Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis

El‐Gazzar, Ahmed; Högler, Wolfgang

doi:10.3390/ijms22020625

Cited by 49 publications

(37 citation statements)

References 130 publications

(73 reference statements)

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“…Trio sequencing, so parents are also sequenced, should be also considered. Conducting this kind of detailed analysis of known OI genes ( El-Gazzar and Hogler, 2021 ) ( https://databases.lovd.nl/shared/genes/COL1A2 ) may well further increase the overall detection rate in subjects with OI. So far, there are 730 pathogenic variants that have been identified in COL1A2 ( https://databases.lovd.nl/shared/variants/COL1A2/unique?search_var_status=%3D%22Marked%22%7C%3D%22Public%22 ).…”

Section: Discussionmentioning

confidence: 99%

“…Approximately 85–90% of OI patients have dominant pathogenic variants in COL1A1 (MIM: 120150 ) and COL1A2 (MIM: 120160 ), which encode the alpha 1 and alpha 2 chains of type I collagen, respectively. To date, mutations in 24 genes have been identified as cause of OI ( El-Gazzar and Hogler, 2021 ). Their encoded gene products exhibit functions in the nucleus, endoplasmic reticulum, Golgi apparatus, cytoskeleton, or in the extracellular matrix.…”

Section: Introductionmentioning

confidence: 99%

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A novel cryptic splice site mutation in COL1A2 as a cause of osteogenesis imperfecta

et al. 2021

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Osteogenesis imperfecta (OI) is an inherited genetic disorder characterized by frequent bone fractures and reduced bone mass. Most cases of OI are caused by dominantly inherited heterozygous mutations in one of the two genes encoding type I collagen, COL1A1 and COL1A2 . Here we describe a five-year-old boy with typical clinical, radiological and bone ultrastructural features of OI type I. Establishing the molecular genetic cause of his condition proved difficult since clinical exome and whole exome analysis was repeatedly reported negative. Finally, manual analysis of exome data revealed a silent COL1A2 variant c.3597 T > A (NM_000089.4), which we demonstrate activates a cryptic splice site. The newly generated splice acceptor in exon 50 is much more accessible than the wild-type splice-site between the junction of exon 49 and 50, and results in an in-frame deletion of 24 amino acids of the C-terminal propeptide. In vitro collagen expression studies confirmed cellular accumulation and decreased COL1A2 secretion to 45%. This is the first report of a cryptic splice site within the coding region of COL1A2. which results in abnormal splicing causing OI. The experience from this case demonstrates that routine diagnostic approaches may miss cryptic splicing mutations in causative genes due to the lack of universally applicable algorithms for splice-site prediction. In exome-negative cases, in-depth analysis of common causative genes should be conducted and trio-exome analysis is recommended.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel cryptic splice site mutation in COL1A2 as a cause of osteogenesis imperfecta

et al. 2021

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“…In most cases, studies on disease mechanisms in vitro and in animal models have indicated defects in collagen secretion and structure, procollagen transport, folding, post-translational modification, processing and crosslinking. By contrast, some forms of OI are associated with impaired mineralization (IFITM5, SERPINF1), or defective osteoblast differentiation and function (SP7, WNT1), rather than a direct defect in type I collagen deposition (13,15).…”

Section: Monogenic Low Bone Mass Disordersmentioning

confidence: 99%

“…For example, non-collagen pathways associated with bone fragility include the osteoblastic WNT signaling pathway (e.g., WNT1, LRP5) which regulates bone formation and the OPG/RANKL system (e.g., TNFRSF11A) which regulates osteoclast activity. Various forms of OI and primary osteoporosis are still incompletely understood; the extremely rare conditions associated with bone fragility continue to hold secrets to our understanding of bone fragility which future research will need to explore (13,15).…”

Section: Monogenic Low Bone Mass Disordersmentioning

confidence: 99%

A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

et al. 2021

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Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.

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“…In addition, osteocytes sense mechanical stimuli through interaction with the surrounding bone matrix, which is also profoundly altered in OI [ 20 , 26 ]. Beyond the collagen abnormalities, non-collagen components of the organic matrix, such as the relative number of proteoglycans, are reduced, while the mineral content of the matrix is increased, which makes the matrix stiffer and more brittle [ 12 , 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Increased Osteocyte Lacunae Density in the Hypermineralized Bone Matrix of Children with Osteogenesis Imperfecta Type I

Mähr

Blouin

Behanová

et al. 2021

IJMS

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Osteocytes are terminally differentiated osteoblasts embedded within the bone matrix and key orchestrators of bone metabolism. However, they are generally not characterized by conventional bone histomorphometry because of their location and the limited resolution of light microscopy. OI is characterized by disturbed bone homeostasis, matrix abnormalities and elevated bone matrix mineralization density. To gain further insights into osteocyte characteristics and bone metabolism in OI, we evaluated 2D osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging in transiliac bone biopsy samples from children with OI type I (n = 19) and age-matched controls (n = 24). The OLS characteristics were related to previously obtained, re-visited histomorphometric parameters. Moreover, we present pediatric bone mineralization density distribution reference data in OI type I (n = 19) and controls (n = 50) obtained with a field emission scanning electron microscope. Compared to controls, OI has highly increased OLS density in cortical and trabecular bone (+50.66%, +61.73%; both p < 0.001), whereas OLS area is slightly decreased in trabecular bone (−10.28%; p = 0.015). Correlation analyses show a low to moderate, positive association of OLS density with surface-based bone formation parameters and negative association with indices of osteoblast function. In conclusion, hyperosteocytosis of the hypermineralized OI bone matrix associates with abnormal bone cell metabolism and might further impact the mechanical competence of the bone tissue.

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Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis

Cited by 49 publications

References 130 publications

A novel cryptic splice site mutation in COL1A2 as a cause of osteogenesis imperfecta

A novel cryptic splice site mutation in COL1A2 as a cause of osteogenesis imperfecta

A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

Increased Osteocyte Lacunae Density in the Hypermineralized Bone Matrix of Children with Osteogenesis Imperfecta Type I

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