T3 세포에서 세포활성 펩타이드 VnP-16의 세포부착능 비교. 기능성 펩타이드 VnP-16 (9.1 μg/cm2)는 사람 정상 상피세포에는 반응하지 않고, 섬유모세포계통의 세포에서만 세포부착능을 유의하게 촉진시켰음. (B-D) 기능성 펩타이드 VnP-16이 사람 치주인대세포에 대한 세포반응 평가. 기능성 펩타이드 VnP-16 (9.1 μg/cm2)은 사람 치주인대세포의 세포부착(B) 및 세포퍼짐 (C & D)을 유의하게 증가시켰음. 결과는 mean ± S.D. (n = 8). *P < 0.01)
표 (a) Schematic illustration of the experimental design and representative images of sphere-forming skin-derived precursor cells (SKPs) following 7, 14, and 21 d of in vitro expansion. Following the initial purification, SKPs that grew as spheres in suspension were dissociated to single cells and regenerated over the course of 1 week. Serum exposure led to the rapid conversion of SKP cultures into mesenchymal precursors. Scale bars, 50 μm. FGF2, fibroblast growth factor 2; EGF, epidermal growth factor; LIF, leukemia inhibitory factor. (b) Fluorescence-activated cell sorting analysis of the surface marker profiles of SKP-derived mesenchymal precursors. (c) Representative image of a monolayer culture of SKP-derived mesenchymal precursors after differentiation for 2 weeks under osteogenic conditions. The cells were stained for mineral deposits using alizarin red S. Scale bar, 50 μm. (d,e) Quantitative (d) and semi-quantitative (e) RT-PCR analyses of the expression levels of osteogenic markers in the mesenchymal precursors (MPs) and osteogenic cells. A reaction without input nucleic acid was run in the first lane as a negative control. Data in d represent the mean ± s.d. (n = 4). *P < 0.01. ALP, alkaline phosphatase; RUNX2, Runt-related transcription factor 2; BSP, bone sialoprotein; GAPDH, glyceraldehyde 3-phosphate dehydrogenase
표 M-CSF and RANKL-induced osteoclast differentiation system
표 VnP-16 promotes osteogenic differentiation through β1 integrin/FAK signaling. (a) The effects of VnP-16 on alkaline phosphatase activity and calcium deposition in SKP-derived mesenchymal precursors (MPs), mouse calvarial osteoblast precursors (MC3T3-E1), and human osteogenic cells (Osteogenic). The cells were cultured in osteogenic differentiation medium containing VnP-16 or SP (50 μg/0.5 ml) for 2 weeks. (b) The effects of PF-573228 on alkaline phosphatase activity and calcium deposition in SKP-derived mesenchymal precursors, MC3T3-E1, and human osteogenic cells. The cells were cultured on VnP-16-treated (9.1 μg/cm2) plates in osteogenic differentiation medium with or without 1 μM PF-573228 for 2 weeks
표 The effects of VnP-16 on M-CSF- and RANKL-induced osteoclast formation, F-actinmediated cytoskeletal organi-zation, and resorptive activity. (a–f) BMMs were cultured for 6 d on plates that were precoated with vehicle (DMSO), vitronectin (0.23 μg/cm2),SP (9.1 μg/cm2),orVnP-16 (9.1 μg/cm2), in the presence of 30ng/ml M-CSF and 100 ng/ml RANKL. (a,d) The induced cells were stained for TRAP (a) and immunostained with DAPI (blue) and rhodamine-phalloidin (F-actin, red) (d). Scale bars, 200 μm. (b) TRAP-positive multinucleated cells containing three or more nuclei were counted as osteoclasts. (c) The sizes of the osteoclasts were obtained by measuring the diameters of multinucleated TRAP-positive cells on 40× photomicrographs. (e,f) The effects of VnP-16 on the bone resorbing activity of osteoclasts. BMMs were cultured for 6 d on Osteo Assay Surface plates that were coated with vehicle (DMSO), vitronectin (0.23 μg/cm2), or synthetic peptide (9.1μg/cm2), in the presence of 30ng/ml M-CSF and 100 ng/ml RANKL. The cells were removed and the resorbed pits were photographed (e). The blue arrows indicate the resorption pits formed by osteoclasts. Scale bars, 200 μm. Bone resorption was assessed by pit area measurements (f). (g) The effect of the concentration of VnP-16 (9.1 μg/cm2)thatblockedosteoclastformation on the proliferation and viability of BMMs. Data in b, c, f, and g represent the mean ± s.d. (n = 4). *P < 0.01
표 The effects of VnP-16 on F-actin-mediated cytoskeletal organi-zation in mature osteoclasts. The osteoclasts were cultured for 1 d on plates that were precoated with vehicle (DMSO), SP (9.1 μg/cm2), or VnP-16 (9.1 μg/cm2), in the presence of 30 ng/ml M-CSF and 100 ng/ml RANKL. The cells were immunostained with DAPI (blue) and rhodaminephalloidin( red). Scale bars, 200 μm
표 The effects of VnP-16 on M-CSF- and RANKL-induced expression levels of osteoclastogenesis- related genes. (a and b) Immunoblotting (a) and densitometric analyses (b) of the osteoclastogenesis-related proteins in BMMs that were cultured for 1–3 days on plates precoated with SP or VnP-16 (9.1 μg/cm2), in the presence of 30 ng/ml M-CSF and 100 ng/ml RANKL. CREB, cAMP-response element-binding protein; ATF-1, activating transcription factor 1. (c and d) Immunoblotting (c) and densitometric analyses (d) of MAPKs in BMMs that were cultured for 3 days on plates precoated with SP or VnP-16 (9.1 μg/cm2), in the presence of 30 ng/ml M-CSF and 100 ng/ml RANKL, serum-starved for 3 h, and stimulated with M-CSF (30 ng/ml) and RANKL (100ng/ml) for the indicated times. ERK, extracellular signal-regulated kinase. Data in b and d (n = 3) represent the mean ± SD
표 The effects of VnP-16 on M-CSF- and RANKL-induced activation of cytoskeletal organizers during osteoclastogenesis. (a–f) Immunoblotting (a, c, and e) and densitometric analyses (b, d, and f) of c-Src, PYK2, and CREB in BMMs (a and b), preosteoclasts (c and d), and mature osteoclasts (e and f). The cells were cultured for 1 day (a and e) or 3 days (c) on plates that were precoated with SP or VnP-16 (9.1 μg/cm2), in the presence of 30 ng/ml M-CSF and 100 ng/ml RANKL, serum-starved for 3 h, and then stimulated with M-CSF (30ng/ml) and RANKL (100ng/ml) for the indicated times. (g–j) Immunoblotting (g and i) and densitometric analyses (h and j) of active (GTP-Rac1) and total Rac1 levels in BMMs (g and h) and preosteoclasts (i and j). The assay conditions were the same as those described for a and c. The cells were lysed and incubated with PAK1 PBD Agarose beads for 1 h at 4 °C. Active Rac1 proteins were detected by immunoblotting using an anti-Rac1 antibody. Data in b, d, f, h, and j represent the mean ± SD (n = 3)
표 The effects of VnP-16 on bone resorbing activity in vitro. (a, b) The effects of VnP-16 on the bone resorbing activity of mature osteoclasts. Mature osteoclasts were cultured for 12 h on Osteo Assay Surface plates that were coated with vehicle (DMSO), vitronectin (0.23 μ g/cm2), or synthetic peptide (9.1μg/cm2), in the presence of 30 ng/ml M-CSF and 100 ng/ml RANKL. The cells were removed and the resorbed pits were photographed (a). The blue arrows indicate the resorption pits formed by osteoclasts. Scale bars, 200 μm. Bone resorption was assessed by pit area measurements (b). Data in b represents the mean ± s.d. (n = 5). *P < 0.01
표 The effects of VnP-16 on the bone resorbing activity and survival of mature osteoclasts. (a–c) Mature osteoclasts were cultured for 24 h on Osteo Assay Surface plates coated with vehicle (DMSO), SP, or VnP-16 (9.1 μg/cm2),in the presence of 30 ng/ml M-CSF and 100 ng/ml RANKL. (a) The cells were removed and the resorbed pits (indicated by blue arrows) were photographed. Scale bars, 200 μm. (b) Bone resorption was assessed by pit area measurement. (c) After TRAP staining, the surviving osteoclasts were counted. Data in b and c represent the mean ± s.d. (n = 4). *P < 0.01 and **P < 0.05
표 The effects of VnP-16 on IL-1-induced bone destruction in vivo. (a–c) The effects of VnP-16 on IL-1-induced bone destruction in vivo. A collagen sponge treated with vehicle (DMSO), IL-1 (2 μg), synthetic peptides (125 μg), or synthetic peptides (125 μg) plus IL-1 (2 μg) was implanted over the calvarial bone of 5-week-old ICR mice. TRAP staining and μCT imaging of whole calvariae were performed (a); the black spots indicate eroded surfaces. Bone mineral content (b) and BV/TV ratio (c) were measured by quantitative bone morphometric analysis. (d–f) Histological sections of calvarial bones were stained with hematoxylin and eosin (d, bottom) and histochemically for TRAP (d, top). The osteoclast number (e) and surface area (f) were determined by histomorphometric analysis. Data in b, c, e, and f represent the mean ± s.d. (n = 5). *P < 0.01 and **P < 0.05
표 백서 두개관 두정골에 순차적으로 critical-sized calvarial defect를 만들고, 펩타이드를 처리한 시킨 지지체를 이식한 모습. 백서 두개관의 두정골에 critical-sized calvarial defect를 만들고, 최소 기능단위 기능성 펩타이드 VnP-16를 처리한 지지체를 이식한 그림
표 Burr-hole 골절 모델 준비. 자성 C57BL/6 마우스에서 마취를 시행한 다음 다리의 털을 깎고 (Shaving), 포비돈으로 소독(Povidone painting) 하였으며, 경골능을 따라 약 1 cm 정도 절개 (Incision)한 후 비복근을 박리 (Exfoliation)시켜 경골 근위 골단으로부터 6-mm 부위에 지름 0.7 mm, 깊이 1.3 mm의 결손부를 형성(Drilling)하였음. 천공 후 결손부 내부를 생리식염수로 충분히 세척 (Saline irrigation)한 다음 펩타이드가 처리된 collagen sponge를 형성한 결손부 내에 조심스레 위치 (Implantation)시켰음. 절개부위는 비흡수성 봉합사로 봉합 (Suture)을 시행하였음
표 Animal surgeries were performed to install the investigated implants. (a) R e p r e s e n t a t i v e photograph after implant placement in a rabbit tibia. Two implants were inserted in the right rabbit tibia. (b) A schematic diagram explains the positions of the inserted implants. The inter-implant distance was about 8-10 mm from center to center. (c) Schematic diagrams show the arrangement of the investigated implant groups. Control is the pure Ti implant. SP means the SP-treated implant, and VnP-16 denotes the VnP-16-treated implant
표 난소절제유도 골손실 모델 (Ovariectomy-induced bone loss model) 준비. 8주령의 자성(female) C57BL/6 마우스를 Zoletil과 zylazine 복강내주사하여 마취시킨 후 요추 상방에 등쪽 정중선을 따라서 0.5~1 cm 크기의 단일 절개를 시행하였음. 절개 후 피하 결합조직을 하방 근육으로부터 박리한 다음 근육을 절개하여 복강으로 접근하였음. 겸자를 이용하여 조심스럽게 난소를 둘러싼 지방 패드를 노출시킨 후 수란관을 지혈겸자로 클리핑(clipping)하였음. 그 후 수란관을 한번 묶어 출혈을 미리 방지하였음. 난소와 지방 패드를 완전히 제거한 다음 수란관을 복강 내로 원위치 시켰음. Sham 그룹의 경우 난소 노출 후 절제 없이 윈위치 시켰음. 반대편의 난소도 동일한 방법으로 제거하였음. 그 후 피부 절개선에 1-2개의 skin stapler(covidien Ilc, Mansfield, MA, USA)로 봉합하였음. 수술 직후 cepazolin (20 mg/kg) 을 피하주사하여 수술 후 감염을 예방하였음
표 The effects of VnP-16 on bone regeneration in vivo. (a) μCT images of the bone defects in each group. Critical-sized rat calvarial defects were implanted with absorbable collagen sponges treated with vehicle (DMSO), rhBMP-2 (2 μg/scaffold), SP (1 mg/scaffold), or VnP-16 (1 mg/scaffold). (b–d) Quantitative bone morphometric analyses of the bone recovery rate (b), BV/TV (c), and calvarial thickness (d) in the region of the defects. (e) μCT images of the bone defects and Masson’s trichrome staining (MT) of rat calvarial sections 2 weeks after transplantation. The triangles indicate the wound edges. For histomorphometric analysis, the specimens were decalcified with 12% EDTA for 4 weeks and embedded in paraffin. The paraffin-embedded samples were sectioned at a thickness of 4 μm and then stained with Masson’s trichrome. Bars, 1 mm. (f) The number of osteoblasts per bone perimeter from rat calvarial sections 2 weeks after transplantation. Ob.N, osteoblast number; B.Pm, bone perimeter. (Scale bars, 50 μm.) (g) qPCR analysis of the expression levels of osteogenic markers in each group. ALP, alkaline phosphatase; BSP, bone sialoprotein. Data in b–d, f, and g represent the mean ± SD (n = 5 per group). **P < 0.01
표 OVX mice exhibit severe trabecular bone loss in the femur. (a–c) μCT reconstruction of metaphyses of distal femurs (a), BMD and BV/TV (b), and trabecular number and separation in sham controls and OVX mice at 12 weeks after OVX. (d) H&E staining of femur sections from sham controls and OVX mice 12 weeks after OVX. Scale bars, 200 μm. (e) Morphometric analysis of osteoblast number in sham controls and OVX mice 12 weeks after OVX. (f) TRAP staining of femur sections from mice after OVX or sham operation. (g) Morphometric analysis of the osteoclast number and osteoclast surface in mice after OVX or sham operation. BS, bone surface. Scale bars, 200 μm. *P < 0.05, **P < 0.01
표 VnP-16 substantially alleviates osteoporosis by reversing OVX-induced bone loss. (a–d) μCT reconstruction of metaphyses of distal femurs (a) as well as BMD (b), BV/TV (c), and trabecular number (d) in OVX mice at 1 week after administration of vehicle, rhBMP-2, SP, or VnP-16. The images represent femurs (a, upper panel) and its trabecular bones (a, lower panel) of vehicle-, rhBMP-2-, or peptide-treated OVX mice. (e and f) Masson’s trichrome (e) and H OC, osteoclasts; M, bone marrow-derived macrophages. Data in b–d, g, h, j, and k represent the mean ± SD (n = 7 per group). *P < 0.05, **P < 0.01
표 VnP-16 reverses estrogen deficiency-induced bone loss in femoral neck trabecular bone. (a) Peptide dosing schedule and experimental groups (b) μCT reconstruction of femoral neck trabecular bone. The images represent femoral neck trabecular bones of vehicle-, zolendronate-, or peptide-treated OVX mice. (c) Morphometric analysis of the bone mineral content(BMC), bone mineral density(BMD), BV/TV, trabecular number, and trabecular space in OVX mice at 1 week after administration of vehicle, zolendronate, SP, or VnP-16. Data in c represent the mean ± SD (n = 14 per group). OVX, ovariectomy; 1st Ad, first administration; 2nd Ad, second administration. *P < 0.05
표 VnP-16 reverses estrogen deficiency-induced bone loss in lumbar spine trabecular bone. (a) Peptide dosing schedule and experimental groups (b) μCT reconstruction of lumbar spine trabecular bone. The images represent lumbar spine trabecular bones of vehicle-, zolendronate-, or peptide-treated OVX mice. (c) Morphometric analysis of the bone mineral content(BMC), bone mineral density(BMD), BV/TV, trabecular thickness, number trabecular number, and trabecular space in OVX mice at 1 week after administration of vehicle, zolendronate, SP, or VnP-16. Data in c represent the mean ± SD (n = 14 per group). OVX, ovariectomy; 1st Ad, first administration; 2nd Ad, second administration. *P < 0.05, **P < 0.01
표 VnP-16 reverses estrogen deficiency-induced bone loss in femoral neck trabecular bone. (a) Peptide dosing schedule and experimental groups (b) μCT reconstruction of femoral neck trabecular bone. The images represent femoral neck trabecular bones of vehicle-, zolendronate-, or peptide-treated OVX mice. (c) Morphometric analysis of the bone mineral content(BMC), bone mineral density(BMD), BV/TV, trabecular number, and trabecular thickness in OVX mice after administration of vehicle, zolendronate, SP, or VnP-16. Data in c represent the mean ± SD (n = 10 per group). OVX, ovariectomy. 1st Ad, 2nd Ad, 3rd, and 4th, first, second, third, and fourth administrations. *P < 0.05 or **P < 0.01 compared to scrambled peptide (SP)
표 VnP-16 inhibits the incidence of arthritis and severity of arthritis score in collagen-induced arthritis model. (a) Experimental schedule. (b)Incidence of arthritis (%). (c) Severity of arthritis score (n = 10 per group)
표 Images and bone-to-implant contact (BIC) and bone area (BA) ratios of the titanum implants 10, 14, and 30 days after insertion. (a) Representative light microscopy photomicrographs of the vehicle-, scrambled peptide (SP)- and VnP-16-coated implants in the rabbit tibia 10, 14, and 30 days after insertion (n = 4 implants per group per time point). The sections were subjected to modified Goldner’s Masson Trichrome staining. (b and c) BIC and BA ratios 10, 14, and 30 days after implantation of vehicle-, scrambled peptide (SP)- and VnP-16-coated implants (n = 4 implants per group per time point). Error bars indicate standard deviation
$Burr-hole defect in the proximal mouse tibia. (a) Micro-computed tomography (microCT) image rendered to show the medial aspect of the tibia (oriented longitudinally) just after surgery. The red line drawn on the tibia measures the distance from the proximal end of the tibia to the centroid of the burr hole. Inset in the right is the magnified image of the circle indicated. (b) MicroCT image of a section along the frontal plane of the fractured tibia immediately after surgery. Inset in the right is the magnified image of the rectangle indicated. The red line drawn measures the depth of the burr hole$ 표 Burr-hole defect in the proximal mouse tibia. (a) Micro-computed tomography (microCT) image rendered to show the medial aspect of the tibia (oriented longitudinally) just after surgery. The red line drawn on the tibia measures the distance from the proximal end of the tibia to the centroid of the burr hole. Inset in the right is the magnified image of the circle indicated. (b) MicroCT image of a section along the frontal plane of the fractured tibia immediately after surgery. Inset in the right is the magnified image of the rectangle indicated. The red line drawn measures the depth of the burr hole

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