Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders

Abstract

Sclerostin is a glycoprotein involved in the regulation of bone metabolism, exclusively secreted by osteocytes. It affects the activity of bone morphogenetic proteins (BMPs) and is an inhibitor of the Wnt/β-catenin metabolic pathway in bone cells. Osteocytes reduce the release of sclerostin in response to mechanical stimuli acting on bone, and thus promote the activation of osteogenic pathway Wnt/β-catenin in osteoblasts. This signaling pathway plays a key role in osteogenesis and bone turnover. Loss of sclerostin gene function is related to 3 different craniotubular hyperostosis processes: sclerosteosis, craniodiaphyseal dysplasia, and van Buchem disease. Additionally, experimental and clinical studies suggest that sclerostin may promote vascular calcification. Antibodies directed against sclerostin stimulate bone formation and represent a new therapeutic option in the treatment of diseases with increased bone resorption, such as osteoporosis and inflammatory diseases where there is generalized bone loss, periarticular osteoporosis, and cartilage damage, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and glucocorticoid-induced osteoporosis (GIO). Antibody use has the potential to offer new therapeutic approaches in the therapy of mineral and bone disorders resulting from chronic kidney disease (CKD-MBD) and vascular calcifications.

WISP-2 expression induced by Teriparatide treatment affects in vitro osteoblast differentiation and improves in vivo osteogenesis

“…Of note, recently it has been shown that osteocytes can be considered as a source of anabolic factors such as Wnt1, able to speed up osteoblastogenesis by triggering Wnt signaling in osteoblasts (Joeng et al, 2017). It is also well known that osteocytes are a source of osteoprotegerin, the potent inhibitor of RANKL, that mediates the inhibition of bone resorption, but conversely they are also the producers of Sclerostin, the most important anti-anabolic regulator of bone formation by osteoblasts (Pietrzyk et al, 2017;Tatsumi et al, 2007;Weinstein et al, 2011;Xiong et al, 2014). During the last decade, in order to regulate the process of bone remodeling in osteoporotic patients, PTH (1-34), also known as TPTD, has been used as an anabolic drug (Bellido et al, 2013;Giannotti et al, 2013;Riek and Towler, 2011).…”

Specification of Sprouty2 functions in osteogenesis in in vivo context

“…Modulation of Runx2 expression by SPRY2 was documented also in other system. 14 Regarding osteocytes identified by their typical marker, sclerostin, 16 Sost mRNA was strongly up-regulated in Spry2-/-tibias. Immunolabelling showed only a slight nonsignificant increase of SOST-positive osteocytes in Spry2-/-tibias.…”

Sclerostin is an independent risk factor for all-cause mortality in kidney transplant recipients

“…In addition, very recent research shows that SOST-Fc vaccination might be a therapeutic approach for preventing osteoporosis [ 42 ]. So far, it has not been established how anti-sclerostin antibodies affect vascular calcifications [ 43 ]. These studies will provide first clinical information’s how sclerostin blocking antibodies might affect vascular calcification or vascular stiffness.…”