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곽한복,Hyun Min Sun,하현일,Jong Ho Lee,김하늬,이장희 한국분자세포생물학회 2008 Molecules and cells Vol.26 No.5
Osteoclasts are multinucleated cells with the unique ability to resorb bone. Elevated activity of these cells under pathologic conditions leads to the progression of bone erosion that occurs in osteoporosis, periodontal disease, and rheumatoid arthritis. Thus, the regulation of osteoclast apoptosis is important for bone homeostasis. In this study, we examined the effects of the Janus tyrosine kinase 2 specific inhibitor AG490 on osteoclast apoptosis. We found that AG490 greatly inhibited osteoclast apoptosis. AG490 stimulated the phosphorylation of Akt and ERK. Adenovirus-mediated expression of dominant negative (DN)-Akt and DN-Ras in osteoclasts inhibited the survival of osteoclasts despite the presence of AG490. Cytochrome c release during osteoclast apoptosis was inhibited by AG490 treatment, but this effect was inhibited in the presence of LY294002 or U0126. AG490 suppressed the pro-apoptotic proteins Bad and Bim, which was inhibited in osteoclasts infected with DN-Akt and DN-Ras adenovirus. In addition, constitutively active MEK and myristoylated-Akt adenovirus suppressed the cleavage of pro-caspase-9 and -3 and inhibited osteoclast apoptosis induced by etoposide. Taken together, our results suggest that AG490 inhibited cytochrome c release into the cytosol at least partly by inhibiting the pro-apoptotic proteins Bad and Bim, which in turn suppressed caspase-9 and -3 activation, thereby inhibiting osteoclast apoptosis.
Tanshinone IIA inhibits osteoclast differentiation through down-regulation of c-Fos and NFATc1
곽한복,양다음,하현일,이종호,김하늬,우은란,이승복,김홍희,이장희 생화학분자생물학회 2006 Experimental and molecular medicine Vol.38 No.3
Bone is a dynamic tissue that is regulated by the activity of bone-resorbing osteoclasts and bone- forming osteoblasts. Excessive osteoclast forma-rheumatoid arthritis. Natural substances may be useful as therapeutic drugs to prevent many di-seases in humans because they avoid the many side effects of treatment with chemical compounds. Here we show that tanshinone IIA isolated from Salvia miltiorrhiza Bunge inhibits the receptor activator of NF-κB ligand (RANKL)-mediated osteoclast differen-tiation of osteoclast precursors. Tanshinone IIA suppressed the expression levels of c-Fos and NFATc1 induced by RANKL. However, retrovirus- mediated overexpression of c-Fos induced the ex-pression of NFATc1 despite the presence of tans-hinone IIA and reversed the inhibitory effect of tanshinone IIA on osteoclast differentiation. Also, NFATc1 retrovirus led to osteoclast diferentiation in the presence of tanshinone IIA. Our results suggest that tanshinone IIA may have a role as a therapeutic drug in the treatment of bone disease such as osteoporosis.
류마티스 관절염 마우스 모델에서 뼈 손상 및 염증에 대한 Sphingosine-1 phosphate의 역할에 관한 연구
곽한복(Han Bok Kwak),권덕수(Deok-Su Kwon),장성조(Sung-Jo Jang),최은영(Eun-Yong Choi),이은경(Eun-Gyeong Lee),박병현(Byoung Hyun Park),김현대(Hyun Dai Kim),서필승(Phil-Seung Seo),김정중(Jeong-Joong Kim),최민규(Min-Kyu Choi),조해중(Hae 대한해부학회 2007 Anatomy & Cell Biology Vol.40 No.4
Sphingosine-1 phosphate (S1P)는 sphingolipid의 대사산물로 생체내에서 세포의 증식, 분화, 이동 및 혈관신생 등 여러 중요한 역할을 수행하고 있다. 그러나 S1P가 이렇게 중요한 역할을 수행하고 있음에도 불구하고 관절염에서의 역할에 대해서는 거의 알려진 바가 없다. 따라서 본 연구는 콜라겐으로 유도된 관절염 모델(collagen induced arthritis, CIA)에서 S1P의 역할을 규명하기 위하여 수행하였다. DBA/1J 쥐의 꼬리에 콜라겐을 피하 주사하여 관절염을 유도하였다. CIA 쥐에서 S1P의 효과를 분석하기 위하여 S1P를 관절염 유도 첫날부터 42일까지 복강에 2일마다 주사하여 관절염이 유발되는 상황을 관찰하였다. 관절염의 유발 정도는 육안으로 평가되었고 관절 염증의 진행정도와 뼈의 손상정도는 관절의 병리조직학적 검사와 CT 및 micro-radiography 등의 방사선적 검사를 통하여 관찰하였다. 또한 관절염의 병리과정에 중요한 역할을 하는 TNF-α, IL-6, RANKL 등 염증유도 및 골 파괴 매개물질들의 발현은 면역조직화학검사를 통하여 분석하였다. DBA/1J 생쥐의 꼬리에 콜라겐을 피하 주사하였을 때 무릎관절과 발목관절에 부종이 발생하면서 관절염이 유도되었다. 반면 S1P를 처리한 군에서는 CIA군에 비해 관절염의 유발 빈도 및 염증을 비롯한 관절의 손상 정도가 현저히 억제되었다. 관절의 조직학적인 소견 및 방사선적 소견에서도 콜라겐에 의한 세포의 침윤, 활막의 비후, 연골과 골의 미란 및 파괴등이 S1P 처리에 의하여 개선되었고 골의 손실도 현저히 억제되었다. 또한 콜라겐에 의하여 류마티스성 관절염에서 중요한 역할을 하는 TNF-α, IL-6, RANKL 등의 염증 매개물질들의 발현이 CIA군에서 증가한 반면 S1P를 처리한 군에서는 억제되었다. 더욱이 S1P는 골수세포가 RANKL에 의하여 파골세포로 분화되는 것을 현저히 억제하였다. 결론적으로 S1P가 CIA의 병리과정에서 발현되는 염증 및 골 파괴 매개 물질의 발현을 억제하여 염증 및 골 손상을 억제하는 것으로 생각되었고, 이는 S1P가 류마티스 관절염의 치료에 고려되어야 할 물질중의 하나임을 제시한다. Sphingosine 1-phosphate (S1P) is a bioactive lipid molecule that mediates cell proliferation, differentiation, migration, and angiogenesis in vivo. However, the roles of S1P on pathogenesis of arthritis have been not completely understood. This study was designed to determine the effects of S1P modulation on collageninduced arthritis (CIA) model. DBA/1J mice were injected with collagen into the tail for induction of CIA model. S1P was administered into the peritoneal cavity every other days from day 1 to day 42 after collagen injection. To determine the degree of damage in CIA, we examined macroscopic findings of CIA. The inflammation and bone destruction of CIA mice were evaluated by histo-patholigy and radiography (CT and microradiography). The expressions of TNF-α, IL-6, and RANKL which have important roles in pathogenesis of rheumatoid arthritis and bone destruction were observed by immuno-histochemical staining. After injection with collagen in the DBA/1J mice, CIA was induced by swelling in the knee and ankle joint. Administration of S1P suppressed damages and incidence of arthritis elicited by collagen. In histologic and radiographic studies, S1P strongly suppressed the infiltration of inflammatory cells, the swelling of synovial membrane, erosion, and the destruction of bone on CIA mice. Injection of S1P resulted in down-regulation of the expression of the pro-inflammatory and bone destruction mediators such as TNF-α, IL-6, and RANKL on CIA mice. Furthermore, S1P suppressed the differentiation of bone marrow cells into osteoclasts by RANKL. In conclusion, this study suggest that S1P has protective effects on inflammation and bone destruction during pathogenesis of CIA, which indicates S1P can be a new possible therapeutic strategy for rheumatoid arthritis
녹용(鹿茸), 홍화자(紅花子) 단일 및 혼합 물 추출물( 抽出物)의 파골세포(破骨細胞) 분화(分化) 억제(抑制)와 골흡수(骨吸收) 억제(抑制) 효과(效果)
안지영,김주호,기지예,곽한복,오재민,김윤경,Ann, Ji-Young,Kim, Ju-Ho,Ki, Ji-Ye,Kwak, Han-Bok,Oh, Jae-Min,Kim, Yun-Kyung 대한한의학방제학회 2010 大韓韓醫學方劑學會誌 Vol.18 No.2
Cervi parvum cornu (Deer Antler) and Carthami tinctorii fructus (Also known as Carthami seed) are widely used for treating osteoporosis and rheumatoid arthritis. In this study, We found out that the water extract of Cervi parvum cornu(WECPC), Carthami tinctorii fructus(WECTF) and their combination have effects of suppressing the RANKL-induced osteoclast differentiation. We assayed mRNA expression levels of NFATc1, c-Fos, TRAP and GAPDHS from bone marrow macrophages(BMMs) by means of RT-PCR. Similarly, the protein expression levels of NFATc1, c-Fos, MAPKs and $\beta$-actin in cell lysates were analyzed by means of Western blotting. then we determined the anti-osteoporotic effects of WECPC, WECTF and their combination using Lipopolysaccharide (LPS)-induced bone-loss mouse. WECPC, WECTF and their combination showed remarkable inhibition on RANKL-treated osteoclast differentiation without cytotoxicity. WECPC suppressed degradation of I-${\kappa}B$. WECPC, WECTF and their combination down-regulated the induction of c-Fos and NFATc1 by RANKL. Lastly, in vivo data showed that WECPC, WECTF and their combination rescued the bone erosion by LPS treatment. Thus, these results demonstrate that WECPC, WECTF and their combination can be efficacious remedies for bone-loss diseases such as osteoporosis and rheumatoid arthritis.
RANKL에 의해 유도되는 뼈파괴세포(Osteoclast) 분화에 미치는 모과의 효과
김광미,이창훈,김윤경,오재민,곽한복,김정중 대한해부학회 2009 Anatomy & Cell Biology Vol.42 No.3
뼈을 흡수하는 뼈파괴세포와 뼈를 형성하는 뼈모세포 사 이의 조화는 뼈 항상성에 중요하다. 특히, 뼈파괴세포 형성 과 활성의 증가는 뼈엉성증, 류마티스 관절염, 치주염과 같 은 뼈 질환을 야기한다. 식물의 천연물질은 새로운 치료제 개발을 위해 많은 관심을 받고 있다. 본 연구의 목적은 뼈파 괴세포의 분화를 억제하는 천연물질의 연구이다. Receptor activator of nuclear factor-κB ligand (RANKL)에 의해서 포 식세포에서 뼈파괴세포로의 분화는 모과 물 추출물의 농도 증감에 따라 억제되었다. 그러나 모과 물 추출물은 대조군 과 비교했을 때 세포독성은 검출되지 않았다. 모과 물 추출 물은 RANKL에 의해 유도되는 p38과 JNK의 인산화를 억 제하였다. RANKL에 의해 유도되는 c-Fos, NFATc1, TRAP, OSCAR mRNA는 모과 물 추출물에 의해 억제되었으며 또 한, c-Fos와 NFATc1 단백질의 발현도 모과 물 추출물에 의 해 억제되었다. 이들의 결과로 모과가 뼈 질환 치료에 유용 한 치료제로 이용될 수 있을 것이라 생각된다. Balance between bone-resorbing osteoclats and bone-forming osteoblasts is important in bone homeostasis. In particular, increased osteoclast formation and activity are responsible for bone diseases such as osteoporosis, rheumatoid arthritis, periodontal disease. Natural metabolites of plants have recently received much attention as lead compounds for the development of novel therapeutic strategy. The purpose of this study was to search the natural products to inhibition osteoclast differentiation. Water extract of papaya significantly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs) in a dose dependent manner. However, water extract of papaya did not affect cytotoxicity when compared with control. Water extract of papaya inhibited the phosphorylation of p38 and JNK induced by RANKL. The mRNA expression of c-Fos, NFATcl, TRAP and OSCAR induced by RANKL was inhibited by water extract of papaya treatment. Also, water extract of papaya suppressed the protein expression of c-Fos and NFATc1 in BMMs treated with RANKL. Taken together, these results suggest that papaya may be a useful drug in the treatment of bone-related disease.
김정영,김정중,김윤경,최민규,오재민,곽한복 대한골대사학회 2012 대한골대사학회지 Vol.19 No.2
Objectives: Osteoporosis is a disease of bones that is thought to result from an imbalance between bone resorption and bone formation. Although osteoporosis itself has no symptoms, osteoporosis caused by osteoclasts leads to an increased risk of fracture. Here we examined the effects of cornus officinalis on receptor activator of nuclear factor-kappaB ligand (RANKL)-mediated osteoclast differentiation. Methods: We evaluated the effects of cornus officinalis on RANKL-induced osteoclast differentiation from bone marrow-derived macrophages (BMMs) and performed a cytotoxicity assay, reverse transcriptase-polymerase chain reaction (RT-PCR), and Western blot analysis. Results: Cornus officinalis significantly inhibits RANKL-mediated osteoclast differentiation in a dose-dependent manner, but without cytotoxicity against BMMs. The mRNA expression of tartrate-resistant acid phosphatase (TRAP),osteoclast-associated receptor (OSCAR), c-Fos, and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) in BMMs treated with RANKL was considerably inhibited by cornus officinalis treatment. Also, cornus officinalis inhibits the protein expression of c-Fos and NFATc1. Cornus officinalis greatly inhibits RANKL-induced phosphorylation of p38 and c-JUN N-terminal kinase (JNK). Also, cornus officinalis significantly suppresses RANKL-induced degradation of I-κB.