Adipocytic sclerostin loop3-LRP4 interaction required by sclerostin to impair whole-body lipid and glucose metabolism
Abstract
Abstract Sclerostin, which has three loops, inhibits bone formation and impairs whole-body lipid and glucose metabolism. The marketed therapeutic sclerostin antibody for postmenopausal osteoporosis (POP) mainly targeting loop2 promotes bone formation and improves whole-body lipid and glucose metabolism. However, FDA/EMA warns of its cardiovascular risk. We previously demonstrate that sclerostin loop3 contributes to the inhibitory effect of sclerostin on bone formation but not its cardioprotective effect. Here we find elevated serum sclerostin levels in both POP-T2DM patients and newly-diagnosed T2DM patients and further demonstrate that sclerostin loop3 participates in the impairment effect of sclerostin on whole-body lipid and glucose metabolism in vivo. Mechanistically, specific blockade of adipocytic sclerostin loop3-LRP4 interaction attenuates the impairment effect of sclerostin on lipid and glucose metabolism in vitro and in vivo. This study provides an innovative strategy, blocking adipocytic sclerostin loop3-LRP4 interaction, to normalize lipid and glucose metabolism in POP-T2DM patients, in cardiovascular safety.
Article Details
Authors (29)
Hewen Jiang
Xiaohui Tao
Sifan Yu
Yihao Zhang
Yuan Ma
Beijing Advanced Innovation Center for Materials Genome Engineering, Institute for Advanced Materials and Technology
Nanxi Li
Shenghang Wang
Ning Zhang
Xin Yang
Shijian Ding
Chuanxin Zhong
Haitian Li
Zhanghao Li
Xiaoxin Wen
Huarui Zhang
Zefeng Chen
Department of Physics, Key Laboratory of Computational Physical Sciences (Ministry of Education), Institute of Computational Physical Sciences, State Key Laboratory of Surface Physics, Fudan University
Meiheng Sun
Hang Luo
College of Materials Science and Engineering
Meishen Ren
Chongguang Lei
Yuanyuan Yu
Jin Liu
Zongkang Zhang
Aiping Lyu
Hui Sheng
Dijie Li
Luyao Wang
Ge Zhang
Bao-Ting Zhang