-
Journal of Cardiovascular Development... Aug 2023Organization of extracellular matrix (ECM) components, including collagens, proteoglycans, and elastin, is essential for maintaining the structure and function of heart...
Organization of extracellular matrix (ECM) components, including collagens, proteoglycans, and elastin, is essential for maintaining the structure and function of heart valves throughout life. Mutations in ECM genes cause connective tissue disorders, including Osteogenesis Imperfecta (OI), and progressive debilitating heart valve dysfunction is common in these patients. Despite this, effective treatment options are limited to end-stage interventions. Mice with a homozygous frameshift mutation in serve as a murine model of OI (), and therefore, they were used in this study to examine the pathobiology of aortic valve (AoV) disease in this patient population at structural, functional, and molecular levels. Temporal echocardiography of mice revealed AoV dysfunction by the late stages of disease in 12-month-old mice. However, structural and proteomic changes were apparent much earlier, at 3 months of age, and were associated with disturbances in ECM homeostasis primarily related to collagen and proteoglycan abnormalities and disorganization. Together, findings from this study provide insights into the underpinnings of late onset AoV dysfunction in connective tissue disease patients that can be used for the development of mechanistic-based therapies administered early to halt progression, thereby avoiding late-stage surgical intervention.
PubMed: 37623368
DOI: 10.3390/jcdd10080355 -
Bioengineering (Basel, Switzerland) Nov 2023The mechanical properties of bone tissue are the result of a complex process involving collagen-crystal interactions. The mineral density of the bone tissue is...
The mechanical properties of bone tissue are the result of a complex process involving collagen-crystal interactions. The mineral density of the bone tissue is correlated with bone strength, whereas the characteristics of collagen are often associated with the ductility and toughness of the bone. From a clinical perspective, bone mineral density alone does not satisfactorily explain skeletal fragility. However, reliable in vivo markers of collagen quality that can be easily used in clinical practice are not available. Hence, the objective of the present study is to examine the relationship between skin surface morphology and changes in the mechanical properties of the bone. An experimental study was conducted on healthy children (n = 11), children with osteogenesis imperfecta (n = 13), and women over 60 years of age (n = 22). For each patient, the skin characteristic length (SCL) of the forearm skin surface was measured. The SCL quantifies the geometric patterns formed by wrinkles on the skin's surface, both in terms of size and elongation. The greater the SCL, the more deficient was the organic collagen matrix. In addition, the bone volume fraction and mechanical properties of the explanted femoral head were determined for the elderly female group. The mean SCL values of the healthy children group were significantly lower than those of the elderly women and osteogenesis imperfecta groups. For the aged women group, no significant differences were indicated in the elastic mechanical parameters, whereas bone toughness and ductility decreased significantly as the SCL increased. In conclusion, in bone collagen pathology or bone aging, the SCL is significantly impaired. This in vivo skin surface parameter can be a non-invasive tool to improve the estimation of bone matrix quality and to identify subjects at high risk of bone fracture.
PubMed: 38135929
DOI: 10.3390/bioengineering10121338 -
JBMR Plus Sep 2023The fracture experience of children and adolescents with osteogenesis imperfecta (OI) type 1 is not well described in the literature. We present data on symptomatic long...
The fracture experience of children and adolescents with osteogenesis imperfecta (OI) type 1 is not well described in the literature. We present data on symptomatic long bones and axial skeleton fractures of all patients aged 0 to 18 years with OI type 1 seen at a specialized bone clinic in Western Australia in the period 2008 to 2020 using a retrospective chart review method. The cohort consisted of 44 patients (21 males, 23 females). Median (interquartile range [IQR]) age was 11.3 (6.2 to 17) years, giving a total of 520 patient-years in the study during which 197 fractures were experienced. The mean fracture rate was 379 fractures per 1000 patient-years (95% confidence interval [CI]: 310 to 440); however, the experience for fractures varied from ≤1 fracture in 23% ( = 10) to two to 20 in 77% ( = 34) of the cohort. Twenty-one patients (48.5%) received bisphosphonates during the study period. In logistic regression, age, but not sex or family history of OI, was a significant predictor of fracture risk. The highest total fracture rate was observed in the age group 0 to <3 years at 469 fractures/1000 patient-years, which declined to 140 fractures/1000 patient-years in the age group 15 to 18 years. The lower limbs were the site of 49.7% of all fractures. The highest rate for lower limb fracture was in the age group 0 to <3 years at 331 fractures/1000 patient-years, decreasing to 0 fractures/1000 patient-years in the age group 15 to 18 years. Upper limb fracture rates increased from 100 fractures/1000 patient-years in the 0 to <3 years age group to 307 fractures/1000 patient-years in the 9 to <12 years age group and then declining to 70 fractures/1000 years in the 15 to 18 years age group. In pediatric patients with OI type 1, fracture risk is highest in early life, especially in the lower limbs. Multidisciplinary care of children with OI should have a particular focus on strategies to prevent these fractures. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
PubMed: 37701152
DOI: 10.1002/jbm4.10782 -
Asian Journal of Surgery Aug 2023
Topics: Pregnancy; Humans; Female; Cesarean Section; Osteogenesis Imperfecta; Anesthesia, General
PubMed: 36925426
DOI: 10.1016/j.asjsur.2023.03.020 -
Orphanet Journal of Rare Diseases Apr 2024Blue sclera is a characteristic and common clinical sign of Osteogenesis Imperfecta (OI). However, there is currently no widely accepted, objective method for assessing...
PURPOSE
Blue sclera is a characteristic and common clinical sign of Osteogenesis Imperfecta (OI). However, there is currently no widely accepted, objective method for assessing and grading blue sclera in individuals with OI. To address this medical need, this study is aimed to design and validate a new method called 'BLUES' (BLUe Eye Sclera) to objectively identify and quantify the blue color in the sclera of patients affected by OI.
METHODS
Sixty-two patients affected by OI and 35 healthy controls were enrolled in the present prospective study, for a total of 194 eyes analyzed. In the 'BLUES' procedure, eye images from patients with OI and control subjects were analyzed to assess and grade the blue level of the sclera using Adobe Photoshop Software. The validation process then involved comparing the results obtained with the 'BLUES' procedure to the judgement of experienced ophthalmologists (JEO). A receiver-operating characteristic (ROC) curve analysis was used to examine the overall discriminatory power. The sensitivity and specificity levels and the Cohen's Kappa (K) indexes of 'BLUES' and 'JEO' were estimated versus the standard OI diagnosis. The K indexes of 'BLUES' versus 'JEO' were also evaluated.
RESULTS
The optimal cut-off point of the scleral blue peak was calculated at 17%. Our findings demonstrated a sensitivity of 89% (CI95%: 0.835-0.945) and specificity of 87% (CI95%: 0.791-0.949) for the 'BLUES' procedure with an agreement versus the diagnosis of OI of 0.747. In comparison, the sensitivity and specificity of 'JEO' ranged from 89 to 94% and 77% to 100%, respectively, with an agreement ranging from 0.663 to 0.871 with the diagnosis of OI. The agreement between 'BLUES 'and 'JEO' evaluations ranged from 0.613 to 0.734.
CONCLUSIONS
Our findings demonstrated an 89% sensitivity and an impressive 87% specificity of our method to analyze the blue sclera in OI. The results indicated high agreement with disease diagnosis and were consistent with evaluations by experienced ophthalmologists. The 'BLUES' procedure appears to be a simple, reliable and objective method for effectively identify and quantify the blue color of the sclera in OI.
Topics: Humans; Osteogenesis Imperfecta; Sclera; Female; Male; Prospective Studies; Adolescent; Child; Adult; Young Adult; Child, Preschool; ROC Curve
PubMed: 38678283
DOI: 10.1186/s13023-024-03192-z -
BMC Primary Care Apr 2024Children and adolescents with complex medical issues need home care services; however, few studies have provided insight into the unmet home care needs of the families...
BACKGROUND
Children and adolescents with complex medical issues need home care services; however, few studies have provided insight into the unmet home care needs of the families of patients with osteogenesis imperfecta (OI). In this study, we aimed to assess the home care needs of caregivers of children and adolescents with OI and the associated factors.
METHODS
A self-administered questionnaire was administered online to 142 caregivers of patients with OI aged 3-17 years between May and October 2022 from 25 provinces in China. The questionnaire comprised 15 questions on demographic variables and 14 questions on home care needs. Chi-square analysis was used to compare group differences for categorical variables. Multivariate binary logistic regression analysis was conducted to examine predictors of caregivers' home care needs.
RESULTS
The study findings indicated that 81.5% of caregivers had high home care needs. The three leading types of home care needs were helping the child carry out physical fitness recovery exercises at home (72.5%), understanding precautions regarding treatment drugs (72.5%), and relieving the child's pain (70.4%). OI patients' poor self-care ability (adjusted odds ratio = 5.9, 95% confidence interval = 1.8-19.0) was related to caregivers' high level of home care needs.
CONCLUSIONS
The findings of this study suggest that future scientific research and nursing guidance should focus on OI patients' physical training, medication management, pain relief, fracture prevention, and treatment. In addition, caregivers of patients with poor self-care ability should receive special attention in the development of interventions. This study can help with addressing the unmet home care needs of caregivers of children and adolescents with OI. It is vital to develop a personalized intervention plan based on patients' self-care ability.
Topics: Child; Humans; Adolescent; Caregivers; Cross-Sectional Studies; Osteogenesis Imperfecta; Needs Assessment; Home Care Services; Surveys and Questionnaires; Pain
PubMed: 38641795
DOI: 10.1186/s12875-024-02367-8 -
Cell Death & Disease Dec 2023TRIC-A and TRIC-B proteins form homotrimeric cation-permeable channels in the endoplasmic reticulum (ER) and nuclear membranes and are thought to contribute to...
TRIC-A and TRIC-B proteins form homotrimeric cation-permeable channels in the endoplasmic reticulum (ER) and nuclear membranes and are thought to contribute to counterionic flux coupled with store Ca release in various cell types. Serious mutations in the TRIC-B (also referred to as TMEM38B) locus cause autosomal recessive osteogenesis imperfecta (OI), which is characterized by insufficient bone mineralization. We have reported that Tric-b-knockout mice can be used as an OI model; Tric-b deficiency deranges ER Ca handling and thus reduces extracellular matrix (ECM) synthesis in osteoblasts, leading to poor mineralization. Here we report irregular cell death and insufficient ECM in long-bone growth plates from Tric-b-knockout embryos. In the knockout growth plate chondrocytes, excess pro-collagen fibers were occasionally accumulated in severely dilated ER elements. Of the major ER stress pathways, activated PERK/eIF2α (PKR-like ER kinase/ eukaryotic initiation factor 2α) signaling seemed to inordinately alter gene expression to induce apoptosis-related proteins including CHOP (CCAAT/enhancer binding protein homologous protein) and caspase 12 in the knockout chondrocytes. Ca imaging detected aberrant Ca handling in the knockout chondrocytes; ER Ca release was impaired, while cytoplasmic Ca level was elevated. Our observations suggest that Tric-b deficiency directs growth plate chondrocytes to pro-apoptotic states by compromising cellular Ca-handling and exacerbating ER stress response, leading to impaired ECM synthesis and accidental cell death.
Topics: Animals; Mice; Growth Plate; Mice, Knockout; Cell Death; Endoplasmic Reticulum; Signal Transduction; Endoplasmic Reticulum Stress; Ion Channels
PubMed: 38123563
DOI: 10.1038/s41419-023-06285-y -
Genes Nov 2023Osteogenesis imperfecta (OI), also known as brittle bone disease, belongs to a rare heterogeneous group of inherited connective tissue disorders. In experienced prenatal... (Review)
Review
Osteogenesis imperfecta (OI), also known as brittle bone disease, belongs to a rare heterogeneous group of inherited connective tissue disorders. In experienced prenatal centers, severe cases of OI can be suspected before birth from the first trimester prenatal ultrasound screening. In this article, we describe a case report of OI suspected at the 26th week of gestation and the patient's outcomes in infancy one year after birth, as well as compare our case to other prenatally or soon-after-birth suspected and/or diagnosed OI clinical case reports in the literature. This case was managed by a multidisciplinary team. In this clinical case, OI was first suspected when prenatal ultrasound revealed asymmetric intrauterine growth restriction and skeletal dysplasia features. The diagnosis was confirmed after birth using gene variant detection via exome sequencing; the gene variant causes OI types I-IV. The familial history was negative for both pregnancy-related risk factors and genetic diseases. At one year old, the patient's condition remains severe with bisphosphonate therapy.
Topics: Pregnancy; Female; Humans; Infant; Osteogenesis Imperfecta; Collagen Type I; Collagen Type I, alpha 1 Chain; Prenatal Diagnosis; Fetal Growth Retardation
PubMed: 38003005
DOI: 10.3390/genes14112062 -
BMJ Open Jun 2024Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile,...
An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol.
INTRODUCTION
Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4.
METHODS AND ANALYSIS
BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in or can be included in the trial.Each subject receives four intravenous doses of 3×10/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover.
ETHICS AND DISSEMINATION
The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals.
TRIAL REGISTRATION NUMBERS
EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.
Topics: Humans; Osteogenesis Imperfecta; Female; Pregnancy; Mesenchymal Stem Cell Transplantation; Infant; Clinical Trials, Phase I as Topic; Multicenter Studies as Topic; Infant, Newborn; Clinical Trials, Phase II as Topic; Mesenchymal Stem Cells; Treatment Outcome; Male; Fetal Stem Cells
PubMed: 38834319
DOI: 10.1136/bmjopen-2023-079767 -
Human Genome Variation Sep 2023Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by brittle bones. In this case report, we describe a patient who suffered from OI type XIV with a...
Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by brittle bones. In this case report, we describe a patient who suffered from OI type XIV with a novel splice site variant in the TMEM38B gene. Further research is needed to better understand the relationship between the phenotype of OI type XIV and this variant.
PubMed: 37696855
DOI: 10.1038/s41439-023-00252-x