A potential next generation Sclerostin inhibitor specifically targets Sclerostin monomer for bone anabolic therapy with low cardiovascular risk to reverse established osteoporosis in ovariectomized rats
Refereed conference paper presented and published in conference proceedings


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摘要Therapeutic antibody against sclerostin for reversing postmenopausal osteoporosis has a safety concern on cardiovascular risk. We found the functional role of sclerostin dimer could not be excluded for cardiovascular system in aortic aneurysm mice (Figure A). Here we identified a promising aptamer aptscl56 which could specifically bined to sclerostin monomer rather than sclerostin dimer (Figure B). Loop3 on sclerostin could be the binding domain for aptscl56 and mechanistically mediate the inhibition potency of aptscl56 to sclerostin’s antagonistic effect on Wnt signaling in vitro (Figure C). In the predicated sclerostin dimer structure, loop3 was buried inside, structurally explaining no binding potential of aptscl56 to sclerostin dimer (Figure C). PEG40k-aptscl56 demonstrated lower cardiovascular risk than therapeutic antibody (Figure D). Furthermore, PEG40k-aptscl56 could promote bone formation, increase bone mass, improve bone microarchitecture integrity and enhance mechanical properties in ovariectomized rats with established osteoporosis (Figure E). Consistent with the in vitro data, the above effects could be completely abolished by exogenously injected loop 3 in the ovariectomized rats (Figure E). This study could facilitate development of the next generation sclerostin inhibitor specifically targeting sclerostin monomer to reverse established osteoporosis, with a low safety concern of cardiovascular risk.
著者Yu Y, Ren Q, Ni S, Liu J, Zhong C, Lu J, Tang Y, Li D, Xie D, Dai R, Zhang H, Dang L, Lyu A, Zhang G, Zhuo Z, Zhang ZK, Zhang BT, Wang L, Li Y, Wong KK, Zhai Z
會議名稱Annual Meeting of the American-Society-for-Bone-and Mineral Research
會議開始日20.09.2019
會議完結日23.09.2019
會議地點Orlando
會議國家/地區美國
會議論文集題名JOURNAL OF BONE AND MINERAL RESEARCH
出版年份2019
月份12
卷號34
期次Suppl 1
頁次264 - 264
國際標準期刊號0884-0431
電子國際標準期刊號1523-4681
語言英式英語

上次更新時間 2020-25-09 於 12:22