Sost haploinsufficiency provokes peracute lethal cardiac tamponade without rescuing the osteopenia in a mouse model of excess glucocorticoids

Javaheri, B; Herbert, E; Hopkinson, M; Al-Jazzar, A; Pitsillides, A A

Abstract

Glucocorticoid-induced secondary osteoporosis is the most predictable side-effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve such deleterious outcome in bone is by antagonizing Wnt/β-catenin signalling. Sclerostin, encoded by Sost gene, is the main negative regulator of the pro-formative and anti-resorptive role of the Wnt signaling pathway in the skeleton. We hypothesized that the partial inactivation of sclerostin function by genetic manipulation will rescue the osteopenia induced by high endogenous glucocorticoid levels. Sost-deficient mice were crossed with an established mouse model of excess glucocorticoids and the effects on bone mass and structure were evaluated. Sost haploinsufficiency did not rescue the low bone mass induced by high glucocorticoids. Intriguingly, the critical manifestation of Sost-deficiency combined with glucocorticoid excess was sporadic, sudden, unprovoked, and non-convulsive death. Detailed histopathological analysis in a wide range of tissues identified peracute haemopericardium and cardiac tamponade to be the cause. These preclinical studies reveal outcomes with direct relevance to ongoing clinical trials exploring the use of anti-sclerostin antibodies as a treatment for osteoporosis. They particularly highlight a potential for increased cardiovascular risk and may inform improved stratification of patients that might otherwise benefit from anti-sclerostin antibody treatment.

Citation

Javaheri, B., Herbert, E., Hopkinson, M., Al-Jazzar, A., & Pitsillides, A. A. (2019). Sost haploinsufficiency provokes peracute lethal cardiac tamponade without rescuing the osteopenia in a mouse model of excess glucocorticoids. American Journal of Pathology, 189(4), 753-761. https://doi.org/10.1016/j.ajpath.2018.12.007

• Journal Article Type: Article
• Acceptance Date: Dec 7, 2018
• Publication Date: Jan 19, 2019
• Deposit Date: Jan 29, 2019
• Publicly Available Date: Jan 30, 2019
• Journal: AMERICAN JOURNAL OF PATHOLOGY
• Print ISSN: 0002-9440
• Electronic ISSN: 1525-2191
• Publisher: American Society for Investigative Pathology (ASIP)
• Peer Reviewed: Peer Reviewed
• Volume: 189
• Issue: 4
• Pages: 753-761
• DOI: https://doi.org/10.1016/j.ajpath.2018.12.007
• Public URL: https://rvc-repository.worktribe.com/output/1383876