Icaritin이 C2C12 세포의 뼈모세포분화에 미치는 영향
Effects of icaritin on osteoblastic differentiation of C2C12 cells
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현재 많이 사용되고 있는 골다공증 치료제는 골파괴세포를 억제하여 뼈흡수를 감소시키는 기전을 가진 약물들이다. 이러한 약물은 뼈교체율 (bone turnover)도 감소시켜 뼈흡수 뿐 아니라 뼈형성도 억제하므로 이미 흡수된 뼈를 재생시키는데는 불리하며, 비전형 대퇴골절과 턱뼈괴사 등의 유해작용을 가지고 있다. 이에 뼈형성을 촉진하고 부작용이 적은 골다공증 치료제의 개발이 필요하다. Icaritin는 한의학에서 골다공증 치료제로 사용되어온 삼지구엽초속(Epimedium) 의 주요 성분으로 뼈형성 증진작용이 보고되었다. 본 연구에서는 icaritin이 미분화 전구세포를 뼈모세포로 분화시킬 수 있는지 알아보기 위하여 다분화능 중간엽전구세포인 C2C12 세포를 이용하여 icaritin의 효과를 연구하였다. 본 연구의 결과로 icaritin이 C2C12 세포증식을 증가시키고 뼈모세포 분화지표인 runt-related transcription factor-2 (Runx2), osterix, alkaline phosphatase (ALP), osteocalcin (OCN) 유전자의 발현을 증가시키며 ALP, OCN의 단백질 발현도 증가시켜 미분화 전구세포가 뼈모세포로 분화되는 것을 촉진시킬 수 있음을 알게 되었으며, 또한 뼈모세포에서 발현되는 뼈파괴세포 분화촉진 인자인 receptor activator of nuclear factor ĸB ligand (RANKL)와 뼈파괴세포 분화억제 인자인 osteoprotegerin (OPG) 중 OPG 유전자 발현을 큰 폭으로 증가시켜 뼈파괴세포의 분화를 억제할 수 있음을 알게 되었다. 이 결과들은 icaritin이 뼈모세포의 분화를 촉진하고 뼈모세포에 의한 뼈파괴세포형성을 억제함으로 새로운 뼈형성 촉진 골다공증 치료약물의 후보물질이 될 수 있음을 보여준다.
Abstract
The most current therapies for osteoporosis have focused on inhibiting bone resorption by osteoclasts. To develop the new anabolic agents for treatment of osteoporosis that have fewer risks compared to conventional therapies, we searched the natural products that derived from traditional Asian medicines which have been used for treatment of bone related diseases. Icaritin is a flavonoid glycoside derived from the herb Epimedium which has beneficial effects on bone formation. To determine the mechanism that icaritin promotes osteogenic differentiation, we examined the effects of icaritin on the osteoblasic differentiation of C2C12 cells, multipotent mesenchymal progenitor cells. Icaritin significantly increased C2C12 cell proliferation. mRNA expression of runt-related transcription factor-2 (Runx2), osterix, osteocalcin (OCN), alkaline phosphatase (ALP) after 72 hours culture with icaritin was significantly increased. Icaritin also increased ALP and OCN protein synthesis and ALP activity. In addition, icaritin increased mRNA expression of both the receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG). However, icaritin increased mRNA expression of OPG much more than RANKL and therefore increased the OPG/RANKL ratio. These results suggest that icaritin stimulates the commitment of undifferentiated non-osteogenic cells into osteoblasts. In addition, icaritin may decrease osteoclast formation regulated by osteoblasts through OPG production.
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