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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 LRP5 gene plays an essential role in the regulation of bone mass. The pathogenetic mutations in the LRP5 gene have been associated with a broad range of skeletal disorders, since their effect on osteoblasts results in an increase or a decrease in bone mass, while the activity of osteoclasts remains unchanged (234,248,298,299). Point mutations in the LRP5 gene have been observed in patients with sclerosing bone dysplasias, such as autosomal dominant osteosclerosis, intraosseous hyperostosis, van Buchem disease, and osteopetrosis type I (300,301). Activating mutations of the LRP5 gene cause the high bone mass syndrome (259,288), whereas inactivating mutations in the same gene lead to the appearance of the rare osteoporosis-pseudoglioma syndrome, which is characterized by skeletal deformities and osteoporotic fractures in childhood as well as by blindness (234). Similarly, transgenic mice expressing a mutated LRP5 gene had an increased BMD (302), while mice with inactivating mutations of the LRP5 gene or lack of LRP5 protein developed a low bone mass phenotype (248,303,304). These data show that the canonical Wnt signaling pathway through LRP5 protein plays an important role in the achievement of peak bone mass.
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.