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Current and emerging pharmacological agents in the treatment of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
James X. Liu, Thomas A. Einhorn
Two well-studied rare autosomal recessive sclerosing bone disorders that are characterized by abnormally high bone mass are sclerosteosis and van Buchem disease. Both diseases have the common etiology of deficient SOST gene function, which leads to impaired synthesis of the secreted glycoprotein sclerostin. Sclerostin has two primary functions that ultimately lead to catabolic effects in bone: it binds to the first propeller of LRP5/6 receptor and directly antagonizes the Wnt/β-catenin pathway in osteoblasts, and also acts on neighboring osteocytes to increase the RANKL expression and the RANKL/osteoprotegerin ratio, thus stimulating osteoclastic bone resorption (23). As a result, patients with sclerostin deficiency have thickened skulls, facial and jawbone enlargement, mandibular prognathism, and frontal bone prominence (24).
Disorders of bone and connective tissue
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
A number of conditions are characterised by increased bone density, including pycnodysostosis, sclerosteosis and van Buchem disease, but true osteopetrosis exists in two principal forms, albeit with heterogeneity: A mild form, often asymptomatic, following autosomal dominant inheritance.A severe childhood form with bone marrow involvement, which is autosomal recessive. A number of loci can be involved.
Precision medicine in osteoporosis and bone diseases
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Fatmanur Hacievliyagil Kazanci, Fatih Kazanci, M. Ramazan Yigitoglu, Mehmet Gunduz
Sclerosteosis occurs due to loss of function mutations in the SOST gene, encoding for sclerostin, an inhibitor of WNT/β-catenin signaling (van Lierop et al., 2011). Van Buchem disease is another autosomal recessive disorder caused by insufficiency of sclerostin. It is caused by a deletion of an enhancer region downstream of SOST, required for adequate sclerostin expression (van Lierop et al., 2013). Another sclerostin-related disorder is craniodiaphyseal dysplasia. It is caused by mutations impairing sclerostin secretion (Kim et al., 2011). After the discovery of molecular pathways of these diseases, sclerostin gained attention as a target to increase BMD in patients with osteoporosis. A monoclonal antibody targeting serum sclerostin, romosozumab, has been developed for osteoporosis treatment (Makras et al., 2015).
Current and emerging osteoporosis pharmacotherapy for women: state of the art therapies for preventing bone loss
Published in Expert Opinion on Pharmacotherapy, 2019
Andreas Fontalis, Eustathios Kenanidis, Rafail Angelos Kotronias, Afroditi Papachristou, Panagiotis Anagnostis, Michael Potoupnis, Eleftherios Tsiridis
Sclerostin–an osteocyte secreted glycoprotein coded for by the SOST gene [17q12-q21]–is a key regulator of osteoblast differentiation and function [6]. It binds to LRP-5/6 co-receptors preventing interactions between Wnt and its receptor, ultimately, leading to phosphorylation and degradation of ß-catenin [94]. As a result, Wnt target genes are not activated, downregulating the canonical Wnt singling pathway responsible for osteoblast differentiation, proliferation and function [95]. Notably, sclerostin has also been shown to promote osteoclast formation through a RANKL-dependent pathway [96]. From a clinical perspective, a study of patients with sclerostin genetic deficiency (van Buchem disease) found that patients had increased bone mass, strength and reduced fracture rates, corroborating the importance of sclerostin in bone metabolism [97]. Another clinical and radiographical entity, caused by mutations in the SOST gene is sclerosteosis which is differentiated by van Buchem disease, by hand malformations and large stature [97]. The synthesis of molecular and clinical evidence rendered sclerostin blocking with a monoclonal antibody an attractive therapeutic target for osteoporosis.
Role of sclerostin and dkk1 in bone remodeling in type 2 diabetic patients
Published in Endocrine Research, 2018
Na Wang, Peng Xue, Xuelun Wu, Jianxia Ma, Yan Wang, Yukun Li
The importance of Wnt ligands (Wnts) in the regulation of bone metabolism has been well established. This finding was first identified when loss-of-function mutations in low-density lipoprotein receptor protein 5 (LRP5) led to disorders associated with OP, as well as when gain-of-function mutations caused disorders with increased bone mass, like Van Buchem disease.6 Wnts are glycoproteins that bind to cell surface co-receptors on osteoblasts, including LRP5/6. Then, a cascade of events results in intracellular activation and translocation of β-catenin into the cell nucleus, thereby binding with transcriptional factors and leading to upregulation of target gene expression.7 Wnts are regulated by several families of secreted antagonists, such as sclerostin and dkk1. These antagonists seem to be primarily synthesized by osteocytes. In adults, sclerostin is usually expressed in osteocytes and late osteoblasts.8 However, dkk1 is expressed in several other tissues, such as endothelial cells, neural cells and platelets.9,10 At some point, changes in the levels of circulating sclerostin and dkk1 reflect changes of a similar magnitude in bone marrow plasma, which might be recognized as a new marker for diagnosing OP in T2DM patients.10 This finding and the ability to measure the levels of sclerostin and dkk1 in blood have ensured further investigation of their role in the physiological and pathological states of OP in patients with T2DM.