The role of sclerostin in vascular calcification and the calcification paradox

Ectopic vascular calcification involves the deposition of calcium-phosphate crystals in the medial layer of the arterial wall. Although vascular calcification is part of the normal aging process, it is accelerated in patients with chronic kidney disease (CKD), diabetes and other metabolic disorders. In these patient populations, vascular calcification importantly contributes to increased morbidity and mortality. An imbalance in osteochondrogenic signaling and anticalcific events, allows the development of arterial calcification. Since vascular media calcification highly resembles bone development and metabolism, the (canonical) Wnt/-catenin signaling, known to be a crucial regulator of bone turnover, might be involved. Furthermore, ectopic vascular calcification is also frequently accompanied by a reduced bone mineral density and disturbed bone turnover, a phenomenon that is referred to as the calcification paradox. In this thesis, the possible involvement of the Wnt/-catenin signaling was investigated by elucidating the role of sclerostin, a negative regulator of this pathway, during vascular calcification. In CKD patients, both serum and urinary sclerostin concentrations are elevated, which is indicative of increased sclerostin production. In this regard, we found that skeletal sclerostin expression was only moderately correlated with circulating sclerostin levels. Therefore it is possible that extra-osseous-produced sclerostin may contribute to the total serum sclerostin concentration and that sclerostin produced in the vasculature, can spill over into the circulation. This is in line with our observations in warfarin-exposed rats. In these rats, we found increased serum levels of sclerostin along with the local production of sclerostin in the calcified vessels. Since osteocytic sclerostin expression remained unchanged, these increased levels are likely to originate from local production in the calcified vessels. Remarkably, despite normal renal function, a mild decrease in bone and mineralized area was observed in this model. Based on these observations, vascular-derived sclerostin might be involved in the calcification paradox by exerting endocrine effects on the bone compartment. To help elucidate the role of sclerostin during vascular calcification, we investigated calcification development in mice with genetic depletion of sclerostin (Sost-/- mice) and in mice treated with an anti-sclerostin antibody. In both models, absence of (functional) sclerostin led to a significantly higher vascular calcium content, indicating a protective role for sclerostin during vascular calcification development. To conclude, this project not only demonstrated that sclerostin is being produced and secreted by transdifferentiated VSMCs, likely in an attempt to slow down vascular calcification but also that sclerostin seems to function as a messenger in the calcification paradox.

Publication year:2022

Keywords:Doctoral thesis

Accessibility:Open