S-Space College of Dentistry/School of Dentistry (치과대학/치의학대학원) Dept. of Dental Science(치의과학과) Theses (Ph.D. / Sc.D._치의과학과)
Trapidil promotes osteogenesis by activating the signaling of BMP
뼈형성단백질 신호전달경로 활성화를 통한 트라피딜의 골형성 촉진
- 치의학대학원 치의과학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 치의학대학원 치의과학과, 2018. 2. 이장희.
- however, an imbalance between these processes causes osteopathic diseases, such as osteoporosis. For osteoporosis therapy, anti-osteoclastic drugs are used to attenuate the upregulated osteoclast activity. However, anti-osteoclasts agents cannot restore already destroyed bone. Thus, bone anabolic agents are required. Studies have shown that inhibition of platelet-derived growth factor receptor (PDGFR) signaling promotes osteogenesis in vitro. However, the therapeutic efficacy of inhibiting PDGF signaling in bone regeneration in vivo and the specific mechanisms by which PDGFR signaling inhibits osteogenic differentiation remain unclear. In the present study, the osteogenic effect of PDGFR inhibition was examined using a PDGFR antagonist, trapidil, in vivo and in vitro, and its mechanisms were evaluated. A rat calvarial defect model was analyzed using micro-computed tomography and histology to determine the pro-osteogenic effect of trapidil in vivo. Trapidil greatly promoted bone regeneration of a defected rat calvariae. In addition, primary mouse calvarial osteoblast precursors were cultured in osteogenic differentiation medium containing trapidil to study the mechanisms. Trapidil induced phosphorylation of Smad1/5/9 and mitogen-activated protein kinase (MAPK), enhancing the expression of runt-related transcription factor 2 (Runx2), a crucial transcription factor for osteogenesis. The pro-osteogenic effects of trapidil were inhibited by LDN193189, a specific inhibitor of the bone morphogenetic protein receptor (BMPR), activin receptor-like kinase 2 (ALK2) and ALK3, and by treatment with a BMP antagonist noggin, as well as ALK3 depletion. Moreover, trapidil showed a synergistic effect with human recombinant BMP2 on osteogenic differentiation. In conclusion, our results demonstrate that trapidil induces osteogenesis through activation of BMP signalling, and that the attenuated PDGFR signalling is involved in the bio-reactivity of a type ⅠBMP receptor, ALK3.
Bone is a continuously renewing tissue which its mass is finely balanced by the bone-forming and -resorbing cells, osteoblasts and osteoclasts, respectively