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The FEBS Journal Aug 2019The limited accessibility of bone and its mineralized nature have restricted deep investigation of its biology. Recent breakthroughs in identification of mutant proteins... (Review)
Review
The limited accessibility of bone and its mineralized nature have restricted deep investigation of its biology. Recent breakthroughs in identification of mutant proteins affecting bone tissue homeostasis in rare skeletal diseases have revealed novel pathways involved in skeletal development and maintenance. The characterization of new dominant, recessive and X-linked forms of the rare brittle bone disease osteogenesis imperfecta (OI) and other OI-related bone fragility disorders was a key player in this advance. The development of in vitro models for these diseases along with the generation and characterization of murine and zebrafish models contributed to dissecting previously unknown pathways. Here, we describe the most recent advances in the understanding of processes involved in abnormal bone mineralization, collagen processing and osteoblast function, as illustrated by the characterization of new causative genes for OI and OI-related fragility syndromes. The coordinated role of the integral membrane protein BRIL and of the secreted protein PEDF in modulating bone mineralization as well as the function and cross-talk of the collagen-specific chaperones HSP47 and FKBP65 in collagen processing and secretion are discussed. We address the significance of WNT ligand, the importance of maintaining endoplasmic reticulum membrane potential and of regulating intramembrane proteolysis in osteoblast homeostasis. Moreover, we also examine the relevance of the cytoskeletal protein plastin-3 and of the nucleotidyltransferase FAM46A. Thanks to these advances, new targets for the development of novel therapies for currently incurable rare bone diseases have been and, likely, will be identified, supporting the important role of basic science for translational approaches.
Topics: Animals; Bone Diseases, Metabolic; Calcification, Physiologic; Humans; Mutation; Osteoblasts; Osteogenesis Imperfecta
PubMed: 31220415
DOI: 10.1111/febs.14963 -
Wiener Medizinische Wochenschrift (1946) Jul 2015The main clinical features of osteogenesis imperfecta (OI) are low bone mass and high bone fragility. While the decrease in bone mass is generally regarded as an... (Review)
Review
The main clinical features of osteogenesis imperfecta (OI) are low bone mass and high bone fragility. While the decrease in bone mass is generally regarded as an indicator of disease severity, bone fragility appears as the hallmark of the disorder. Bone has a multiscale hierarchical structural organization and is optimized to resist to fractures. In OI, modifications at the molecular level affect the total mechanical integrity of the bone. A specific characteristic in OI is that the bone matrix is abnormally high mineralized independently of the underlying mutation or clinical severity. The increased matrix mineralization affects bone material quality, leading to increased stiffness and brittleness and making bone prone to fractures. The purpose of this review is to give further insights on bone matrix mineralization in OI and to discuss advantages and pitfalls of invasive and noninvasive imaging techniques.
Topics: Absorptiometry, Photon; Adolescent; Biopsy; Bone Density; Bone Matrix; Child; Diagnostic Imaging; Fractures, Spontaneous; Humans; Osteogenesis Imperfecta; Risk Factors; Tomography, X-Ray Computed
PubMed: 26208477
DOI: 10.1007/s10354-015-0369-2 -
Wiener Medizinische Wochenschrift (1946) Jul 2015
Topics: Child; Child, Preschool; Comorbidity; Female; Genes, Dominant; Genes, Recessive; Genotype; Humans; Infant; Infant, Newborn; Osteogenesis Imperfecta; Pregnancy; Rare Diseases; Translational Research, Biomedical
PubMed: 26169996
DOI: 10.1007/s10354-015-0377-2 -
Nursing Children and Young People Sep 2016Brittle bone disease is also known as osteogenesis imperfecta, Vrolik syndrome and Lobstein syndrome. The condition is not gender specific and is present in all...
Brittle bone disease is also known as osteogenesis imperfecta, Vrolik syndrome and Lobstein syndrome. The condition is not gender specific and is present in all cultures. As the name of the disease suggests, the bones of people who have it are brittle and prone to fracture.
Topics: Bone Density Conservation Agents; Diphosphonates; Fractures, Bone; Humans; Osteogenesis Imperfecta; Physical Therapy Modalities; Quality of Life
PubMed: 27615580
DOI: 10.7748/ncyp.28.7.17.s18 -
Osteoporosis International : a Journal... Dec 2016Osteogenesis imperfecta (OI) is the most prevalent heritable bone fragility disorder in children. It has been known for three decades that the majority of individuals... (Review)
Review
Osteogenesis imperfecta (OI) is the most prevalent heritable bone fragility disorder in children. It has been known for three decades that the majority of individuals with OI have mutations in COL1A1 or COL1A2, the two genes coding for collagen type I alpha chains, but in the past 10 years defects in at least 17 other genes have been linked to OI. Almost all individuals with a typical OI phenotype have a mutation in one of the currently known genes. Regarding medical treatment, intravenous bisphosphonate therapy is the most widely used medical approach. This has a marked effect on vertebra in growing children and can lead to vertebral reshaping after compression fractures, but there is little effect of bisphosphonate therapy on the development of scoliosis. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. Newer medications with anti-resorptive and bone anabolic action are being investigated in an attempt to improve on the efficacy of bisphosphonates but the safety and efficacy of these new approaches in children with OI is not yet established.
Topics: Adolescent; Bone and Bones; Child; Collagen Type I; Diphosphonates; Humans; Mutation; Osteogenesis Imperfecta; Scoliosis
PubMed: 27492436
DOI: 10.1007/s00198-016-3723-3 -
Pediatric Clinics of North America Dec 2014Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that presents with a wide clinical phenotype spectrum: from perinatal lethality and severe... (Review)
Review
Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that presents with a wide clinical phenotype spectrum: from perinatal lethality and severe deformities to very mild forms without fractures. Most cases of OI are due to autosomal dominant mutations of the type I collagen genes. A multidisciplinary approach with rehabilitation, orthopedic surgery, and consideration of medical therapy with bisphosphonates underpins current management. Greater understanding of the pathogenesis of OI may lead to novel, therapeutic approaches to help improve clinical symptoms of children with OI in the future.
Topics: Child; Diphosphonates; Humans; Orthopedic Procedures; Osteogenesis Imperfecta; Physical Therapy Modalities
PubMed: 25439022
DOI: 10.1016/j.pcl.2014.08.010 -
Clinical Genetics Jan 2021Osteogenesis imperfecta (OI) is a relatively common genetic skeletal disorder with an estimated frequency of 1 in 20 000 worldwide. The manifestations are diverse and... (Review)
Review
Osteogenesis imperfecta (OI) is a relatively common genetic skeletal disorder with an estimated frequency of 1 in 20 000 worldwide. The manifestations are diverse and although individually rare, the several different forms contribute to the production of a significant number of affected individuals with considerable morbidity and mortality. During the last decade, there have been extensive molecular investigations into the etiology of OI and these advances have direct relevance to the medical management of the disorder, and the purpose of this review is to document the history and evolution of the nosology of OI. The current nosology, based on molecular concepts, which are crucial in the identification of genotype-phenotype correlations in persons with OI, is also outlined. The successive revisions of the nosology and classification of OI have highlighted the importance of the nomenclature of the condition in order for it to be recognized by clinicians, scientists and patient advocacy groups. In this way, improved counseling of patients and individualized, tailored therapeutic approaches based on the underlying pathophysiology of the individual's type of OI have been facilitated.
Topics: Bone and Bones; Genetic Association Studies; Humans; Osteogenesis Imperfecta; Phenotype
PubMed: 32901963
DOI: 10.1111/cge.13846 -
Metabolism: Clinical and Experimental Mar 2018Osteogenesis imperfecta (OI) is the most common inherited form of bone fragility and includes a heterogenous group of genetic disorders which most commonly result from... (Review)
Review
Osteogenesis imperfecta (OI) is the most common inherited form of bone fragility and includes a heterogenous group of genetic disorders which most commonly result from defects associated with type 1 collagen. 85%-90% of cases are inherited in an autosomal dominant manner and are caused by mutations in the COL1A1 and COL1A2 genes, leading to quantitative or qualitative defects in type 1 collagen. In the last decade, defects in several other proteins involved in the normal processing of type 1 collagen have been described. Recent advances in genetics have called for reconsideration of the classification of OI, however, most recent classifications align with the classic clinical classification by Sillence. The hallmark of the disease is bone fragility but other tissues are also affected. Intravenous bisphosphonates (BPs) are the most widely used intervention, having significant favorable effects regarding areal bone mineral density (BMD) and vertebral reshaping following fractures in growing children. BPs have a modest effect in long bone fracture incidence, their effects in adults with OI concerns only BMD, while there are reports of subtrochanteric fractures resembling atypical femoral fractures. Other therapies showing promising results include denosumab, teriparatide, sclerostin inhibition, combination therapy with antiresorptive and anabolic drugs and TGF-β inhibition. Gene targeting approaches are under evaluation. More research is needed to delineate the best therapeutic approach in this heterogeneous disease.
Topics: Adult; Bone Density; Child; Humans; Osteogenesis Imperfecta
PubMed: 28625337
DOI: 10.1016/j.metabol.2017.06.001 -
JBJS Reviews Jun 2021Osteogenesis imperfecta (OI) is a rare congenital disorder that affects connective tissue. (Review)
Review
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Osteogenesis imperfecta (OI) is a rare congenital disorder that affects connective tissue.
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Modern medicine has mitigated the mortality that is associated with OI, allowing patients to live a near-normal life span.
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The degenerative process in OI is probably accelerated because of subclinical intra-articular fractures, joint laxity, and distorted femoral and acetabular anatomy.
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Total hip arthroplasty is seldom performed in patients with OI; it is technically difficult due to bone fragility, deformity, soft-tissue alteration, acetabular protrusion, the risk of intraoperative and postoperative fractures, and joint laxity.
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This review highlights that patients with OI need hip arthroplasty procedures at an early age and that early revision surgery can be expected. New-generation uncemented implants may improve implant survivorship.
Topics: Acetabulum; Arthroplasty, Replacement, Hip; Femur; Humans; Osteogenesis Imperfecta; Reoperation
PubMed: 34101698
DOI: 10.2106/JBJS.RVW.20.00171 -
Journal of Bone and Mineral Research :... Apr 2016Osteogenesis imperfecta entrains changes at every level in bone tissue, from the disorganization of the collagen molecules and mineral platelets within and between... (Review)
Review
Osteogenesis imperfecta entrains changes at every level in bone tissue, from the disorganization of the collagen molecules and mineral platelets within and between collagen fibrils to the macroarchitecture of the whole skeleton. Investigations using an array of sophisticated instruments at multiple scale levels have now determined many aspects of the effect of the disease on the material properties of bone tissue. The brittle nature of bone in osteogenesis imperfecta reflects both increased bone mineralization density-the quantity of mineral in relation to the quantity of matrix within a specific bone volume-and altered matrix-matrix and matrix mineral interactions. Contributions to fracture resistance at multiple scale lengths are discussed, comparing normal and brittle bone. Integrating the available information provides both a better understanding of the effect of current approaches to treatment-largely improved architecture and possibly some macroscale toughening-and indicates potential opportunities for alternative strategies that can influence fracture resistance at longer-length scales.
Topics: Bone Density; Fractures, Bone; Humans; Osteogenesis Imperfecta
PubMed: 26987995
DOI: 10.1002/jbmr.2835