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Pathogenesis: Molecular mechanisms of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Anastasia E. Markatseli, Theodora E. Markatseli, Alexandros A. Drosos
The genes that encode the Wnt-16 protein (314), Fzd1 receptor (315), APC protein (316), Sfrp1 (317), Dkk2 protein (317), and the main transcription factor involved in the differentiation of osteoblasts RUNX2 (318–322) have also been associated with BMD. Of note, experiments on mice showed that the absence of RUNX2 transcription factor is associated with skeletal aplasia (323). Furthermore, mutations in the SOST gene encoding sclerostin are responsible for sclerosteosis. Of note, sclerosteosis is an autosomal disease characterized by an increase in BMD, which is due to the deficiency of the sclerostin protein (324).
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).
Metabolic and endocrine bone disorders
Published in Ashley W. Blom, David Warwick, Michael R. Whitehouse, Apley and Solomon’s System of Orthopaedics and Trauma, 2017
In terms of the Wnt pathway, activating mutations of the Wnt receptor LRP5 lead to marked elevations in bone mass (Whyte et al., 2004). The Wnt ligand sclerostin, the production of which by osteocytes is suppressed by mechanical strain, is thought to play an important role in regulating bone cell activity in response to skeletal loading. Loss of function mutations in sclerostin lead to sclerosteosis, a rare familial disorder characterized by marked elevations in bone mass, and complications such as cranial nerve palsies arising from bone overgrowth. The sclerostin antibody romosozumab is currently in development as a new anabolic treatment for osteoporosis (McClung et al., 2014).
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.
Monoclonal antibodies for treating osteoporosis
Published in Expert Opinion on Biological Therapy, 2018
Maria Felicia Faienza, Mariangela Chiarito, Gabriele D’amato, Graziana Colaianni, Silvia Colucci, Maria Grano, Giacomina Brunetti
One of the uncertainties of sclerostin inhibition is the development of bone overgrowth and skeletal deformities, as seen in sclerosteosis and van Buchem’s disease, conditions that feature homozygous mutations. Encouragingly, heterozygous subjects with these mutations have modest levels of sclerostin, augmented bone formation, and bone mass but no bone overgrowth [102–104]. In the FRAME study, the occurrence of hyperostosis was similar between the romosozumab treatment group and the placebo group [98].
Recent advances in models for screening potential osteoporosis drugs
Published in Expert Opinion on Drug Discovery, 2018
D. Merlotti, M. Materozzi, T. Picchioni, S. Bianciardi, M. Alessandri, R. Nuti, L. Gennari
Indeed, rather than from classical biochemical assays and in vitro models, the discovery of these drugs directly arose from the study of rare human disorders showing Mendelian inheritance as well as from the respective knock-out or transgenic animal models. For example, since 2001, a series of studies aimed at identifying the genetic causes of rare human disorders of bone metabolism showing Mendelian inheritance led to the discovery of a major pathway regulating bone formation, involving the lipoprotein-receptor-related protein 5 (LRP-5) and the Wnt signaling cascade [63]. In fact, gain of function and loss of function mutations in LRP5 gene were associated with, respectively, the autosomal high bone mass syndrome or the osteoporosis pseudoglioma syndrome [64–66]. Following these reports, it was demonstrated that in osteoblasts, Wnt proteins bind to the LRP5/LRP6 complex promoting intracellular stabilization of β-catenin, which translocates to the nucleus and regulates gene expression of proteins that are important for cell differentiation and bone formation [63]. Of interest, parallel genetic studies revealed the existence of different mutations within the SOST gene, encoding sclerostin (an extracellular inhibitor of Wnt signaling) or downstream the same gene as a cause of Sclerosteosis and van Buchem’s disease, respectively, two rare autosomal-recessive syndromes with endosteal hyperostosis, high bone mass, and absence of skeletal fractures [67–69]. Consistent with this observation, knockout of Sost leads to a progressive high bone mass phenotype in mice, while transgenic mice overexpressing Sost showed a low bone mass phenotype resulting from significantly decreased osteoblast activity and bone formation [63,70]. The lack of any clinical feature other than high bone mass observed in heterozygous carriers of sclerosteosis as well as in heterozygous knockout mice suggested that reduced levels of sclerostin can be associated with better skeletal health without the phenotypic complications of the disease. This, together with the observation that sclerostin is almost exclusively expressed by osteocytes made this extracellular protein an attractive target for the development of compounds with anabolic activity on bone [70]. Thus, two monoclonal humanized antibodies against sclerostin, blomosozumab, and romosozumab were recently developed and tested in different animal models. Interestingly, the preclinical models not only included OVX animals or hindlimb immobilized rats but also different models of secondary osteoporosis, such as type 1 or 2 diabetic mice and mice exposed to high-dose corticosteroids [71]. All these preclinical studies demonstrated that in different conditions of bone fragility, sclerostin antibody administration is able to improve bone formation, bone density, bone volume, trabecular thickness, and finally bone strength. Importantly, the pattern of transient stimulation of bone formation coupled with simultaneous suppression of bone resorption observed with these compounds is unprecedented as a mechanism among therapies for osteoporosis. Only romosozumab has progressed to phase II and phase III studies in humans.