SOST
Dan family protein SOST, also called sclerostin, is an osteocyte-expressed negative regulator of bone formation[1]. Mechanistically, SOST binds LRP5/LRP6 and inhibits canonical Wnt/β-catenin signaling, thereby limiting osteoblast differentiation and bone accrual[2][3]. In disease genetics, loss of SOST causes sclerosteosis with progressive skeletal overgrowth, linking SOST deficiency to high bone mass models[4]. Compared with SOSTDC1, SOST acts as a monomeric, weak BMP antagonist, whereas SOSTDC1 forms a stable dimer and inhibits BMP signaling more strongly[5]. For experimental applications, anti-sclerostin antibodies and small-molecule inhibitors provide tools to activate Wnt-related osteogenesis in osteoporosis and bone-regeneration models[6][7].- SOST research should prioritize osteocyte-Wnt signaling, osteoblast differentiation, and measurable bone formation endpoints. - Isoform comparisons should separate SOST from SOSTDC1 when designing BMP versus Wnt pathway studies.
References:
- [1]. van Bezooijen RL, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004 Mar 15;199(6):805-14. [Content Brief]
- [2]. Li X, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005 May 20;280(20):19883-7. [Content Brief]
- [3]. Semënov M, et al. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem. 2005 Jul 22;280(29):26770-5. [Content Brief]
- [4]. Brunkow ME, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001 Mar;68(3):577-89. [Content Brief]
- [5]. Gipson GR, et al. Characterization of the different oligomeric states of the DAN family antagonists SOSTDC1 and SOST. Biochem J. 2020 Sep 18;477(17):3167-3182. [Content Brief]
- [6]. Cosman F, et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med. 2016 Oct 20;375(16):1532-1543. [Content Brief]
- [7]. Sangadala S, et al. Sclerostin small-molecule inhibitors promote osteogenesis by activating canonical Wnt and BMP pathways. Elife. 2023 Aug 10;12:e63402. [Content Brief]
