Sclerostin, encoded by the human SOST gene on chromosome 17q21.31, is an approximately 24 kDa secreted glycoprotein of the DAN family of BMP antagonists expressed in Homo sapiens. It is produced almost exclusively by mature, mineral-embedded osteocytes within the lacunar-canalicular system of bone, with lower expression in some chondrocytes and osteoclasts. Sclerostin contains a cystine-knot (C-terminal cystine knot-like, CTCK) domain that mediates binding to the extracellular domains of the low-density lipoprotein receptor-related proteins LRP5 and LRP6, the co-receptors of canonical Wnt signaling. By binding LRP5/6, sclerostin prevents formation of the Wnt-Frizzled-LRP5/6 ternary complex, blocking recruitment of Axin to the receptor and stabilizing beta-catenin in the cytosol; this suppresses canonical Wnt/beta-catenin signaling in osteoblast lineage cells, inhibiting osteoblast differentiation, proliferation, and bone matrix production while promoting osteoblast apoptosis. Sclerostin is retained in the bone compartment by binding LRP4 on osteoblast surfaces, and is transported through the canalicular network to bone surfaces. It is down-regulated by mechanical loading, parathyroid hormone (PTH), and estrogen, all of which increase bone formation; loss-of-function SOST mutations cause sclerosteosis or van Buchem disease, characterized by high bone mass. Sclerostin is a secreted protein that localizes to the bone extracellular matrix and to the circulation.