Sclerostin loop3: a potential target for developing a next generation sclerostin inhibitor for bone anabolic therapy with low cardiovascular concern
Refereed conference paper presented and published in conference proceedings

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AbstractSclerostin is an antagonist of bone anabolic Wnt signaling pathway. Antibody against sclerostin for postmenopausal osteoporosis has been approved by US FDA, with a boxed warning for potential cardiovascular risk. Therefore, it is desirable to develop a next generation sclerostin inhibitor with low cardiovascular concern. Sclerostin has a protective role in cardiovascular system by inhibiting the proinflammatory cytokines to prevent aortic aneurysm and atherosclerosis development in ApoE-/- mice induced by angiotensin II (AngII). Sclerostin has three loops within its central region. We found sclerostin regulated skeletal and cardiovascular system via different loops (Fig 1a). Loop2 and/or loop3 played important roles in inhibiting Wnt signaling and osteogenic potential in MC3T3-E1 cells (Fig 1b). Either loop2&3 deficiency by genetic truncation or loop2&3 inhibition by sclerostin antibody could attenuate the suppression effects of sclerostin on the expression of inflammatory cytokines and chemokines in macrophages and VSMCs, whereas loop3 deficiency by genetic truncation maintained the above suppression effects of sclerostin in macrophages and VSMCs with AngII infusion in vitro (Fig 1c&d). Therefore, we hypothesized that specifically targeting sclerostin loop3 could promote bone formation and maintain sclerostin loop3-independent cardiovascular protective effect. We have tailored screened an ssDNA aptamer aptscl56 which selectively targeting human sclerostin loop3 by using full length sclerostin as the positive target, and loop3 deficient sclerostin as the negative target (Fig 2). The aptamer had a high inhibition effect to sclerostin’s antagonistic effect on Wnt signaling in vitro, but had no effect on the expression of inflammatory cytokines and chemokines in macrophages and VSMCs, with AngII infusion in vitro (Fig 1&2). Furthermore, by mutation studies, we found residues R114, Q116, R117, V118, Q119, E126, P128, K132, V133, and R134 on sclerostin loop3 were the functional sites in antagonizing Wnt signaling.Residues D111, R112, Y113, L120, L121 and C122 on loop3, and nucleotides T13C14G15, C23T24T25 and T30G31G32 on the aptamer could be the binding sites between sclerostin and the aptamer. This study could help to understand the functional mechanism of sclerostin and provide a strong basis for the development of the next generation sclerostin inhibitor specifically targeting loop3 to promote bone formation with a low cardiovascular concern.
All Author(s) ListYu YY, Wang LY, Ni SJ, Zhuo ZJ, Chu HY, Zhang N, Li DJ, Liu J, Lyu AP, Zhang BT, Zhang G
Name of ConferenceAnnual Meeting of the American-Society-for-Bone-and Mineral Research (ASBMR) 2020
Start Date of Conference11/09/2020
End Date of Conference15/09/2020
Place of ConferenceVirtual
Country/Region of ConferenceUnited States of America
Volume Number35
Issue NumberSuppl 1
Place of PublicationUSA
Article numberP-657
Pages252 - 252
LanguagesEnglish-United States

Last updated on 2022-15-01 at 00:35