Abstract
Sclerostin is a well-known inhibitor of bone formation that acts on Wnt/β-catenin signaling. This manuscript considers the possible role of sclerostin in vascular calcification, a process that shares many similarities with physiological bone formation. Rats were exposed to a warfarin-containing diet to induce vascular calcification. Vascular smooth muscle cell transdifferentiation, vascular calcification grade, and bone histomorphometry were examined. The presence and/or production of sclerostin was investigated in serum, aorta, and bone. Calcified human aortas were investigated to substantiate clinical relevance. Warfarin-exposed rats developed vascular calcifications in a time-dependent manner which went along with a progressive increase in serum sclerostin levels. Both osteogenic and adipogenic pathways were upregulated in calcifying vascular smooth muscle cells, as well as sclerostin mRNA and protein levels. Evidence for the local vascular action of sclerostin was found both in human and rat calcified aortas. Warfarin exposure led to a mildly decreased bone and mineralized areas. Osseous sclerostin production and bone turnover did not change significantly. This study showed local production of sclerostin in calcified vessels, which may indicate a negative feedback mechanism to prevent further calcification. Furthermore, increased levels of serum sclerostin, probably originating from excessive local production in calcified vessels, may contribute to the linkage between vascular pathology and impaired bone mineralization.
Highlights
Cardiovascular disease is responsible for a substantial part of mortality among the elderly and patients with diabetes, chronic kidney disease (CKD), hypertension, and osteoporosis
One of the key events during the vascular calcification process is the transdifferentiation of vascular smooth muscle cells (VSMCs), a process that potentially affords the capacity for being exploited as an important therapeutic target [2]
Since VSMCs originate from mesenchymal stem cells, dedifferentiated VSMCs could theoretically transdifferentiate towards adipocytes instead of osteoblasts/chondrocytes
Summary
Cardiovascular disease is responsible for a substantial part of mortality among the elderly and patients with diabetes, chronic kidney disease (CKD), hypertension, and osteoporosis. Sclerostin is a positively charged molecule which is filtered by the negatively charged glomerular membrane [14] Taken together, this allows us to put forward the hypothesis that sclerostin, originating from excessive local production in calcified vessels, may spill over to the serum by which it may prevent further progression of (vascular) calcifications and contribute to the high incidence of low bone turnover in CKD patients [15]. The precise role of sclerostin in VSMC transdifferentiation and the development of vascular calcifications, as well as its potential role in the bone–vascular axis, is poorly understood This issue should be of particular clinical interest given the recent therapeutic introduction of an antisclerostin antibody treatment to stimulate bone formation [16]. In this study, a time-dependent characterization of this model at the level of the vessels and the bone was coupled to an in-depth investigation of sclerostin biology
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