<3230B1C731C8A32DB8F1C2F72E687770>

Size: px

Start display at page:

Download "<3230B1C731C8A32DB8F1C2F72E687770>"

민기 허
5 years ago
Views:

1 대한내분비학회지 : 제 20 권제 1 호 2005 원저 조혈모세포이식후혈청 RANKL 와 OPG 의농도변화가골대사및골밀도에미치는영향 가톨릭대학교의과대학내과학교실, 조혈모세포이식센터 4, 미즈메디병원 1, 한림의과대학내과학교실 2, 성균관의과대학내과학교실 3 태현정 백기현 오은숙 1 오기원 2 이원영 3 김혜수한제호 차봉연 이광우 손호영 강성구 김춘추 4 강무일 The Changes in the Serum RANKL and OPG levels after Bone Marrow Transplantation: Association with Bone Mineral Metabolism Hyun-Jung Tae, Ki-Hyun Baek, Eun-Sook Oh 1, Ki-Won Oh 2, Won-Young Lee 3, Hye-Soo Kim, Je-Ho Han, Bong-Yun Cha, Kwang-Woo Lee, Ho-Young Son, Sung-Koo Kang, Choon-Choo Kim 4, Moo-Il Kang Department of Internal Medicine and Hemopoietic Stem Cell Transplantation Center 4, The Catholic University of Korea, College of Medicine, Department of Internal Medicine, The Hallym University of Korea, College of Medicine 2, and Sungkyunkwon University School of Medicine 3, Mizmedi Hospital 1, Seoul, Korea ABSTRACT 4) Background: The loss of bone mass is usually detected after bone marrow transplantation (BMT), particularly during the early post-transplant period. We recently reported that enhanced bone resorption following BMT was related to both the steroid dose and increase in IL-6. It was also suggested damage of the marrow microenvironment due to myeloablation and changes in bone growth factors contribute to post-bmt bone loss. Recently, the interactions of OPG and RANKL have been reported to be crucial in osteoclastogenesis and therefore in bone homeostasis. There are few data on the changes in RANKL/OPG status during the post-bmt period. This study investigated the changes in the levels of RANKL and OPG during the post-bmt period, and also assessed whether the changes in these cytokine levels actually influenced bone turnover and post-bmt bone loss. Methods: We prospectively investigated 110 patients undergoing allogenic BMT and analyzed 36 (32.4±1.3 years, 17 men and 19 women) where DEXA was performed before and 1 year after the BMT. The serum bone turnover marker levels were measured before and 1, 2, 3, 4 and 12 wks, 접수일자 : 2004 년 7 월 23 일통과일자 : 2005 년 1 월 26 일책임저자 : 강무일, 가톨릭대학교의과대학성모병원내과

2 - 태현정외 12 인 : 조혈모세포이식후혈청 RANKL 와 OPG 의농도변화가골대사및골밀도에미치는영향 - 6 Ms, and 1 yr after the BMT. The serum srankl and OPG levels were measured in all patients before and 1, 3 and 12 wks after the BMT. Results: The mean bone losses in the lumbar spine and total proximal femur, which were calculated as the percent change from the baseline to 1 yr, were 5.2 (P<0.01) and 11.6% (P<0.01), respectively. The mean serum ICTP, a bone resorption marker, increased progressively until 3 and 6 months after the BMT, but decreased gradually thereafter, reaching the basal values after 1 year. The serum osteocalcin levels decreased progressively until 3 wks after the BMT, then increased transiently at 3 and 6 Ms, but returned to the basal level by 1 yr. The serum srankl and OPG levels had increased significantly by weeks 1 and 3 compared with the baseline (P<0.01), but decreased at 3 months. The srankl/opg ratio increased progressively until 3 weeks, but then decreased to the basal values. During the observation period, the percent changes from the baseline in the serum RANKL levels and RANKL/OPG ratio showed positive correlations with the percent changes from the baseline serum ICTP levels. Patients with higher RANKL levels and RANKL/OPG ratio during the early post-bmt period lost more bone mass at the lumbar spine. Conclusion: In conclusion, dynamic changes in the srankl and OPG levels were observed during the immediate post-bmt period, which were related to a decrease in bone formation and loss of L-spine BMD during the year following the BMT. Taken together, these results suggest that increased srankl levels and srankl/opg ratios could be involved in a negative balance in bone metabolism following BMT (J Kor Soc Endocrinol 20:40~51, 2005). ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key Words: OPG, srankl, Bone marrow transplantation, Osteoporosis, Bone mineral density 서론골재형성과정은파골세포의활성화로부터시작되며, 조혈모세포로부터파골세포로의분화및활성화는골수기질세포에서분비되는여러가지국소성인자들에의해조절되어진다. 최근종양괴사인자수용체 (tumor necrosis factor receptor) 의일종인 osteoprotegerin (OPG) 과이의 ligand인 receptor activator of NF-κB ligand (RANKL) 이규명되었고이들이파골세포분화과정을조절하는데중요한역할을하는것으로밝혀졌다 [1]. 골수기질세포에서분비되는 OPG는파골세포의증식및활성화를억제하는사이토카인으로 RANKL/ OPG 농도비가골량을적절하게유지하고골재형성의균형을조절하는역할을하며 [2~5] 이균형이깨질경우골다공증및골경화증등과같은대사성골질환이 초래될수있다 [6]. 다양한혈액질환의확립된치료법으로인정되고있는조혈모세포이식술은고형장기이식과는달리환자의연령이젊고진단후비교적짧은기간내에이식을시행한다는특성이있다. 그럼에도불구하고이식초기에골형성의급격한감소와골흡수의증가로인해단기간에골소실이발생하는특성이있으며따라서골대사를연구하는데적합한모델의하나이다. 이식후골소실의중요한원인으로는기저질환의영향, 성선기능저하증, 면역억제제와함께전신방사선조사나고용량의항암치료로인한조골세포및조골전구세포의손상이관련되어있는것으로알려졌다 [7~10]. 이외에도이식후초기에나타나는인터루킨 -6의증가와 FGF-2 및 IGF-1의감소가이식후발생되는골량소실과관련이있음이확인되었다 [11,12]. 그러나이식후골수

3 - 대한내분비학회지 : 제 20 권제 1 호 기질세포에서분비되는 RANKL와 OPG의농도변화와이것이이식후골소실의병인적역할을담당하는지에대한연구는없는실정이다. 본연구에서는조혈모세포이식술을시행한환자를대상으로조혈모세포이식전및이식후의말초혈액으로부터 RANKL와 OPG 및 RANKL/OPG 농도비를측정하여같은시기의혈청에서측정한골교체표지자와의상관관계를관찰하여 RANKL와 OPG가조혈모세포이식술후골대사에미치는영향을알아보고자하였다. 또한이환자들을대상으로이식전및이식 1 년후에골밀도를각각측정하여이식후혈청 RA- NKL와 OPG의농도변화가이식후 1년동안의골소실에미치는영향을알아보고자하였다. 대상및방법 1. 대상다양한혈액질환으로동종조혈모세포이식을시행받은 110명의환자를전향적으로연구하였다. 사망, 재발, 전원및검사를거부한환자를제외하고이식전과이식후 1년째의골밀도를측정할수있었던 36명 ( 남자 17명, 여자 19명 ) 을대상으로하였다. 대상군의평균연령은 32.4±1.3세이었으며평균체중과신장은각각 63.4±10.1 kg과 164.8±9.8 cm이었고연구에참여한여자는모두폐경전이었다. 기저혈액질환은각각백혈병 33명, 중증재생불량성빈혈 2명, 골수이형성증후군 1명이었다. 이식전처치로전신방사선조사를시행한환자는 20 명 (56%) 이었으며분할방사선조사방법으로 3~4일간총 1000~1320 cgy를조사하였고, 29명 (80.6%) 은전처치로서이식전고용량의 cyclophosphamide (60 mg/ kg/day) 를 2일에서 4일간투여받았다. 모든환자들에서거부반응및이식편대숙주질환을예방하기위하여골수이식전날 5 mg/kg의 cyclosporine A를주사하였고골수이식당일부터이식후 20일까지 3 mg/kg로주사하다가이후부터는경구로바꾸어 6개월에서 1년간투여하였다. 또한이식편대숙주반응을예방하기위하여 methotrexate를이식후 4일간 ( 제1일, 3일, 6일및 11일 ) 에 10 mg/m 2 / 일의용량으로투여하였다. 대부 분의환자들은혈소판감소로인한출혈을예방하기위하여비정기적으로혈소판을수혈받았으며이때부작용을예방하기위하여부신피질호르몬을투여하였고이식편대숙주질환, BOOP (bronchiolitis obliterans organizing pneumonia), 거대세포바이러스감염증, 주폐포자충폐렴등이동반된경우에는고용량의부신피질호르몬을투여받았다. 모든환자에서이식후생착까지의백혈구감소기간동안 G-CSF 5 μg/kg/ 일을투여하였고말초혈액의절대중성구수치가 1 109/L 이상으로증가하면투여를중단하였다. 이식후 3주에생착여부를확인하기위해실시한골수천자및생검에서대상환자모두생착이성공하였고거부반응이있었던증례는없었다. 2. 방법 36명의환자에서조혈모세포이식전및이식후 1 주, 2주, 3주, 4주, 3개월, 6개월및 1년에각각말초혈액을채취한후혈청을분리하여영하 20 이하에보관한다. 보관된혈청으로부터 RANKL, OPG, osteocalcin, ICTP 및 creatinine 농도를측정하였다. 골형성표지자인 osteocalcin(n-tact R osteo SP, Incstar, USA) 과골흡수표지자인 ICTP (Telopeptide ICTP, Orion Diagnostica, Finland) 는기간별로채혈한후영하 20 이하에서저장보관하였던혈청에서방사면역방법을이용하여측정하였으며, interassay 및 intraassay 변이계수 (coefficients of variation) 는각각 7.7% 및 5.4%, 10.7% 및 3.6% 이었다. 혈청 OPG는 ELISA 방법으로측정하였다. 인체 OPG에대한단클론항체를 96-well plate에결합시키고혈청을분주시켜배양하고이위에 OPG와결합하는 peroxidase가표지된단클론항체와 tetramethylbenzidine (TMB) 기질을분주한다. 450 nm에서흡수되는파장을 microplate reader (Nippon InterMed, Tokyo, Japan) 에서정량측정하였으며 sensitivity는 30 pg/ml 이고 interassay 및 intraassay 변이계수 (coefficients of variation) 는각각 9.0% 및 6.9% 이었다. 혈청 total srankl의측정도 ELISA 방법으로시행하였는데인체 RANKL에대한단클론항체가결합되어있는 96-well plate에혈청과 OPG를함께분주

4 - 태현정외 12 인 : 조혈모세포이식후혈청 RANKL 와 OPG 의농도변화가골대사및골밀도에미치는영향 Bone Mineral Density ( g/cm 2 ) %, P< Lumbar Spine 2-4 BMD Proximal Femur BMD 11.6%, P< Pre-BMT 1 Year F-U Fig. 1. The changes in BMD before and after BMT. The mean bone loss in the lumbar spine and proximal femur calculated as the percent change from the basline to the level at 12 months after BMT was 5.2% (P<0.05) and 11.6% (P<0.01) respectively. 시켜배양하여유리 srankl에 OPG가결합된상태로 plate의항체에결합되도록한다음이위에 OPG 와결합하는 peroxidase가표지된단클론항체와 tetramethylbenzidine (TMB) 기질을분주한후 microplate reader에서정량측정하였다. sensitivity는 1.5 pg/ml 이고 interassay 및 intraassay 변이계수 (coefficients of variation) 는각각 10% 및 3.0% 이었다. 골밀도는이식전및이식 1년후에각각이중에너지 X선흡수계측기인 Lunar Expert (Lunar, Madison, USA) 를이용하여 2번째에서 4번째까지의요추부와근위대퇴골 (total proximal femur) 에서측정하였다. 골밀도측정기의정밀도오차는요추및대퇴골부위에서각각 1% 이었다. 3. 통계학적분석모든자료는평균 ± 표준오차로표시하였고, 통계학적분석은 paired t-test 방법을사용하였으며 p value 가 0.05 미만인경우를통계학적으로유의하다고판정하였다. RANKL와 OPG의변화와골교체표지자및 골밀도변화사이의상관관계를확인하기위해서이변량상관분석을하였다. 모든통계분석은 SPSS for window를이용하여시행하였다. 결과 1. 골밀도의변화대상환자 36명중모두에서조혈모세포이식전과 1 년후의골밀도를측정하였다. 평균요추부골밀도는이식전 1.156±0.031 g/cm 2 에서이식 1년후 1.097± g/cm 2 으로 5.2% 감소하였으며 (P<0.05), 평균근위대퇴골골밀도는 1.077±0.027 g/cm 2 에서 ±0.025 g/cm 2 으로 11.6% 감소하였다 (P<0.01) (Fig. 1). 2. 골교체표지자의변화골흡수표지자인 ICTP는이식후 6개월까지증가하다가이식후 1년에는이식전수준으로회복하였다. 골형성표지자인 osteocalcin은이식후 3주까지감소하다가이후 6개월까지유의하게증가하였으며

5 - 대한내분비학회지 : 제 20 권제 1 호 Osteocalcin Creatinine ICTP Osteocalcin (ng/ml), ICTP (ng/ml) Creatinine (mg/dl) 2 * 2 0 Pre-BMT 1 Week 2 Week 3 Week 4 Week 3 Months 6 Months 12 Months 0 Fig. 2. The changes of serum bone turnover markers, before and after BMT. Data are given as mean value±sem. Immediately after BMT, ICTP was progressively increased, reaching its peak at 6 months. Thereafter it declined to the baseline at 12 months. Osteocalcin was progressively decreased, reaching its nadir at 3 weeks. Thereafter, it recovered back to the baseline level by 12 months. Serum creatinine levels were within the normal range throughout the entire observation period. *, P<0.05;, P<0.01 against the basal value. Table 1. The Correlations Between the Percentage Changes from the Baseline to 1 year in the BMD at the Lumbar Spine and Proximal Femur and the Percentage Changes in OPG srankl(%) OPG(%) srankl/opg(%) 1wk 3wk 3Ms 1wk 3wk 3Ms 1wk 3wk 3Ms L2-4 (%) -0.36* * Femur (%) L2-4 (%): the percentage changes from the baseline to 1 yr in the BMD at the lumbar spine (lumbar vertebrae L2-L4) femur (%): the percentage changes from the baseline to 1 yr in the BMD at the proximal femur. srankl (%): the percentage changes from baseline in the srankl OPG (%): the percentage changes from baseline in the OPG srankl/opg (%): the percentage changes from baseline in the srankl/opg *, P<0.05 이식후 1년에는거의이식전수준으로회복되었다 (Fig. 2). 3. 말초혈액의 RANKL, OPG 및 RANKL/ OPG 의변화 혈청 RANKL 와 OPG 는이식후점점증가하여이 식후 3주에최고치를형성하였고이후감소하였다. 이식후 3개월에혈청 RANKL는거의이식전수준으로회복되었으며혈청 OPG는여전히이식전보다높은수준을유지하였다. 혈청 RANKL/OPG는이식후 3주에최고치를형성하였다 (Fig. 3)

6 - 태현정외 12 인 : 조혈모세포이식후혈청 RANKL 와 OPG 의농도변화가골대사및골밀도에미치는영향 - A B Serum OPG (pg/ml) OPG Serum total srankl (pg/ml) s total srankl 0 Pre-BMT 1 Week 3 Weeks 3 Months 0 Pre-BMT 1 Week 3 Weeks 3 Months C srankl/opg ratio srankl/opg srankl/opg ratio Pre-BMT 1 Week 3 Weeks 3 Months Fig. 3. The changes in the OPG, srankl levels and srankl/opg ratio in the peripheral blood before and after BMT. The data are reported as a mean value±sem. A&B, After BMT, the serum OPG and srankl levels was progressively increased, reaching a peak at 3 week, which declined thereafter. C, The serum srankl/opg ratio was highest at post- BMT 3 weeks., p<0.01 against the basal value. 4. 말초혈액 RANKL, OPG 및 RANKL/ OPG 와골밀도와의관계 이식전및이식후 1주, 3주, 3개월의각시기별로혈청 RANKL, OPG 및 RANKL/OPG의기저치에대한변화율과이식전후요추부및근위대퇴골골밀도변화율간의상관관계를관찰하였다. 이식후 1주에혈청 RANKL 및 RANKL/OPG와요추부골밀도변화 율간에통계학적으로유의한음의상관관계가관찰되었다 (Table 1). 5. 말초혈액 RANKL, OPG 및 RANKL/ OPG 와골교체표지자와의관계 이식전및이식후 1주, 3주, 3개월의각시기별로혈청 RANKL, OPG 및 RANKL/OPG와혈청 osteocalcin 및 ICTP 사이의상관관계를관찰한결과, 이식

7 - 대한내분비학회지 : 제 20 권제 1 호 Table 2. The Correlations Between Serum OPG and Bone Turnover Markers Following BMT. Serum Levels of OPG and srankl were Determined Before BMT, and at 1 and 3 wk and 3 Months after BMT. Correlation Coefficients were Calculated from Matched time point. n=36. OC, Serum Osteocalcin; ICTP, Serum Collagen I Carboxy-Terminal Telopeptide OC ICTP pre 1wk 3wk 3Ms pre 1wk 3wk 3Ms OPG srankl srankl/opg Table 3. The Correlations Between the Percentage Changes in srankl and srankl/opg and the Percentage Changes in ICTP Following BMT. Serum Levels of OPG and srankl were Determined Before BMT, and at 1 and 3 wk and 3 months after BMT. Correlation Coefficients were Calculated from Matched time Point ICTP (%) 1wk 3wk 3Ms srankl (%) * srankl/opg (%) * 0.20 ICTP(%): the percentage changes from baseline in the serum collagen I carboxy-terminal telopeptide. srankl (%): the percentage changes from baseline in the srankl srankl/opg (%): the percentage changes from baseline in the srankl/opg *, P<0.05 Against the Basal Value. 후혈청 OPG와 ICTP사이의양의상관관계가관찰되나통계학적으로유의하지는않았다 (Table 2). 그러나각시기별로혈청 RANKL, OPG 및 RANKL/OPG의기저치에대한변화율과혈청 osteocalcin 및 ICTP의기저치에대한변화율사이의상관관계를관찰한결과 ICTP의변화율에대하여이식후 3주에는 RANKL/ OPG의변화율과, 이식후 3개월에는 RANKL의변화율과통계적으로유의한양의상관관계를관찰할수있었다 (Table 3). 고찰치명적인만성질환의치료방법으로장기이식이시행됨에따라이식후수명은연장되었으나이로인한합병증이문제가되고있는실정이다. 다양한조혈모세포질환의확립된치료로이용되고있는조혈모세포 이식술후에도성선기능저하증, 갑상선기능이상, 뇌하수체기능이상, 당뇨병등과같은내분비학적합병증이발생할수있으며, 골다공증또한이식후흔히발생할수있는합병증이다. 최근저자등은조혈모세포이식후처음 1년동안에급격한골소실이유발되어 5~10% 의척추및대퇴부골밀도감소가발생한다고보고한바있으며 [12] Canastaneda 등도골수이식후평균 33.6개월이경과된환자들의 33% 에서골감소증과 18% 에서골다공증을관찰할수있었다고보고하였다 [13]. 조혈모세포이식후발생하는골소실에는다양한원인요소가관여하는데환자의기저질환자체의영향, 성선기능저하증, 이식편대숙주질환의예방및치료를위해사용하는스테로이드나 cyclosporine 등의면역억제제의사용이중요한원인으로알려져있으며 [7,8]. 이외에도저자들은이식후전신방사선조사및고용량

8 - 태현정외 12 인 : 조혈모세포이식후혈청 RANKL 와 OPG 의농도변화가골대사및골밀도에미치는영향 - 의화학요법에의해골수기질세포및조골세포가손상을받아골형성이감소하고 [9,10] 이식후인터루킨-6 및종양괴사인자-α 와같은사이토카인의증가와 FGF-2 와 IGF-I과같은골성장인자의감소가이식후골밀도감소에도영향을미치는것을관찰하였다 [11,12]. 신장이나심장과같은고형장기이식후에도조혈모세포이식후와마찬가지로이식초기에급격한골밀도감소가나타나며이식후사용되는스테로이드와 cyclosporin 등과같은면역억제제가중요한원인으로알려져있다 [14,15]. 폐경후골다공증및전신적질환과관련된골다공증발생에있어서골수기질세포에서분비되는여러가지사이토카인이조혈모세포로부터파골세포로의분화및활성화를조절하여병인적역할을담당한다는사실은이미잘알려져있다. 최근에는 TNF receptor superfamily에속하는 glycoprotein인 osteoprotegerin (OPG) 와 receptor activator of NF-κB ligand (RANKL) 이파골세포의분화과정을조절하는것으로밝혀졌다 [16,17]. RANKL는세포막에위치할뿐만아니라유리형 (soluble form of RANKL, srankl) 으로도존재하며파골세포전구체에존재하는 RANK에결합하여파골세포의형성및활성을증가시킨다. RANKL를투여하면생쥐에서과칼슘혈증및골다공증이유발됨이보고되고있다 [1,18,19]. 이러한 RANKL의골흡수활성은 OPG에의해조절되는데이는 RANKL와결합하여 RANKL와 RANK간의상호작용을방해하는역할을하므로파골세포의형성이억제된다 [20,21]. 기존의동물실험결과를살펴보면 OPG knock-out mice에서극심한골다공증이조기에발현되었고척추골절을포함한다발성골절로인해치명율이증가하였고 [22,23] 4주연령의쥐에일주일동안매일재조합 OPG를피하주사한결과해면골의골량이 3배증가하는것으로관찰되었다 [24]. RANKL와 OPG에대한인체에서의연구는부족한상태이며, 최근정상성인에서혈중 OPG 농도를측정하여골밀도및골대사와의상관성에대해보고된바있으나 [25,26] 이식직후골소실이뚜렷이발생하는조혈모세포이식후의 RA- NKL와 OPG 변화및그임상적의의에대해서는알려진바가없다. 이에저자들은본연구를통하여조혈 모세포이식후 RANKL와 OPG의변화가이식후골밀도변화에미치는영향을알아보고자하였다. 기존의보고에의하면심장이식후 3개월과 6개월에측정한혈청 OPG 수치는이식전에비하여각각 41%, 47% 의감소를보이며이식후혈청 OPG의감소는대퇴경부의골밀도감소와관련성이있음이관찰되었다 [27]. 만성신부전이있는경우혈청 OPG의배설이제대로이루어지지않기때문에정상인에비해혈청 OPG가상승되어있는데신장이식을시행할경우크레아티닌제거율이상승함에따라혈청 OPG의신장을통한배설증가로현저히감소하지만크레아티닌제거율이안정화된이후에도지속적으로혈청 OPG 수치가감소한다고보고된바있다 [28]. 이러한고형장기이식후혈청 OPG의감소는모두이식후사용되었던스테로이드와 cyclosporin 등의면역억제제가원인이라고설명하고있으며이것은스테로이드와 cyclosporin이조골세포에서의 OPG 생성을감소시킨다는실험연구결과와도일치되는것이다 [29~31]. 그러나본연구에서는기존의고형장기이식에서와는달리조혈모세포이식후에혈청 OPG가점점증가하여이식후 3주에최고치를형성하고이후감소하는추세를보이나이식후 3개월에도여전히이식전보다높은수준을유지하는것을관찰할수있었다. 조혈모세포이식후혈청 OPG가상승하는것은그정확한기전을명확히설명하기는어렵다. 본연구에서고형장기이식후혈청 OPG 감소의원인으로알려진스테로이드의효과를살펴보면먼저스테로이드의경우본연구에참여한환자들이복용한스테로이드의양은하루평균 11.1mg으로고형장기이식에서보다훨씬적은양이었으며복용한스테로이드의양과혈청 OPG 수치사이에의유의한상관관계는관찰되지않았다. 이식후혈청 OPG 감소에영향을줄수있는또다른인자인 cyclosporin의경우조혈모세포이식후일률적으로정해진용량이투여되었으므로 cyclosporin이이식후혈청 OPG 수치에미치는영향을감별하기어려웠다. 또한이식전전신방사선조사유무도이식후혈청 OPG 수치에영향을미치지않았다. 혈청 OPG 수치의상승과함께본연구에서는조혈모세포이식후 RANKL와 RANKL/OPG가상승하고이것이이식후

9 - 대한내분비학회지 : 제 20 권제 1 호 골흡수표지자인 ICTP의상승과요추부골밀도의감소와통계학적으로유의한상관관계를나타내는것으로관찰되었고이러한결과를통하여조혈모세포이식후골소실에는기존에알려진고용량의화학요법으로인한골수기질세포의손상이나면역억제제사용외에도이식후증가하는 RANKL가관련이있음을확인할수있었으며폐경후골다공증에서와같이골형성감소와골흡수증가에대한보상기전으로혈청 OPG 가증가하는것처럼 [16] 이식후에도 RANKL의상승에따른골흡수증가에대한보상작용으로이식후 OPG가상승하는것으로추측된다. 본연구에서는이식후혈청 RANKL 수치와 RAN- KL/OPG가근위대퇴골골밀도변화와는유의한상관관계를나타내지않았다. 이는이식후혈청 OPG 수치와 RANKL 수치의변화가부위별골소실에미치는영향이다르기때문일것이라고생각되며이에대한추가연구가더필요하리라사료된다. 또한혈청 OPG 는여러조직에서생성될수있으며 [17] 혈청 RANKL 와 OPG가골수내미세환경에서의수치를반영하는것이아니므로골대사에미치는영향을파악하는데제한점이있다. 향후골수내에서의수치와혈청에서의수치와의상관관계분석등을포함한추가연구가필요하리라사료된다. 앞으로이와같은연구를통하여조혈모세포이식후 RANKL와 OPG가상승하는기전을설명하고나아가이식후골다공증의발생에있어서의 RANKL와 OPG의병인적역할을이해하는데도움이될것으로기대된다. 요약연구배경 : 조혈모세포이식후발생하는골소실에는이식후초기의급격한골흡수증가및골형성감소가관여한다. 이러한골재형성불일치에최근파골세포의분화과정을조절하는사이토카인으로알려진 RANKL와 OPG가미치는영향에대해서는알려진바가없다. 본연구에서는조혈모세포이식전, 후로말초혈액에서 RANKL, OPG 및 RANKL/OPG의변화를알아보고, 이들이조혈모세포이식후의골형성과골흡수에미치는영향및이식후발생되는골량소실과 의연관성을관찰하였다. 방법 : 36명의환자에서조혈모세포이식전및이식후각각말초혈액을채취한후혈청을분리하여 RA- NKL, OPG, osteocalcin, ICTP 및 creatinine 농도를측정하였다. 또한골밀도는이식전및이식 1년후에각각이중에너지 X선흡수계측기를이용하여요추부와근위대퇴골에서측정하였다. 결과 : 이식 1년후평균요추부골밀도는 5.2% 감소하였고평균근위대퇴골골밀도는 11.6% 감소하였다. 골흡수표지자인혈청 ICTP는이식전에비해이식후 6개월까지점차의의있게증가하다가이후감소하였다. 또한골형성표지자인 osteocalcin은이식후 3주까지는점차감소하다가이후증가하여이식후 3 개월및 6개월에기저치보다통계학적으로유의하게증가한후감소하였다. 혈청 RANKL와 OPG는이식후점점증가하여이식후 3주에최고치를형성하였고이후감소하였다. 혈청 RANKL/OPG도이식후 3주에가장높은상승을보였다. 혈청 OPG는골흡수표지자인 ICTP와변화양상이유사하였으나통계학적으로의미있는연관성은관찰할수없었다. 그러나 ICTP 의변화율은이식후 3주에는 RANKL/OPG의변화율과, 이식후 3개월에는 RANKL의변화율과통계적으로유의한양의상관관계를관찰할수있었으며이식후 1주에혈청 RANK 및 RANKL/OPG와요추부골밀도변화율간에통계학적으로유의한음의상관관계가관찰되었다. 결론 : 이식후골형성의저하와골흡수의급격한증가로골소실이발생하게되고이러한골흡수증가와골형성감소에는기존에알려진고용량의화학요법이나면역억제제의사용외에이식후상승하는 RAN- KL가기여하는것을관찰할수있었고 RANKL의상승에의한골소실에대한보상기전으로이식후 OPG 가상승하는것이라추측된다. 참고문헌 1. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T,

10 - 태현정외 12 인 : 조혈모세포이식후혈청 RANKL 와 OPG 의농도변화가골대사및골밀도에미치는영향 - Higashio K, Udagawa N, Takahashi N, Suda T: Osteoclast differentiation factor is a ligand for osteoproteogerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 95: , Tsukii K, Shima N, Mochizuki S, Yamaguchi K, Kinosaki M, Yano K, Shibata O, Udagawa N, Yasuda H, suda T, Higashio K: Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha, 25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Biochem Biophys Res Commun 246: , Takai H, Kanematsu M, Yano K, Tsuda E, Higashio K, Ikeda K, Watanabe K, Yamada Y: Transforming growth factor-beta stimulate the production of osteoprotegerin/osteoclastogenesis inhibitory factor by bone marrow stromal cells. J Biol Chem 273: , Lories RJ, Luyten FP. Osteoprotegerin and osteoprotegerin-ligand balance: a new paradigm in bone metabolism providing new therapeutic targents. Clin Rheumatol 20:3-9, Aubin JE, Bonnelye E: Osteoprotegerin and its ligand: a new paradigm for regulation of osteoclastogenesis and bone resorption. Osteoporos Int 11: , Lazner F, Gowen M, Pavasovic D, Kola I: Osteopetrosis and osteoporosis: two sides of the same coin. Hum Mol Genet 8: , Ebeling PR, Thomas DM, Erbas B, Hopper JL, Szer J, Grigg AP: Mechanisms of bone loss following allogenic and autologous hematopoietic stem cell transplantation. J Bone Miner Res 14: , Weibaecher KN: Mechanisms of osteoporosis after hematopoietic cell transplantation. Biol Blood Marrow Transplant 6: , Banfi A, Podest M, Fazzuoli L, Sertoli MR, Venturini M, Santini G, Cancedda R, Quatro R: High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors. Cancer 92: , Lee WY, Cho SW, Oh ES, Oh KW, Lee JM, Yoon KH, Kang MI, Cha BY, Lee KW, Son HY, Kang SK, Kim CC: The effect of bone marrow transplantation on the osteoclastic differentiation of human bone marrow stromal cells. J Clin Endocrinol Metab 87: , Lee WY, Kang MI, Oh ES, Oh KW, Han JH, Cha BY, Lee KW, Son HY, Kang SK, Kim CC: The role of cytokines in the changes in bone turnover following bone marrow transplantation. Osteoporos Int 13:62-68, Kang MI, Lee WY, Oh KW, Han JH, Song KH, Cha BY, Lee KW, Son HY, Kang SK, Kim CC: The short-term changes of bone mineral metabolism after bone marrow transplantation. Bone 26: , Castaneda S, Carmona L, Carvajal I, Arranz R, Diaz A, Garcia-Vadillo A: Reduction of bone mass in women after bone marrow transplantation. Calcif Tissue Int 60: , Heaf J, Tvedegaard E, Kanstrup IL, Fogh-Andersen N: Bone loss after renal transplantation: role of hyperparathyroidism, acidosis, cyclosporine and systemic disease. Clin Transplant 14: , Shane E, Rivas M, McMahon DJ, Staron RB, Silverberg SJ, Seibel MJ, Mancini D, Michler RE, Aaronson K, Addesso V, Lo SH: Bone loss and turnover after cardiac transplantation. J Clin Endocrinol Metab 82: , Yano K, Tsuda E, Washida N, Kobayashi F, Goto M, Harada A, Ikeda K, Higashio K, Yamada Y: Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in

11 - 대한내분비학회지 : 제 20 권제 1 호 postmenopausal women with osteoporosis. J Bone Miner Res 14: , Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, Kanno T, Murakami A, Tsuda E, Morinaga T, Higashio K: Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 139: , Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ: Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93: , Lee SK, Lorenzo JA: Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology 140: , Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL: The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 15: 2-12, Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocrine Rev 20: , Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, Sato Y, Nakagawa N, Yasuda H, Mochizuki S, Gomibuchi T, Yano K, Shima N, Washida N, Tsuda E, Morinaga T, Higashio K, Ozawa H: Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/ osteoprotegerin. Biochem Biophys Res Commun 247: , Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS: osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12: , Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ, et al: Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89: , Khosla S, Arrighi HM, Melton LJ 3rd, Atkinson EJ, O'Fallon WM, Dunstan C, Riggs BL: Correlates of osteoprotegerin levels in women and men. Osteoporos Int 13: , Khosla S, Atkinson EJ, Dunstan CR, O'Fallon WM: Effect of estrogen versus testosterone on circulating osteoprotegerin and other cytokine levels in normal elderly men. J Clin Endocrinol Metab 87: , Fahrleitner A, Prenner G, Leb G, Tscheliessnigg KH, Piswanger-Solkner C, Obermayer-Pietsch B, Portugaller HR, Berghold A, Dobnig H: Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation. Bone 32:96-106, Sato T, Tominaga Y, Iwasaki Y, Kazama JJ, Shigematsu T, Inagaki H, Watanabe I, Katayama A, Haba T, Uchida K, Fukagawa M: Osteoprotegerin levels before and after renal transplantation. Am

12 - 태현정외 12 인 : 조혈모세포이식후혈청 RANKL 와 OPG 의농도변화가골대사및골밀도에미치는영향 - J Kidney Dis 38(4 Suppl. 1):S175-7, Vidal NO, Brandstrom H, Jonsson KB, Ohlsson C: Osteoprotegerin mrna is expressed in primary human osteoblast-like cells: down-regulation by glucocorticoids. J Endocrinol 159: , 1998 potential mechanism of post-transplant osteoporosis and vascular disease. J Bone Miner Res 14(Supple.1):S176, Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC, Khosla S: Stimulation of 30. Hofbauer LC, Riggs BL, Dunstan CR, O'Brien T, Khosla S: Cyclosporine A and glucocorticoids inhibit osteoprotegerin production in human osteoblastic and coronary artery smooth muscle cells: osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 140: ,

Kaes010.hwp

Kaes010.hwp 갑상선자극호르몬이갑상선암세포의 VEGF, 신생혈관형성, 성장, 침윤및전이에미치는영향 Effects of TSH on the Production of VEGF, Angiogenesis, Growth, Invasion and Metastasis in Thyroid Cancer Cells Euy Young Soh, M.D., Hee Boong Park, M.D.,