scholarly journals Osteogenesis Imperfecta: Mechanisms and signaling pathways connecting classical and rare OI types

2021 ◽  
Author(s):  
Milena Jovanovic ◽  
Gali Guterman-Ram ◽  
Joan C Marini
Keyword(s):  
Osteogenesis Imperfecta ◽  
Signaling Pathways ◽  
Type I Collagen ◽  
Cholesterol Metabolism ◽  
Bone Mineralization ◽  
Major Protein ◽  
Type I ◽  
High Bone Mass ◽  
Skeletal Deformity ◽  
Related Disorder

Abstract Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous skeletal dysplasia characterized by bone fragility, growth deficiency and skeletal deformity. Previously known to be caused by defects in type I collagen, the major protein of extracellular matrix, it is now also understood to be a collagen-related disorder caused by defects in collagen folding, post-translational modification and processing, bone mineralization and osteoblast differentiation, with inheritance of OI types spanning autosomal dominant and recessive as well as X-linked recessive. This review provides the latest updates on OI, encompassing both classical OI and rare forms, their mechanism and the signaling pathways involved in their pathophysiology. There is a special emphasis on mutations in type I procollagen C-propeptide structure and processing, the later causing OI with strikingly high bone mass. Types V and VI OI, while notably different, are shown to be interrelated by the IFITM5 p.S40L mutation that reveals the connection between the BRIL and PEDF pathways. The function of Regulated Intramembrane Proteolysis has been extended beyond cholesterol metabolism to bone formation by defects in RIP components S2P and OASIS. Several recently proposed candidate genes for new types of OI are also presented. Discoveries of new OI genes add complexity to already-challenging OI management; current and potential approaches are summarized.

scholarly journals Current approach to diagnosis and treatment of children with osteogenesis imperfecta

2019 ◽  
Vol 7 (2) ◽  
pp. 87-102
Author(s):  
Mikhail E. Burtsev ◽  
Aleksandr V. Frolov ◽  
Aleksei N. Logvinov ◽  
Dmitry O. Ilyin ◽  
Andrey V. Korolev
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Bone Mineralization ◽  
Bone Dysplasia ◽  
Multidisciplinary Care ◽  
Recovery Process ◽  
Long Bone ◽  
Type I ◽  
Mineral Density ◽  
Genetic Classification

Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by bone fragility and long bone deformities. Approximately 85% of OI cases are caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2), which affect the quantity or structure of collagen. The remaining percentage of cases is caused by mutation in the proteins responsible for posttranslational modification, processing and crosslinking of collagen, bone mineralization, and osteoblast differentiation. In the past decade, new recessive, dominant, and X-linked inheritance. As a result, new types of OI were added to the Sillence classification, and a new genetic classification consisting of XVIII types is formed. Treatment of patients with OI is a complex task which requires a multidisciplinary care. Pharmacological treatment is based on bisphosphonate treatment, which increases the bone mineral density. In this article, we will describe other approaches in which the effectiveness is studied. Surgical treatment of the fractures and deformities of the extremities showed a positive effect on the patients’ quality of life, despite existing complications. There are a lot of debates about the choice between telescopic and non-telescopic fixators. Rehabilitation plays huge role in the recovery process after fracture and surgeries. Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by bone fragility and long bone deformities. Approximately 85% of OI cases are caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2), which affect the quantity or structure of collagen. The remaining percentage of cases is caused by mutation in the proteins responsible for posttranslational modification, processing and crosslinking of collagen, bone mineralization, and osteoblast differentiation. In the past decade, new recessive, dominant, and X-linked inheritance. As a result, new types of OI were added to the Sillence classification, and a new genetic classification consisting of XVIII types is formed. Treatment of patients with OI is a complex task which requires a multidisciplinary care. Pharmacological treatment is based on bisphosphonate treatment, which increases the bone mineral density. In this article, we will describe other approaches in which the effectiveness is studied. Surgical treatment of the fractures and deformities of the extremities showed a positive effect on the patients’ quality of life, despite existing complications. There are a lot of debates about the choice between telescopic and non-telescopic fixators. Rehabilitation plays huge role in the recovery process after fracture and surgeries.

scholarly journals Osteogenesis imperfecta: an update on clinical features and therapies

2020 ◽  
Vol 183 (4) ◽  
pp. R95-106 ◽  
Author(s):  
Ronit Marom ◽  
Brien M Rabenhorst ◽  
Roy Morello
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Bone Mineralization ◽  
Cardiovascular Complications ◽  
Bone Fragility ◽  
Type I ◽  
Mineral Density ◽  
Multiple Systems ◽  
Pathogenic Variants ◽  
Genes Encoding

Osteogenesis imperfecta (OI) is an inherited skeletal dysplasia characterized by bone fragility and skeletal deformities. While the majority of cases are associated with pathogenic variants in COL1A1 and COL1A2, the genes encoding type I collagen, up to 25% of cases are associated with other genes that function within the collagen biosynthesis pathway or are involved in osteoblast differentiation and bone mineralization. Clinically, OI is heterogeneous in features and variable in severity. In addition to the skeletal findings, it can affect multiple systems including dental and craniofacial abnormalities, muscle weakness, hearing loss, respiratory and cardiovascular complications. A multi-disciplinary approach to care is recommended to address not only the fractures, reduced mobility, growth and bone pain but also other extra-skeletal manifestations. While bisphosphonates remain the mainstay of treatment in OI, new strategies are being explored, such as sclerostin inhibitory antibodies and TGF beta inhibition, to address not only the low bone mineral density but also the inherent bone fragility. Studies in animal models have expanded the understanding of pathomechanisms of OI and, along with ongoing clinical trials, will allow to develop better therapeutic approaches for these patients.

Hyperactivation of RAP1 and JAK/STAT Signaling Pathways Contributes to Fibrosis during the Formation of Nasal Capsular Contraction

2021 ◽  
pp. 1-12
Author(s):  
Meng Wu ◽  
Ming Li ◽  
Hong-Ju Xie ◽  
Hong-Wei Liu
Keyword(s):  
Signaling Pathways ◽  
Type I Collagen ◽  
Ex Vivo ◽  
Capsular Contracture ◽  
Silicone Implant ◽  
Type I ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Functional Changes ◽  
Stat Signaling

Silicone implant-based augmentation rhinoplasty or mammoplasty induces capsular contracture, which has been acknowledged as a process that develops an abnormal fibrotic capsule associated with the immune response to allogeneic materials. However, the signaling pathways leading to the nasal fibrosis remain poorly investigated. We aimed to explore the molecular mechanism underlying the pathogenesis of nasal capsular contracture, with a specific research interest in the signaling pathways involved in fibrotic development at the advanced stage of contracture. By examining our recently obtained RNA sequencing data and global gene expression profiling between grade II and grade IV nasal capsular tissues, we found that both the RAP1 and JAK/STAT signaling pathways were hyperactive in the contracted capsules. This was verified on quantitative real-time PCR which demonstrated upregulation of most of the representative component signatures in these pathways. Loss-of-function assays through siRNA-mediated Rap1 silencing and/or small molecule-directed inhibition of JAK/STAT pathway in ex vivo primary nasal fibroblasts caused a series of dramatic behavioral and functional changes, including decreased cell viability, increased apoptosis, reduced secretion of proinflammatory cytokines, and synthesis of type I collagen, compared to control cells, and indicating the essential role of the RAP1 and JAK/STAT signaling pathways in nasal capsular fibrosis. Our results sheds light on targeting downstream signaling pathways for the prevention and therapy of silicone implant-induced nasal capsular contracture.

scholarly journals Restoration of Osteogenesis by CRISPR/Cas9 Genome Editing of the Mutated COL1A1 Gene in Osteogenesis Imperfecta

2021 ◽  
Vol 10 (14) ◽  
pp. 3141
Author(s):  
Hyerin Jung ◽  
Yeri Alice Rim ◽  
Narae Park ◽  
Yoojun Nam ◽  
Ji Hyeon Ju
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Disease Modeling ◽  
Bone Fragility ◽  
Osteogenic Potential ◽  
Type I ◽  
Gene Correction ◽  
Col1a1 Gene ◽  
Collagen Formation

Osteogenesis imperfecta (OI) is a genetic disease characterized by bone fragility and repeated fractures. The bone fragility associated with OI is caused by a defect in collagen formation due to mutation of COL1A1 or COL1A2. Current strategies for treating OI are not curative. In this study, we generated induced pluripotent stem cells (iPSCs) from OI patient-derived blood cells harboring a mutation in the COL1A1 gene. Osteoblast (OB) differentiated from OI-iPSCs showed abnormally decreased levels of type I collagen and osteogenic differentiation ability. Gene correction of the COL1A1 gene using CRISPR/Cas9 recovered the decreased type I collagen expression in OBs differentiated from OI-iPSCs. The osteogenic potential of OI-iPSCs was also recovered by the gene correction. This study suggests a new possibility of treatment and in vitro disease modeling using patient-derived iPSCs and gene editing with CRISPR/Cas9.

scholarly journals Intracellular and Extracellular Markers of Lethality in Osteogenesis Imperfecta: A Quantitative Proteomic Approach

2021 ◽  
Vol 22 (1) ◽  
pp. 429
Author(s):  
Luca Bini ◽  
Domitille Schvartz ◽  
Chiara Carnemolla ◽  
Roberta Besio ◽  
Nadia Garibaldi ◽  
...  
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Type I ◽  
Tandem Mass ◽  
Type Ii ◽  
Type Iii ◽  
Bioinformatic Tools ◽  
Proteomic Approach ◽  
Fibrillin 1 ◽  
Heritable Disorder

Osteogenesis imperfecta (OI) is a heritable disorder that mainly affects the skeleton. The inheritance is mostly autosomal dominant and associated to mutations in one of the two genes, COL1A1 and COL1A2, encoding for the type I collagen α chains. According to more than 1500 described mutation sites and to outcome spanning from very mild cases to perinatal-lethality, OI is characterized by a wide genotype/phenotype heterogeneity. In order to identify common affected molecular-pathways and disease biomarkers in OI probands with different mutations and lethal or surviving phenotypes, primary fibroblasts from dominant OI patients, carrying COL1A1 or COL1A2 defects, were investigated by applying a Tandem Mass Tag labeling-Liquid Chromatography-Tandem Mass Spectrometry (TMT LC-MS/MS) proteomics approach and bioinformatic tools for comparative protein-abundance profiling. While no difference in α1 or α2 abundance was detected among lethal (type II) and not-lethal (type III) OI patients, 17 proteins, with key effects on matrix structure and organization, cell signaling, and cell and tissue development and differentiation, were significantly different between type II and type III OI patients. Among them, some non–collagenous extracellular matrix (ECM) proteins (e.g., decorin and fibrillin-1) and proteins modulating cytoskeleton (e.g., nestin and palladin) directly correlate to the severity of the disease. Their defective presence may define proband-failure in balancing aberrances related to mutant collagen.

Type I Collagen Biosynthesis by Skin Fibroblasts from Patients with Idiopathic Juvenile Osteoporosis

1995 ◽  
Vol 89 (1) ◽  
pp. 69-73 ◽  
Author(s):  
Andrew E. Pocock ◽  
Martin J. O. Francis ◽  
Roger Smith
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
The Other ◽  
Type I ◽  
Osteogenesis Imperfecta Type ◽  
Unrelated Control ◽  
Type Iii ◽  
Collagen Peptides ◽  
Idiopathic Juvenile Osteoporosis ◽  
Osteogenesis Imperfecta Type I

1. Skin fibroblast lines were cultured from nine patients who had the features of idiopathic juvenile osteoporosis, six relatives, five unrelated control subjects and three unrelated patients with osteogenesis imperfecta type I. Some patients with idiopathic juvenile osteoporosis were adults whose previous osteoporosis was in remission. Two patients with idiopathic juvenile osteoporosis were siblings and one patient with idiopathic juvenile osteoporosis had a daughter with severe osteogenesis imperfecta (type III). 2. The ratio of type III to type I collagen, synthesized by fibroblasts, was increased in two of the patients with osteogenesis imperfecta type I and in the daughter with osteogenesis imperfecta type III, but was normal in all the other patients with idiopathic juvenile osteoporosis and the other relatives. 3. Radiolabelled collagen was digested by cyanogen bromide and separated on SDS-PAGE. Unreduced collagen peptides migrated normally, except those from both the two siblings with idiopathic juvenile osteoporosis. In these two lines, abnormal migration suggested the presence of collagen I mutations. 4. The secretion of synthesized collagen by these two idiopathic juvenile osteoporosis lines and two others was reduced to only 43–45% as compared with a line from a 13-year-old control subject, which was defined as 100%. The three osteogenesis imperfecta type I lines secreted 18–37%, the other five idiopathic juvenile osteoporosis lines secreted 57–75%, the relatives (including the daughter with severe osteogenesis imperfecta) secreted 49–115% and the controls secreted 69–102%. 5. We conclude that qualitative abnormalities of type I collagen associated with a reduction in total secreted collagen synthesis may occur in a minority of patients with idiopathic juvenile osteoporosis; these patients could represent a subset of patients with this disorder.

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