TNF계 CD137L 및 RANKL의 파골세포와 T 세포에 대한 활성조절

홍성준,박재홍,이현우,이긍호 大韓小兒齒科學會 2008 대한소아치과학회지 Vol.35 No.4

본 연구는 TNFR family인 CD137 및 RANK. 파골세포의 CD137L와 T 세포의 RANKL 간의 역신호에 의한 이들 세포의 역할을 알아보고자 하였다. 이에 RANKL 및 CD137L 자극으로 유도되는 역신호 전달에 의한 T 세포 활성과 파골세포분화에 미치는 영향을 규명하고자 웅성 생쥐의 골수세포와 T 세포를 공동배양하여 다음과 같은 결과를 얻었다. 1. 생쥐 단핵세포주 및 골수유도 단핵전구세포에서 CD137L이 발현되며, CD137L 단클론 항체로 자극을 주었을 경우 파 골세포 표지단백절인 TRAP 양성 파골세포의 형성이 억제되었다. 2. 활성화된 CD4^(+) 및 CD8^(+) T 세포에서 RANKL을 발현하였으며 RANKL의 유사 수용체인 OPG 재조합 단백질을 처리하여 CD4^(+) 및 CD8^(+) T 세포의 세포증식이 억제되었다. 이 연구의 결과는 CD137자극에 의한T세포활성 및 RANK 자극에 의한파골세포분화및 활성이 각각수용체에 결합하는 라이겐드의 역신호에 의해 억제되었는데, 이는 파골세포와 T 세포의 과도한 활성을 제어하는 생체의 항상성조절에 관여하는 기전으로 생각된다. Resorption of alveolar bone in periodontitis is due to excessive differentiation and activation of osteoclasts. Bacterial antigens causing periodontitis activates CD4 T cells, which leads to expressing RANK ligand (RANKL) on CD4 T cells. RANKL binds RANK on preosteoclasts or osteoclasts, and enhances the differentiation preosteoclasts into osteoclasts and the activation of mature osteoclasts. CD137, one of TNF receptor (TNFR) family, expressed on activated T cells binds with CD137 ligand (CD137L) on antigen presenting cells. Cross-linking of CD137 by CD137L acts as T cell co-stimulatory signals and, therefore, enhances the activation of T cell. In this study, I elucidated the biological responses of CD137L on (pre)osteoclasts and RANKL on T cells in the context of in vivo interaction between T cells and osteoclasts. RAW264.7. murine monocytic cells, constitutively express CD137L. Ligation of CD137L with anti-CD137L mAb inhibited RANKL-induced osteoclast formation in a dose-dependent manner. Bone marrow cells are expressed CD137L by the treatment with M-CSF. Cross-linking of CD137L abolished M-CSF/RANKL-evoked the formation of multi-nucleated osteoclasts. Both mouse CD4 and CD8 T cells are expressed RANKL following their activation. Ligation of RANKL with OPG, the decoy receptor for RANKL, inhibited both CD4 and CD8 T cell proliferation. These effects were attributed to RANKL-induced apoptosis. These data indicate that CD137L and RANKL on osteoclasts and T cells, respectively provide them with inhibitory signal.

The role of p38 MAP kinase on RANKL regulation in mouse periodontal ligament fibroblasts

김재철,최득철,김영준,Kim, Jae-Cheol,Cui, De-Zhe,Kim, Young-Joon The Korean Academy of Periodontoloy 2007 Journal of Periodontal & Implant Science Vol.37 No.2

Receptor activation of nuclear factor ${\kappa}$ B ligand (RANKL)은 파골세포의 분화와 기능에 중요한 역할을 하는 단백질로 이들 물질의 조절에는 p38 MAP kinase가 관여한다. 그러나 치주인대 섬유모세포에서 RANKL 발현 시 p38 MAP kinase의 역할은 잘 알려져 있지 않다. 이에 이번 연구는 마우스 치주인대 섬유모세포의 $IL-1{\beta}-induced$ RANKL 발현과정에서 p38의 역할을 규명하고자 하여 다음과 같은 결과를 얻었다. 마우스 치주인대 섬유모세포에 $IL-1{\beta}$ (1ng/ml)의 자극은 수용성 RANKL의 합성을 증가시켰다. 수용성 RANKL의 합성은 p38 MAP kinase 억제제인 SB203580에 의해 농도 의존적으로 억제되었으나 다른 MAP kinase 억제제인 SP600125, JNK 억제제와 PD98059, ERK 억제제에 의해서는 수용성 RANKL의 합성이 조절되지 않았다. NF-kB 억제제에 의해서도 수용성 RANKL의 합성이 억제되지 않았다. RANKL 유전자의 발현은 $IL-1{\beta}$로 자극 시에는 대조군에 비해 약 5배의 발현 증가를 보였으나 SB203580으로 전처치 시 $IL-1{\beta}$ (1ng/ml)로 자극시보다 약 1.5배의 감소를 보였다. 그러나 SP600125, PD98059, 및 NF-kB 억제제로 전처치한 경우에는 $IL-1{\beta}$로 자극한 경우와 비슷한 수준을 보였다. $IL-1{\beta}$로 자극 시 RANKL 유전자의 반감기가 90분 이었으나 SB203580로 전처치 후 $IL-1{\beta}$로 자극 시 RANKL 유전자의 반감기는 60분으로 감소하였다. Cycloheximide 전처리 시 SB203580에 의한 RANKL 유전자 발현 억제가 관찰되지 않았다. 단백질 분석결과 p38 MAP kinase의 인산화 활성은 30분까지 증가하였으나 그 이후 감소하여 2시간째에는 그 발현이 미약하였다. SB203580로 전처치 후 $IL-1{\beta}$로 자극 시 p38 MAP kinase의 인산화 활성이 감소하였다. 이상의 결과는 p38 MAP kinase가 RANKL 유전자 조절에 중요한 역할을 담당하고 있음을 시사한다.

두부 외상을 동반한 골절 환자의 혈청에서 Receptor Activator of Nuclear Factor-κB Ligand와 Osteoprotegerin의 변화

박신영 ( Shin Young Park ),서근택 ( Kuen Tak Suh ),류창훈 ( Chang Hoon Ryu ),우승훈 ( Seung Hun Woo ),이정섭 ( Jung Sub Lee ),김성장 ( Seong Gang Kim ) 대한골절학회 2008 대한골절학회지 Vol.21 No.2

목적: RANKL과 OPG는 골의 재형성에 있어 파골기전의 중요한 조절 인자이며, 골절의 치유 과정에 관여한다. 그러나 두부 외상과 골절이 있는 환자에서 이들에 대한 연구는 부족하다. 이에 두부 외상을 동반한 골절 환자군과 골절 환자군의 혈청에서 이들의 변화를 분석하여 비교하였다. 대상 및 방법: 두부 외상과 골절이 있는 18명의 남자 환자와 골절이 있는 20명의 남자 환자, 대조군으로 건강한 20명의 남자를 선정하였다. 두부외상-골절군과 골절군에서 수상 후 수 시간 내, 수상 후 4, 8, 12주에 혈액을 채취하여 RANKL과 OPG의 변화를 분석하였다. 결과: 두부외상-골절군은 외상 후 8, 12주에 골절군에 비하여 RANKL의 발현이 낮았으며 두부외상-골절군에서 골절군에 비하여 외상 후 4, 8,12주에 OPG의 발현이 증가되었다. 두부외상-골절군에서 외상 후 수 시간 내, 4, 8, 12주에 대조군보다 RANKL/OPG의 비율이 낮았으며, 두부외상-골절군에서 골절군에 비해 외상 후 8주와 12주에 RANKL/OPG 비율이 낮았다. 결론: 두부 외상과 골절이 있는 환자에서 RANKL, OPG, RANKL/OPG의 비율의 변화를 보았고, 두부 외상과 골절이 있는 환자에서 이들의 변화가 골절 환자에서 보다 오랫동안 지속되었다. Purpose: Receptor activator of nuclear factor-κ B ligand (RANKL), osteoprotegerin (OPG) have been shown to be important regulators of osteoclastogenesis during bone remodeling, and their expressions were examined during fracture healing in a mouse model of tibial fracture. However, studies linking RANKL and OPG in patients with head injury and fracture are lacking. We evaluated the changes in serum levels of RANKL and OPG in patients with head injury and fracture (head injury group) and in patients with fracture (fracture group) and compared these with levels found in healthy control subjects. Materials and Methods: 18 male patients of head injury and fracture and 20 male patients of fracture alone were enrolled. 20 healthy men were recruited to serve as controls. Within the first few hours of admission to hospital, at 4, 8 and 12 weeks after injury 20 ml of blood were obtained from 18 patients with head injury and fracture and 20 patients with fracture only. Results: RANKL levels were significantly lower in the head injury group than in the fracture group at 8 and 12 weeks after injury. OPG levels were significantly higher in the head injury group than in the fracture group at 4, 8 and 12 weeks after injury. RANKL/OPG ratios were significantly lower in the head injury group than in the controls immediately after and 4, 8 and 12 weeks after injury, and were significantly lower in the head injury group than in the fracture group at 8 and 12 weeks after injury. Conclusion: We have shown changes in the profiles of RANKL, OPG and RANKL to OPG ratio. The altered RANKL, OPG and RANKL/OPG ratio in the head injury group lasted longer than in those of the fracture group.

The expression patterns of RANKL and OPG in murine tooth eruption

Hwang, Kyung-Mun,Kim, Eun-Jung,Kim, Hyun-Jung,,Kim, Young-Jin,Nam, Soon-Hyeun 大韓小兒齒科學會 2006 대한소아치과학회지 Vol.33 No.2

치아의 맹출은 치아기 (dental organ)와 치조골의 세포와 연관된 매우 복잡한 과정이다. 우선 치아 맹출이 일어나기 전에 파골세포가 치낭으로 집결하게 된다. 이러한 치낭의 역할은 파골세포와 조골세포의 상호작용으로 이루어 지는 골개조와 밀접한 관련이 있는데, 이는 치아 맹출과 연관된 많은 유전자들이 치낭에서 발현되기 때문이다. RANKL는 TNF ligand family로써 조골세포에 존재하며 파골세포의 형성 및 전구세포로 부터의 활성화를 유도한다. 이러한 RANKL은 OPG에 의해 그 작용이 억제되며 RANKL와 OPG의 상대적인 비율이 파골세포의 형성에 영향을 미친다. 또한 Runx2유전자의 변이는 조골세포의 분화와 활성에 차질을 가져오고 결국 RANKL/OPG pathway를 통해 파골세포 형성에 영향을 줄 수 있다. 치아의 발육 및 맹출에 미치는 RANKL 및 OPG의 영향을 알아보고 Runx2와의 연관성을 알아보기 위해 in situ hybridization 방법으로 태생 1, 3, 5, 7, 9, 11일된 쥐의 하악 및 제1대구치를 사용하여 실험을 실시한 결과 RANKL, OPG, Runx2의 mRNA가 태생 1일부터 11일까지 치낭 및 치아주위조직에 특성있게 나타났다. 이중 태생 5일에서 9일 사이에 RANKL 및 Runx2는 치아의 교합면측과 하방 치조골 부위의 발현이 강하게 나타난 반면 OPG는 약한 발현을 보였다. 이는 또한 파골세포의 활성부위를 알아보기 위해 TRAP염색을 실시하여 태생 5일에서 9일 사이에 최대의 활성화를 나타낸 결과와 연광성 있게 나타났다. RANKL, OPG, Runx2의 특성있는 발현양상들을 종합해 볼 때, 치아 맹출은 치낭, 치아기, 치조골 사이의 상호 작용을 통해 이루어 지며, 이는 치낭이 치아 맹출에 있어서 매우 중요하다는 것을 의미한다. 또한, 이러한 유전자들 (RANKL, OPG, Runx2) 이 치아의 맹출에 중요한 역할을 하는 것으로 사료된다. Tooth eruption is a complex and tightly regulated process that involves cells of the tooth organ and the surrounding alveolus. Osteoclast precursors must be recruited into the dental follicle prior to the onset of eruption. This function of dental follicle may be regarded as the ability of bone remodeling characterized by the interaction of osteoclasts and osteoblasts. This is because tooth eruption is a localized event in which many of the genes required for eruption are expressed in the dental follicle. RANKL is a membrane-bound protein that is a member of the TNF ligand family, which is present on bone marrow stromal cells and osteoblasts, and induces osteoclast formation and activation from precursor cell. The biologic effect of RANKL is inhibited by OPG and, in bone, the relative ratio of RANKL and OPG modulates osteoclastogenesis. To evaluate the roles of RANKL and OPG in tooth eruption and the relations with the expression pattern of Runx2, in situ hybridization was performed with mandibles of mice at postnatal stage 1, 3, 5, 7, 9 and 11. mRNA of RANKL, OPG, and Runx2 are expressed in dental follicle and surrounding tissue from P1 to 11. To determine the sites of osteoclastic activity duing tooth eruption, mandibles were dissected. Peak osteoclastic activity in alveolar bone along the occlusal and basal regions was observed from P5 to 9, with osteoclasts in these regions being large and strongly TRAP-positive. The specific spatic-temporal expression patterns of RANKL, OPG and Runx2 in our study suggest that tooth eruption could be progressed through the interactions of molecular signaling among dental follicle, dental organ and alveolar bone, furthermore it means that dental follicle is quite important in tooth eruption. In addition, it indicates that these genes (RANKL, OPG, and Runx2) play critical roles in tooth eruption.

Osteoprotegerin(OPG)-receptor Activator of NF-kB Ligand(RANKL) 유전자 다형성과 전혈세포에서의 OPG, sRANKL 생산 사이의 연관성

김용진,김훈,채수진,박경아,서창석,김석현,최영민,문신용,김정구 대한골다공증학회 2007 Osteoporosis and Sarcopenia Vol.5 No.1

Objective: To investigate the association between polymorpjhisms of osteoprotegerin(OPG), and receptor activator of nuclear factor-[kappa]B ligand(RANKL) genes and production of OPG, and soluble RANKL (sRANKL) by whole blood cellsin Korean postmenopausal women. Methods: The OPG gene T245G, G1181C, and the RANKL gene rs2277438 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) in 267 Korean postmenopausal women. The production of OPG and sRANKL by lipopolysaccharide-stimulated whole blood cells were also measured. Results: The productions of OPG, sRANKL and the ratio of RANKL×1000/OPG by lipopolysaccharide-stimulated whole blood cells were not different according to the OPG gene T245G, G1181C, and the RANKL gene rs2277438 polymorphisms. No significant differences in the productions of OPG, sRANKL and the ratio of RANKL×1000/OPG were noted among the haplotype genotypes of OPG gene T245G and G1181C polymorphisms. There were no significant differences in the productions of OPG, sRANKL and the ratio of RANKL ×1000/OPG among combined genotypes of OPG gene G1181C and RANKL gene rs2277438 polymorphisms. Conclusion: The OPG gene T245G, G1181C, and the RANKL gene rs2277438 polymorphisms do not affect the production of OPG, and sRANKL by lipopolysaccharide-stimulated whole blood cells. 목적:한국 폐경여성에서 OPG와 RANKL 유전자 다형성 양상과 전혈세포에서의 OPG, sRANKL 생산 사이에 연관성이 있는가를 분석하고자 하였다. 방법:자연폐경여성 267명에서 OPG T245G, G1181C 다형성양상과 RANKL rs2277438 A/G 다형성 양상을 PCR-RFLP(Polymerase Chain Reaction-Restriction Fragment Length Polymorphism)와 염기서열분석으로 분석하고 lipopolysaccharide로 자극한 전혈세포에서 혈청 OPG와 sRANKL의 생산을 측정하였다. 결과: OPG T245G, OPG G1181C 및 RANKL rs2277438 유전자 다형성 양상에 따른 전혈세포에서의 OPG와 sRANKL 생산, RANKL×1000/OPG 비는 유의한 차이가 없었다. OPG T245G와OPG G1181C 다형성으로 구성된 haplotype 유전자형에 따른 전혈세포에서의 OPG 와 sRANKL 생산량, RANKL×1000/OPG 비 또한 유의한 차이가 없었다. OPG G1181C와 RANKL rs2277438 유전자 다형성의 복합 유전자형에 따른 전혈세포에서의 OPG와 sRANKL 생산, RANKL×1000/ OPG 비도 유사한 양상을 보였다. 결론: 한국 폐경여성에서 OPG 유전자의 T245G와G1181C 다형성 및 RANKL 유전자의 rs2277438 A/G 다형성은 전혈세포에서의 OPG와 sRANKL 생산에 영향을 미치지 않는다.

재치환 인공관절 주위 조직에서 Osteoprotegerin [OPG]과 Osteoprotegerin ligand [OPGL]의 발현

유명철(Myung Chul Yoo),조윤제(Yoon Je Cho),김인환(In Whan Kim),양형인(Hyung In Yang),김강일(Kang Il Kim),전영수(Young Soo Chun),고동오(Dong Oh Ko) 대한정형외과학회 2004 대한정형외과학회지 Vol.39 No.2

골파괴를 동반한 중이진주종에서 RANKL과 OPG mRNA의 발현

변재용,차창일,여승근,김성완,조중생 대한이비인후과학회 2005 대한이비인후과학회지 두경부외과학 Vol.48 No.8

Background and Objectives:Bone resorption in middle ear cholesteatoma is mostly responsible for serious complications of the disease, but the pathogenesis of destruction due to bone resorption has not been fully elucidated, although osteoclast activation have been indicated in reports to have a major effect. We have investigated if the receptor activator of NF-κB ligand (RANKL), a cytokine that is arguably the most critical regulator of osteoclast differentiation and activation and its natural inhibitor, osteoprotegerin (OPG), may be important in the bone loss of cholesteatoma. Also, we evaluated the correlation of RANKL and OPG level with the extent of bone destruction. Subjects and Method:A real time RT-PCR was performed to determine and quantify the expression of RANKL and OPG mRNA in 13 cases of cholesteatoma and 8 cases of normal auditory canal skin. Result:1) All cholestatoma and normal external auditory canal skin expressed both mRNA of RANKL and OPG 2) mRNA of RANKL in cholesteatoma were expressed significantly higher than normal external auditory canal skin (p<0.05). 3). The ratio of RANKL to OPG concentration was significantly higher in cholesteatoma than in the normal external auditory canal skin (p<0.05). 4) The ratio of RANKL to OPG was significantly correlated to the extent of bone destruction (p<0.05). Conclusion:These findings suggest the RANKL-OPG loop feedback system is defined in cholesteatoma. RANKL may play a role in the bone destruction ofcholesteatoma. In particular, the balance in the ratio of RANKL to OPG is more important than RANKL

Effect of Osteotropic Agents on the Expression of RANKL and OPG in Saos-2 Cells

Kim, Si Nae,Kim, Yong Hee,Kim, Gwan-Shik,Baek, Jeong-Hwa Korean Academy of Oral Biology and the UCLA Dental 2002 International Journal of Oral Biology Vol.27 No.1

Various osteotropic agents that influence bone resorption are known to act primarily via osteoblasts/stromal cells. Recently, receptor activator of nuclear factor-kB ligand (RANKL) and osteoprotegerin (OPG) have been suggested to be key molecules that regulate osteoclast differentiation and activation. RANKL induces osteoclastogenesis and activates mature osteoclasts while OPG acts as a physiologic inhibtor of RANKL. It is conceivable, therefore, that change in RANKL and OPG expression in osteoblasts/stromal cells affect their ability to support osteoclast formation, activity and survival. In this study, we examined the effects of several osteotropic agents on RANKL and OPG mRAN expression in Saos-2 human osteoblastic cells. Cells were exposed to parathyroid hormone (PYH, 10^-8M), 1,25-dihydroxyvitamin D_3 (1,25(OH)_2D_3, 10^-8M), dexamethasone (10^-8M), interleukin-1β (IL-1β, 5ng/ml), tumor necrosis factor-α (TNF-α, 5ng/ml), transforming growth factor-β (TNF-β, 5ng/ml), or insulin-like growth factor-I (IGF-I, 10ng/ml) for 2, 4, 8, and 24h, and mRNA levels were analyzed by semi-quantitative reverse transcription-polymerase chain reaction. All the tested osteotropic agents more or less regulated both RANKL and OPG mRNA level during the examined period. RaNKL/OPG ratio was up-regulated by PTH, 1,25(OH)_2D_3, dexamethasone, TGF-β, IGF-I, and increased RANKL/OPG ratio was maintained up to 24h. IL-1β and TNF-α transiently they greatlhy decreased RANKL/OPG ratio. These results showed that RANKL and OPG could be potential targets for bone resorption regulation by osteotropic hormenes, cytokines, and growth factors. However, regulatory patterns were not alvays coincident with in vivo or in vitro effects on osteoclastogenesis, implying that RANKL and OPG are not the sole mediators of their action.

Isoproterenol Increases RANKL Expression in a ATF4/NFATc1-Dependent Manner in Mouse Osteoblastic Cells

Baek, Kyunghwa,Park, Hyun-Jung,Baek, Jeong-Hwa,Kim, Hyung-Ryong MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.10

<P>Sympathetic nervous system stimulation-induced β-adrenergic signal transduction is known to induce bone loss and increase of osteoclast activity. Although isoproterenol, a nonspecific β-adrenergic receptor agonist, has been shown to increase receptor activator of NF-κB ligand (RANKL), the details of the regulatory mechanisms remain unclear. In the present study, we investigated the role of the nuclear factor of activated T-cells (NFAT) in isoproterenol-induced RANKL expression in C2C12 and in primary cultured mouse calvarial cells. Isoproterenol increased nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and RANKL expressions at both mRNA and protein levels and increased NFAT reporter activity. NFATc1 knockdown blocked isoproterenol-mediated RANKL expression. Isoproterenol also promoted cAMP response element-binding protein 1 (CREB1) and activating transcription factor 4 (ATF4) phosphorylation. Isoproterenol-mediated transcriptional activation of NFAT was blocked by protein kinase A (PKA) inhibitor H89. Isoproterenol-induced CREB1, ATF4, NFATc1, and RANKL expressions were suppressed by H89. Mutations in cAMP response element-like or NFAT-binding element suppressed isoproterenol-induced <I>RANKL</I> promoter activity. Chromatin immunoprecipitation analysis demonstrated that isoproterenol increased NFAT-binding and ATF4-binding activities on the mouse <I>RANKL</I> promoter, but did not increase CREB1-binding activity. Association of NFATc1 and ATF4 was not observed in a co-immunoprecipitation study. ATF4 knockdown suppressed isoproterenol-induced NFAT binding to the <I>RANKL</I> promoter, whereas NFATc1 knockdown did not suppress isoproterenol-induced ATF4 binding to the <I>RANKL</I> promoter. ATF4 knockdown suppressed isoproterenol-induced expressions of NFATc1 and RANKL. These results suggest that isoproterenol increases RANKL expression in an ATF4/NFATc1-dependent manner.</P>

류마티스 관절염 동물 모델에서 활막의 RANKL/OPG mRNA 발현 비율 및 IL-17의 효과

이준희 ( Jun Hee Lee ),김근태 ( Geun Tae Kim ),류선 ( Sun Ryu ),김주인 ( Ju In Kim ),백승훈 ( Seung Hoon Baek ),김성일 ( Sung Il Kim ) 대한류마티스학회 2006 대한류마티스학회지 Vol.13 No.2

Objective: To investigate the synovial mRNA expression of receptor activator of NFκB (RANK), RANK ligand (RANKL), osteoprotegerin (OPG) and RANKL/OPG mRNA expression ratio, and to evaluate the effects of IL-17 in experimental rheumatoid arthritis (RA) model. Methods: After induction of collagen-induced arthritis (CIA) by type II collagen in DBA1 mice, mice were anesthetized at day 28 and a small aperture in the skin of the knee was performed. Mice, in which arthritis of knee was present, were selected and divided into 3 groups, and phosphate-buffered saline (PBS group), IL-17 (IL-17 group) or anti-IL-17 monoclonal antibody (anti-IL-17 group) was injected to both knee joint at day 28 and 32. At day 35, mice were sacrificed and synovium of knee joints were isolated. Synovial mRNA expression of RANKL, RANK and OPG was assessed by real-time RT-PCR and immunohistochemical stain. Results: Synovial RANKL and RANK mRNA expressions were significantly different among IL-17, PBS, anti-IL-17 and normal group (IL-17>PBS>anti-IL-17>normal group), and synovial OPG mRNA expressions in PBS, IL-17 and anti-IL-17 group were significantly high than those in normal group, however, there was no significant difference among IL-17, PBS and anti-IL-17 group. RANKL/OPG mRNA ratio was significantly different among these groups (IL-17>PBS>anti-IL-17>normal group). In immunohistochemical stain, RANKL, RANK and OPG-positive cells were expressed at synovium. Conclusion: Synovial RANKL/OPG mRNA ratio was enhanced in CIA, and IL-17 induced higher RANKL/OPG ratio in the synovium of CIA, which was blocked by anti-IL-17 antibody. These results suggest that RANKL/OPG mRNA ratio play an important roles on bone destruction, and IL-17 may be actively involved in bone destruction by enhancing RANKL/OPG ratio in CIA model.