Sclerostin Downregulation Globally by Naturally Occurring Genetic Variants, or Locally in Atherosclerotic Plaques, Does Not Associate With Cardiovascular Events in Humans
| Autor: | Ciara Vangjeli, James R Staley, Peter Hall, Martin Armstrong, Rogely W. Boyce, Alison Wolfreys, Ian D. van Koeverden, Gerard Pasterkamp, Remi Okoye, Gill Holdsworth, James R. Turk |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty GENETICS Endocrinology Diabetes and Metabolism Population Romosozumab Down-Regulation 030209 endocrinology & metabolism Bone resorption 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Bone Density Internal medicine medicine Humans Orthopedics and Sports Medicine PHENOMEWIDE ASSOCIATION STUDY Myocardial infarction education SCLEROSTIN Stroke Aged Bone mineral Aged 80 and over education.field_of_study Alendronate business.industry Fibrous cap Original Articles Middle Aged medicine.disease Plaque Atherosclerotic CARDIOVASCULAR 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry Cardiovascular Diseases Sclerostin Female Original Article business BONE MINERAL DENSITY SOST |
| Zdroj: | Journal of Bone and Mineral Research |
| ISSN: | 1523-4681 |
| Popis: | Inhibition of sclerostin increases bone formation and decreases bone resorption, leading to increased bone mass, bone mineral density, and bone strength and reduced fracture risk. In a clinical study of the sclerostin antibody romosozumab versus alendronate in postmenopausal women (ARCH), an imbalance in adjudicated serious cardiovascular (CV) adverse events driven by an increase in myocardial infarction (MI) and stroke was observed. To explore whether there was a potential mechanistic plausibility that sclerostin expression, or its inhibition, in atherosclerotic (AS) plaques may have contributed to this imbalance, sclerostin was immunostained in human plaques to determine whether it was detected in regions relevant to plaque stability in 94 carotid and 50 femoral AS plaques surgically collected from older female patients (mean age 69.6 ± 10.4 years). Sclerostin staining was absent in most plaques (67%), and when detected, it was of reduced intensity compared with normal aorta and was located in deeper regions of the plaque/wall but was not observed in areas considered relevant to plaque stability (fibrous cap and endothelium). Additionally, genetic variants associated with lifelong reduced sclerostin expression were explored for associations with phenotypes including those related to bone physiology and CV risk factors/events in a population‐based phenomewide association study (PheWAS). Natural genetic modulation of sclerostin by variants with a significant positive effect on bone physiology showed no association with lifetime risk of MI or stroke. These data do not support a causal association between the presence of sclerostin, or its inhibition, in the vasculature and increased risk of serious cardiovascular events. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). |
| Databáze: | OpenAIRE |
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