Abstract
Osteogenesis imperfecta (OI) is characterized by low bone mass, poor bone quality and high fracture risk. Standard treatment for OI patients is limited to bisphosphonates, which only incompletely corrects the bone phenotype and has uncertainty for long-term risk of atypical femoral fractures. Therefore, it is desirable to develop an innovative bone anabolic drug for treatment of OI. Sclerostin, which binds to Lrp5 and antagonizes canonical Wnt signaling, is a novel target for bone anabolic therapy for OI. Humanized therapeutic antibody against sclerostin (Scl-Ab) for reversing established postmenopausal osteoporosis could increase cardiovascular risks. Thus, there is also growing a concern that osteogenesis imperfecta patients with underlying cardiovascular diseases may suffer from greater cardiovascular risks after Scl-Ab treatment. So it is necessary to develop the next generation sclerostin inhibitor without cardiovascular risk. Sclerostin is a biomarker of cardiovascular mortality. We found that the functional role of the dimeric form of sclerostin could not be excluded for cardiovascular system in aortic aneurysm mice. Here, we performed SELEX to identify aptamer candidates aptscl which could specifically target sclerostin monomer, but no binding to dimer, and characterized the affinity and inhibition potency to sclerostin. By sclerostin truncation and mutation analysis, loop 3 on sclerostin could be identified as the binding domain for aptscl. By protein-protein docking, the structure of sclerostin dimer was
predicted and loop 3 was buried inside the dimer, structurally explaining no binding potential of aptscl to sclerostin dimer. We performed chemical modifications and PEG40k conjugation to enhance the serum stability and resist renal filtration of the conjugated aptscl in vivo, respectively. In safety evaluations, we developed genetic mice, which were hybridized by ApoE-/- mice and Col1a2+/G610C OI mice, to compare the parameters of cardiovascular risk between PEG40k-aptscl and Scl-Ab groups. Evidenced by the analysis with micro-CT, bone histomorphometry and biomechanical testing, PEG40k-aptscl could promote bone formation, increase bone mass, improve bone microarchitecture integrity and enhance mechanical properties of lumbar vertebrae body in OI mice. Taken together, this study could facilitate development of the next generation sclerostin inhibitor specifically targeting sclerostin monomer for OI treatment, with a low safety concern of cardiovascular risk.
predicted and loop 3 was buried inside the dimer, structurally explaining no binding potential of aptscl to sclerostin dimer. We performed chemical modifications and PEG40k conjugation to enhance the serum stability and resist renal filtration of the conjugated aptscl in vivo, respectively. In safety evaluations, we developed genetic mice, which were hybridized by ApoE-/- mice and Col1a2+/G610C OI mice, to compare the parameters of cardiovascular risk between PEG40k-aptscl and Scl-Ab groups. Evidenced by the analysis with micro-CT, bone histomorphometry and biomechanical testing, PEG40k-aptscl could promote bone formation, increase bone mass, improve bone microarchitecture integrity and enhance mechanical properties of lumbar vertebrae body in OI mice. Taken together, this study could facilitate development of the next generation sclerostin inhibitor specifically targeting sclerostin monomer for OI treatment, with a low safety concern of cardiovascular risk.
Original language | English |
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Pages | 47 |
Number of pages | 1 |
Publication status | Published - Sept 2019 |
Event | 2019 Annual Meeting of the American Society for Bone and Mineral Research, ASBMR 2019 - Orange County Convention Center, Orlando, United States Duration: 20 Sept 2019 → 23 Sept 2019 https://asbmr.onlinelibrary.wiley.com/doi/abs/10.1002/jbmr.3936 (Conference abstracts) https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.3936 (Conference website) |
Conference
Conference | 2019 Annual Meeting of the American Society for Bone and Mineral Research, ASBMR 2019 |
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Country/Territory | United States |
City | Orlando |
Period | 20/09/19 → 23/09/19 |
Internet address |
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