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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AbstractTherapeutic 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.
All Author(s) ListYu 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
Name of ConferenceAnnual Meeting of the American-Society-for-Bone-and Mineral Research
Start Date of Conference20/09/2019
End Date of Conference23/09/2019
Place of ConferenceOrlando
Country/Region of ConferenceUnited States of America
Proceedings TitleJOURNAL OF BONE AND MINERAL RESEARCH
Year2019
Month12
Volume Number34
Issue NumberSuppl 1
Pages264 - 264
ISSN0884-0431
eISSN1523-4681
LanguagesEnglish-United Kingdom

Last updated on 2021-16-10 at 23:50