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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.
Non-Accidental Injury
Published in Amy-lee Shirodkar, Gwyn Samuel Williams, Bushra Thajudeen, Practical Emergency Ophthalmology Handbook, 2019
Haemorrhagic disease of the newborn, sickle cell retinopathy, ECMO treatment, retinopathy of prematurity, galactosemia, Henoch–Schönlein purpura, thrombocytopaenic purpura, maternal ingestion of cocaine, meningitis, intracranial vascular malformation, optic disc drusen, tuberous sclerosis, xlinked retinoschisis, intraocular surgery, severe hypertension, homocystinuria, glutaric aciduria, osteogenesis imperfecta, osteoporosis-pseudoglioma syndrome, incontinentia pigmenti, central retinal vein occlusion, infections, fibromuscular dysplasia, Terson's syndrome, asphyxia, RetCam screening.
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
Osteoporosis-pseudoglioma syndrome is an autosomal recessive disorder that is characterized by severe bone loss and extreme fragility of bones. Loss of function mutations in the LRP5 gene have been reported to cause the disease.
Associations between WNT signaling pathway-related gene polymorphisms and risks of osteoporosis development in Chinese postmenopausal women: a case–control study
Published in Climacteric, 2022
Z. Yang, J. Liu, J. Fu, S. Li, Z. Chai, Y. Sun
Low-density lipoprotein receptor-related protein 5 (LRP5) is located on chromosome 11q13.4 and encodes a WNT receptor that regulates osteoblastic activity and bone mass [19]. LRP5 is also related to glucose and cholesterol metabolism, and thus LRP5 is involved in the development of metabolic diseases, such as diabetes, obesity and vascular diseases [20]. Moreover, numerous studies have indicated that the LRP5 gene influences BMD and fracture [21]. Mouse models showed that LRP5 regulates bone formation by controlling osteoblast proliferation [22]. In humans, loss of LRP5 expression was linked to osteoporosis-pseudoglioma syndrome (low BMD and skeletal fragility) [23]. However, there were no studies on the association of LRP5 polymorphisms (rs2291467, rs11228240 and rs12272917) with osteoporosis risk among Chinese postmenopausal women.
Clinical characteristics and mutation spectrum in 33 Chinese families with familial exudative vitreoretinopathy
Published in Annals of Medicine, 2022
Jianbo Mao, Yijing Chen, Yuyan Fang, Yirun Shao, Ziyi Xiang, Hanxiao Li, Shixin Zhao, Yiqi Chen, Lijun Shen
The genetic causes of FEVR are numerous. The most common aetiology can be attributed to an autosomal dominant inheritance, but may also include autosomal recessive and X-linked recessive inheritance [2,3]. Currently, 15 genes and one locus are known to be associated with FEVR. Of these, 11 genes, including tetraspanin-12 (TSPAN12), zinc finger protein 408 (ZNF408), catenin alpha 1 (CTNNA1), catenin delta 1 (CTNND 1), atonal homolog 7 (ATOH7), RCC1 and BTB domain-containing protein 1 (RCBTB1), integrin-linked kinase (ILK), jagged canonical Notch ligand 1 (JAG1), discs large MAGUK scaffold protein 1 (DLG1), low-density-lipoprotein receptor-related protein 6 (LRP 6) and exudative vitreoretinopathy 3 (EVR3) on chromosome 11p12-13 [4–14], are non-syndromic. The remaining genes are associated with systemic diseases. The proteins encoded by low-density-lipoprotein receptor-related protein 5 (LRP5) are associated with osteoporosis-pseudoglioma syndrome [15], and the Norrie disease protein (NDP) is associated with Norrie disease [16]. The protein encoded by kinesin family member 11 (KIF11) [17] can cause autosomal dominant microcephaly with or without chorioretinopathy, lymphedema or intellectual disability. Catenin beta 1 (CTNNB1) is also an uncommon cause of microcephaly [18]. Frizzled-4 (FZD4) variants can result in hearing deficits and developmental delays [19]. Current research indicates that only around 40–50% of cases of FEVR harbour identifiable genetic variants [20–22], while the relationship between the genotype and clinical manifestations is complex, which are responsible for the challenges in early clinical diagnosis and effective treatment.
Growth factor signalling in osteoarthritis
Published in Growth Factors, 2018
Canonical Wnt signalling could be regarded as the most important pathway in bone biology if we focus on human genetic studies to identify the pivotal genes in bone diseases. A prominent example is that loss-of-function mutations in LRP5 cause reduced bone mass in patients with the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (Gong et al., 2001). Mechanistic studies confirmed the role of LRP5 as a co-receptor in the canonical Wnt signalling, of which its crucial role in bone formation was substantiated by numerous additional human and mouse genetic studies. Like the TGF-β superfamily and Hh proteins, the members of the Wnt family are also secreted proteins playing fundamental functions in a variety of processes in animal development. The central event in the Wnt signalling regarding its activation or deactivation is the stabilization or degradation of β-catenin, a transcriptional regulator. In the absence of Wnt, β-catenin would undergo phosphorylation by the destruction complex comprised of Axin, APC, and GSK3 and then degradation by the ubiquitin-proteasome system. Upon the physical interaction between Wnt and its receptors Frizzled and LRP5/6, the destruction complex is recruited by the receptors to the cell membrane and the ubiquitination of β-catenin is blocked, resulting in the stabilization and accumulation of β-catenin proteins, which translocate to the nucleus and activate transcription of its target genes (Nusse and Clevers, 2017). It is notable that Wnts also bind to some subfamilies of tyrosine kinase receptors, including those from the related to tyrosine kinase (RYK) and RTK-like orphan receptor (ROR) subfamilies, regulating canonical Wnt signalling and other pathways (Roy et al., 2018). However, their functional roles in OA pathogenesis remain to be identified.