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  • 02월 23일 15시 이후 : 초록수정 불가능, 일정확인 및 검색만 가능

A novel PPARγ agonist KR62980 modulates both resorption and formation of bone while preventing bone loss in vivo mice models

2009년 2월 25일 11시 05분 46초
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목 15시 : 40분
의약화학 - Drug Discovery for Prevention of Aging and Improvement in Quality of Life
저자 및
한국화학연구원 신약플랫폼 기술팀, Korea
The PPARγ nuclear receptor regulates osteoblast-adipocyte fate choice (inducing adipocytic while inhibiting osteoblastic differentiation) We have previously reported that KR62980, a new selective novel peroxisome proliferator-activated receptor g modulator, currently development for management of type 2 diabetes mellitus. In this study, we investigated whether KR62980 exhibits any effects on regulation of bone mass including osteoclastogenesis and osteoblastogenes. KR62980 induced alkaline phosphatase (ALP) activity and increased extracellular matrix calcification in osteoprogenitor calvaria-derived primary cells and MC3T3E1 cells. Real time RT-PCR analysis revealed that KR62980 also increased the mRNA transcripts of specific genes involved in osteoblastic differentiation, including bone sialoprotein (BSP), osteocalcin (OC), alkaline phosphatase, Runx-2, and PPAR1. However, KR62980 did not upregulate PPAR2 and ap2 associated with adipocyte differentiation in primary preosteoblastic cells. Furthermore, using an ex vivo neonatal clvaria implantation system, we showed that KR62980 enhanced the osteogenic activity for new bone formation. In addition, in order to examine if the KR62980 is related to an interference with osteoclast differentiation, we incubated human peripheral blood mononuclear cells (PBMC) with Wyeth 14643, ciprofibrate, gamma-linoleic acid and EPA in addition to osteoclast differentiating factors, RANK-L, MCSF and dexametazone. In addition, KR62980 was related to an interference with osteoclast differentiation. We incubated mouse bone marrow mononuclear cells (BMM) with osteoclast differentiating factors, RANK-L, MCSF and dexametazone. Bone mineral content and density (BMC and BMD, respectively) were measured in femur by X-ray computed microtomography (microCT). KR62980 treatment increased BMC and BMD of femur to a greater extent in ovariectomy (OVX) of mice. Furthermore, when bone marrow cells from each group were used to isolate osteoblast progenitors, KR62980 treated group exhibited the highest level of calcium mineralization, as assessed by Alizarin Red staining, and ALP activity using ALP activity staining kit. Taken together, these results suggest that KR62980 may have potential as a drug candidate for treating bone diseases in vivo and in vitro.