Data availability
Source data are provided with this paper. The raw data for the main text and supplementary information have been made available as downloadable Excel files. Source data are provided with this paper.
References
-
Bernard, D. M. A. et al. Type 2 diabetes and osteosarcopenia: double trouble? A cross-sectional pilot study in Malaysia. J. ASEAN Federation Endocr. Soc. 38, 18–18 (2023).
-
Leidig-Bruckner, G. et al. Prevalence and determinants of osteoporosis in patients with type 1 and type 2 diabetes mellitus. BMC Endocr. Disord. 14, 1–13 (2014).
-
Wen, Y. et al. Correlation of osteoporosis in patients with newly diagnosed type 2 diabetes: a retrospective study in Chinese population. Front. Endocrinol. 12, 531904 (2021).
-
Li, J., Ren, Y., Li, S. & Li, J. Relationship between sclerostin (SOST) expression and genetic loci rs851056, rs1230399 polymorphisms and bone mineral density in postmenopausal women with type 2 diabetes in Xinjiang. Diab. Metab. Syndr. Obes. 14, 4443–4450 (2021).
-
Shah, A. D., Shoback, D. & Lewiecki, E. M. Sclerostin inhibition: a novel therapeutic approach in the treatment of osteoporosis. Int. J. Women’s. Health 7, 565–580 (2015).
-
Holdsworth, G., Roberts, S. J. & Ke, H. Z. Novel actions of sclerostin on bone. J. Mol. Endocrinol. 62, R167–R185 (2019).
-
Krause, C. et al. Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways. J. Biol. Chem. 285, 41614–41626 (2010).
-
Krishna, S. M. et al. Wnt signaling pathway inhibitor sclerostin inhibits angiotensin II-induced aortic aneurysm and atherosclerosis. Arterioscler Thromb. Vasc. Biol. 37, 553 (2017).
-
Bovijn, J. et al. Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics. Sci. Transl. Med. 12, eaay6570 (2020).
-
Kim, S. P. et al. Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc. Natl. Acad. Sci. USA 114, E11238–E11247 (2017).
-
Jiang, H. et al. The role of sclerostin in lipid and glucose metabolism disorders. Biochem. Pharmacol. 215, 115694 (2023).
-
Veverka, V. et al. Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation. J. Biol. Chem. 284, 10890–10900 (2009).
-
Cosman, F. et al. Romosozumab treatment in postmenopausal women with osteoporosis. N. Engl. J. Med. 375, 1532–1543 (2016).
-
Tanaka, S. & Matsumoto, T. Sclerostin: from bench to bedside. J. Bone Min. Metab. 39, 332–340 (2021).
-
Veverka, V. et al. Characterization of the structural features and interactions of sclerostin. J. Biol. Chem. 284, 10890–10900 (2009).
-
Food U, Administration D. FDA approves new treatment for osteoporosis in postmenopausal women at high risk of fracture. News Release 9, (2019).
-
Huang, J. et al. SOST/Sclerostin impairs the osteogenesis and angiogesis in glucocorticoid-associated osteonecrosis of femoral head. Mol. Med. 30, 167 (2024).
-
Golledge, J. & Thanigaimani, S. Role of sclerostin in cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 42, e187–e202 (2022).
-
Yu, Y. Y. et al. Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation. Nat. Commun. 13, 4241 (2022).
-
Wang, L. Y. et al. Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice. Theranostics 12, 5645–5674 (2022).
-
Yu, S. et al. Discovery of the small molecular inhibitors against sclerostin loop3 as potential anti-osteoporosis agents by structural based virtual screening and molecular design. Eur. J. Med. Chem. 271, 116414 (2024).
-
Zhong, C. et al. Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity. Nat. Commun. 15, 8588 (2024).
-
Zhang, H. et al. A bimolecular modification strategy for developing long-lasting bone anabolic aptamer. Mol. Ther. Nucleic Acids 34, 102073 (2023).
-
Zhang, Y. et al. Strategies for developing long-lasting therapeutic nucleic acid aptamer targeting circulating proteins: the present and the future. Front. Cell Dev. Biol. 10, 1048148 (2022).
-
Karagiannis, T. et al. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia 65, 1251–1261 (2022).
-
Alhindi, Y. & Avery, A. The efficacy and safety of oral semaglutide for glycaemic management in adults with type 2 diabetes compared to subcutaneous semaglutide, placebo, and other GLP-1 RA comparators: a systematic review and network meta-analysis. Contemp. Clin. Trials Commun. 28, 100944 (2022).
-
Wilding, J. P. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989 (2021).
-
Zong, Y. et al. Structural basis of agrin-LRP4-MuSK signaling. Genes Dev. 26, 247–258 (2012).
-
Kim, S. P. et al. Lrp4 expression by adipocytes and osteoblasts differentially impacts sclerostin’s endocrine effects on body composition and glucose metabolism. J. Biol. Chem. 294, 6899–6911 (2019).
-
Katchkovsky, S., Chatterjee, B., Abramovitch-Dahan, C. V., Papo, N. & Levaot, N. Competitive blocking of LRP4-sclerostin binding interface strongly promotes bone anabolic functions. Cell Mol. Life Sci. 79, 113 (2022).
-
García-Martín, A. et al. Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 97, 234–241 (2012).
-
Gaudio, A. et al. Sclerostin levels associated with inhibition of the Wnt/β-catenin signaling and reduced bone turnover in type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 97, 3744–3750 (2012).
-
Huo, X. et al. Risk of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China: a cross-sectional study. Lancet Diab. Endocrinol. 4, 115–124 (2016).
-
Gilbert ZA, Muller A, Leibowitz JA, Kesselman MM. Osteoporosis prevention and treatment: the risk of comorbid cardiovascular events in postmenopausal women. Cureus 14, e24117 (2022).
-
(FDA) USFaDA. Press Announcements: FDA approves new treatment for osteoporosis in postmenopausal women at high risk of fracture. https://www.fda.gov9, (2019).
-
González-Salvatierra, S. et al. Cardioprotective function of sclerostin by reducing calcium deposition, proliferation, and apoptosis in human vascular smooth muscle cells. Cardiovasc Diabetol. 22, 301 (2023).
-
Kadowaki, T. et al. Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an East Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial. Lancet Diab. Endocrinol. 10, 193–206 (2022).
-
Hansen, M. S. et al. Once-weekly semaglutide versus placebo in adults with increased fracture risk: a randomised, double-blinded, two-centre, phase 2 trial. EClinicalMedicine 72, 102624 (2024).
-
Gerbaix, M., Ammann, P. & Ferrari, S. Mechanically driven counter-regulation of cortical bone formation in response to sclerostin-neutralizing antibodies. J. Bone Min. Res. 36, 385–399 (2021).
-
Jiang, R. et al. One-step bioprocess of inulin to product inulo-oligosaccharides using bacillus subtilis secreting an extracellular endo-inulinase. Appl. Biochem. Biotechnol. 187, 116–128 (2019).
-
Lyu, S., Zhang, C., Hou, X. & Wang, A. Tag-based pull-down assay. Methods Mol. Biol. 2400, 105–114 (2022).
-
Ukita, M., Yamaguchi, T., Ohata, N. & Tamura, M. Sclerostin enhances adipocyte differentiation in 3T3-L1 cells. J. Cell Biochem. 117, 1419–1428 (2016).
-
Gubu, A. et al. Unique quinoline orientations shape the modified aptamer to sclerostin for enhanced binding affinity and bone anabolic potential. Mol. Ther. Nucleic Acids 35, 102146 (2024).
-
Parlee, S. D., Lentz, S. I., Mori, H. & MacDougald, O. A. Quantifying size and number of adipocytes in adipose tissue. Methods Enzymol. 537, 93–122 (2014).
-
Lin, S. et al. The effects of atorvastatin on the prevention of osteoporosis and dyslipidemia in the high-fat-fed ovariectomized rats. Calcif. Tissue Int. 96, 541–551 (2015).
Acknowledgements
This study was supported by the direct grant of The Chinese University of Hong Kong (Project No. 4054660), National Key R&D Program of China (No. 2018YFA0800804), Hong Kong General Research Fund from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project Nos. 12100725, 12100921, 12102120, 12102223, 12102524, 14103121, 14103420 and 14109721), Theme-Based Research Scheme from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. T12-201/20-R), Young Scientists Fund of the National Natural Science Foundation of China (Grant No. 82300988), Shenzhen-Hong Kong-Macau Science and Technology Plan Project (Category C) (Grant No. SGDX20230821095359002), Basic and Applied Basic Research Fund from Department of Science and Technology of Guangdong Province (Project No. 2019B1515120089), Inter-institutional Collaborative Research Scheme from Hong Kong Baptist University (Project No. RC-ICRS/19-20/01), University-Industry Collaboration Programme from Innovation and Technology Commissions of the Hong Kong Special Administrative Region, China (Project No. UIM/298), University-Industry Collaboration Programme from Innovation and Technology Commissions of the Hong Kong Special Administrative Region, China (Project No. UIM/328), Key Project of Research and Development Plan of Hunan Province (Project No. 2022WK2010), and Youth’s Project of Guangdong Basic and Applied Basic Research Fund (GDSTC No. 2022A1515110044).
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Communications thanks Antonino Catalano, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Jiang, H., Tao, X., Yu, S. et al. Adipocytic sclerostin loop3-LRP4 interaction required by sclerostin to impair whole-body lipid and glucose metabolism. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68526-w
-
Received:
-
Accepted:
-
Published:
-
DOI: https://doi.org/10.1038/s41467-026-68526-w
