Professor Ma Daqing from the School of Medicine at Imperial College London (Fellow of the European Academy of Clinical Sciences), Professor Zhang Ge from the Law Institute of Translational Medicine of Bone and Joint Diseases at Hong Kong Baptist University, and Professor Lv Aiping from the Institute of Integrated Bioinformatics and Translational Science at Hong Kong Baptist University (Fellow of the European Academy of Sciences) collaborated to conduct a comprehensive genome-wide association analysis (GWAS) of the SOST variants in the expansive U.K. Biobank dataset and found that mutations on sclerostin loop2 were associated with cardiovascular abnormalities.

UK Biobank was a large-scale, long-term biobank project that started in 2006 in UK to study the impact of genetic and environmental factors on disease development. It contained the genetic characteristics and health information of 500,000 participants. Sclerostin acts as an internal antagonist of bone anabolic Wnt signaling pathway and inhibits bone formation. A monoclonal antibody against sclerostin, romosozumab, has been demonstrated to effectively increase bone mineral density, reduce vertebral and nonvertebral fracture risks. However, serious cardiovascular adverse events were reported in the romosozumab group in clinical trials. The US FDA and the European EMA limited the use of romosozumab for the treatment of osteoporosis to one year in clinics. The EMA also strictly limited the use of romosozumab to osteoporotic patients without a history of cardiovascular disease. Sclerostin antibody mainly targeted loop2 and loop3 of sclerostin. In order to learn more about the association between specific domains of sclerostin and cardiovascular risk, researchers from Imperial College London (School of Medicine) and Hong Kong Baptist University collaborated to conduct a GWAS study on the UK Biobank to screen out the potential sites on sclerostin that could be associated with cardiovascular abnormalities. This study discovered that SOST variants in the sclerostin loop2 region were more significantly associated with cardiovascular abnormalities than those in other regions of the SOST gene.

This research also supported the discovery of the joint research team formed by Professor Zhang Ge from the Law Institute of Translational Medicine of Bone and Joint Diseases at Hong Kong Baptist University, Professor Yu Yuanyuan from the International Cooperation Platform for Adapter Translational Medicine and Drug Discovery in the Guangdong-Hong Kong-Macao Greater Bay Area, and Chair Professor Lu Aiping of the Institute of Information Medicine and Translational Science (Fellow of the European Academy of Clinical Sciences). This team found that sclerostin loop2 could participate in the protective effect of sclerostin on the cardiovascular system, and the cardiovascular protective effect of sclerostin was independent of loop3 (Yu Y , et al. Nat Commun 2022; Wang L, et al. Theranostics 2022; Yu S, et al. Acta Pharm Sin B 2022).

The above-mentioned genetic studies of clinical samples and molecular mechanism studies of transgenic animal models could help facilitating the development of a new generation of sclerostin inhibitors for the treatment of osteoporosis with low cardiovascular risk by specifically targeting sclerostin loop3. At the same time, it also indicated new research directions for understanding the molecular mechanism of how sclerostin participated in protecting the cardiovascular system.

Dr. Ma Daqing, MD, is a fellow of the European Academy of Sciences in Clinical Sciences, Macintosh Chair Professor at Imperial College London, the Director of the Anesthesiology Research Center of the Department of Surgery and Oncology at Imperial College Westminster Hospital, the former President of the Society of Chinese Life Scientists in the UK, the Executive Vice Chairman of the Chinese Professors Association, a Qiu Shi Scholar Chair Professor at Zhejiang University, and Kennedy Visiting Professor at Hong Kong Baptist University.

Professor Ma Daqing’s academic contributions include: 1) Taking the lead in studying the protective effects of inert gases (Xenon and argon) on the brain, lungs and kidneys (including kidney transplantation), and maintaining a world-renowned status in this field; 2) Banning the use of Xenon and argon gas in athletes according to Professor Ma’s Xenon The World Anti-Doping Organization (WADA); 3) Discovering that general anesthetics in cancer surgery could be used through hypoxia-inducible factor 1α to regulating cancer cell behavior in the field of oncology or the first time; 4) Studying the mechanism of neurocognitive impairment after surgery in the elderly, elucidating the association between postoperative delirium and cognitive dysfunction and neuroinflammation for the first time.

These achievements have provided irrefutable evidence of improved long-term perioperative patient outcomes and had a profound impact on anesthesia medicine and related clinical medical disciplines worldwide. Professor Ma Daqing has published more than 350 related papers in the field of biomedicine (H index 75 and citation > 19,000), and ranked the 25,386^th among 100,000 scholars in various disciplines in the global scholar database.

References

1.       Yu Y, Wang L, Ni S, Li D, Liu J, Chu HY, Zhang N, Sun M, Li N, Ren Q, Zhuo Z, Zhong C, Xie D, Li Y, Zhang ZK, Zhang H, Li M, Zhang Z, Chen L, Pan X, Xia W, Zhang S, Lu A, Zhang BT, Zhang G. Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation. Nat Commun. 2022 Jul 22;13(1):4241. doi: 10.1038/s41467-022-31997-8. PMID: 35869074; PMCID: PMC9307627.

2.       Wang L, Yu Y, Ni S, Li D, Liu J, Xie D, Chu HY, Ren Q, Zhong C, Zhang N, Li N, Sun M, Zhang ZK, Zhuo Z, Zhang H, Zhang S, Li M, Xia W, Zhang Z, Chen L, Shang P, Pan X, Lu A, Zhang BT, Zhang G. Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice. Theranostics. 2022 Jul 18;12(13):5645-5674. doi: 10.7150/thno.63177. PMID: 35966595; PMCID: PMC9373813.

3.       Yu S, Li D, Zhang N, Ni S, Sun M, Wang L, Xiao H, Liu D, Liu J, Yu Y, Zhang Z, Yeung STY, Zhang S, Lu A, Zhang Z, Zhang B, Zhang G. Drug discovery of sclerostin inhibitors. Acta Pharm Sin B. 2022 May;12(5):2150-2170. doi: 10.1016/j.apsb.2022.01.012. Epub 2022 Jan 21. PMID: 35646527; PMCID: PMC9136615.