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Pharmaceuticals (Basel, Switzerland) Oct 2023() is a group of connective tissue disorders leading to abnormal bone formation, mainly due to mutations in genes encoding collagen type I (Col I). Osteogenesis is...
() is a group of connective tissue disorders leading to abnormal bone formation, mainly due to mutations in genes encoding collagen type I (Col I). Osteogenesis is regulated by a number of molecules, including microRNAs (miRNAs), indicating their potential as targets for therapy. The goal of this study was to identify and analyze the expression profiles of miRNAs involved in bone extracellular matrix (ECM) regulation in patients diagnosed with type I caused by mutations in or . Primary skin fibroblast cultures were used for DNA purification and sequence analysis, followed by analysis of miRNA expression. Sequencing analysis revealed mutations of the or genes in all patients, including four previously unreported. Amongst the 40 miRNAs analyzed, 9 were identified exclusively in cells and 26 in both patients and the controls. In the latter case, the expression of six miRNAs (hsa-miR-10b-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, has-miR-204-5p, has-miR-216a-5p, and hsa-miR-449a) increased, while four (hsa-miR-129-5p, hsa-miR-199b-5p, hsa-miR-664a-5p, and hsa-miR-30a-5p) decreased significantly in cells in comparison to their expression in the control cells. The identified mutations and miRNA expression profiles shed light on the intricate processes governing bone formation and ECM regulation, paving the way for further research and potential therapeutic advancements in and other genetic diseases related to bone abnormality management.
PubMed: 37895885
DOI: 10.3390/ph16101414 -
Calcified Tissue International Mar 2024Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational... (Review)
Review
Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis and clinical trials are ongoing to study their effectiveness in OI adults. Additionally, novel bone-protective agents are in preclinical studies and various phases of OI clinical trials. This review summarizes current knowledge on available pharmacologic agents and current drug trials involving OI participants. A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in August 2022. Articles screened were restricted to adults. A ClinicalTrials.gov database search of all studies involving "osteogenesis imperfecta" was performed in August 2023. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving bone mineral density. As of yet, no clinical trials are available that adequately evaluate the usefulness of current therapies in reducing fracture risk. Several therapeutics, including teriparatide, setrusumab, anti-TGF-β antibodies, and allogeneic stem cells, are being studied in clinical trials. Preclinical studies involving Dickkopf-1 antagonists present promising data in non-OI bone disease, and could be useful in OI. Research is ongoing to improve therapeutic options for adults with OI and clinical trials involving gene-editing may be possible in the coming decade.
PubMed: 38472351
DOI: 10.1007/s00223-024-01188-2 -
Morphologie : Bulletin de L'Association... May 2024In addition to bone fragility, patients with osteogenesis imperfecta (OI) type III have typical craniofacial abnormalities, such as a triangular face and maxillary...
OBJECTIVES
In addition to bone fragility, patients with osteogenesis imperfecta (OI) type III have typical craniofacial abnormalities, such as a triangular face and maxillary micrognathism. However, in the osteogenesis imperfecta mouse (oim), a validated model of OI type III, few descriptions exist of craniofacial phenotype. Treatment of OI mostly consists of bisphosphonate administration. Cathepsin K inhibition has been tested as a promising therapeutic approach for osteoporosis and positive results were observed in long bones of cathepsin K knocked out oim (oim/CatK). This craniometry study aimed to highlight the craniofacial characteristics of oim and Cathepsin K KO mouse.
MATERIALS AND METHODS
We analyzed the craniofacial skeleton of 51 mice distributed in 4 genotype groups: Wt (control), oim, CatK, oim/CatK. The mice were euthanized at 13 weeks and their heads were analyzed using densitometric (pQCT), X-ray cephalometric, and histomorphometric methods.
RESULTS
The craniofacial skeleton of the oim mouse is frailer than the Wt one, with a reduced thickness and mineral density of the cranial vault and mandibular ramus. Different cephalometric data attest a dysmorphism similar to the one observed in humans with OI type III. Those abnormalities were not improved in the oim/CatK group.
CONCLUSION
These results suggest that oim mouse could serve as a complete model of the human OI type III, including the craniofacial skeleton. They also suggest that invalidation of cathepsin K has no impact on the craniofacial abnormalities of the oim model.
PubMed: 38788496
DOI: 10.1016/j.morpho.2024.100785 -
Matrix Biology : Journal of the... Aug 2023Osteogenesis Imperfecta (OI) is a heritable collagen-related bone dysplasia characterized by bone fractures, growth deficiency and skeletal deformity. Type XIV OI is a...
Osteogenesis Imperfecta (OI) is a heritable collagen-related bone dysplasia characterized by bone fractures, growth deficiency and skeletal deformity. Type XIV OI is a recessive OI form caused by null mutations in TMEM38B, which encodes the ER membrane intracellular cation channel TRIC-B. Previously, we showed that absence of TMEM38B alters calcium flux in the ER of OI patient osteoblasts and fibroblasts, which further disrupts collagen synthesis and secretion. How the absence of TMEM38B affects osteoblast function is still poorly understood. Here we further investigated the role of TMEM38B in human osteoblast differentiation and mineralization. TMEM38B-null osteoblasts showed altered expression of osteoblast marker genes and decreased mineralization. RNA-Seq analysis revealed that cell-cell adhesion was one of the most downregulated pathways in TMEM38B-null osteoblasts, with further validation by real-time PCR and Western blot. Gap and tight junction proteins were also decreased by TRIC-B absence, both in patient osteoblasts and in calvarial osteoblasts of Tmem38b-null mice. Disrupted cell adhesion decreased mutant cell proliferation and cell cycle progression. An important novel finding was that TMEM38B-null osteoblasts had elongated mitochondria with altered fusion and fission markers, MFN2 and DRP1. In addition, TMEM38B-null osteoblasts exhibited a significant increase in superoxide production in mitochondria, further supporting mitochondrial dysfunction. Together these results emphasize the novel role of TMEM38B/TRIC-B in osteoblast differentiation, affecting cell-cell adhesion processes, gap and tight junction, proliferation, cell cycle, and mitochondrial function.
Topics: Animals; Humans; Mice; Cell Adhesion; Collagen; Ion Channels; Multiomics; Osteoblasts; Osteogenesis; Osteogenesis Imperfecta
PubMed: 37348683
DOI: 10.1016/j.matbio.2023.06.004 -
Matrix Biology : Journal of the... Aug 2023Osteogenesis imperfecta (OI) is a family of rare heritable skeletal disorders associated with dominant mutations in the collagen type I encoding genes and recessive...
Cell differentiation and matrix organization are differentially affected during bone formation in osteogenesis imperfecta zebrafish models with different genetic defects impacting collagen type I structure.
Osteogenesis imperfecta (OI) is a family of rare heritable skeletal disorders associated with dominant mutations in the collagen type I encoding genes and recessive defects in proteins involved in collagen type I synthesis and processing and in osteoblast differentiation and activity. Historically, it was believed that the OI bone phenotype was only caused by abnormal collagen type I fibrils in the extracellular matrix, but more recently it became clear that the altered bone cell homeostasis, due to mutant collagen retention, plays a relevant role in modulating disease severity in most of the OI forms and it is correlated to impaired bone cell differentiation. Despite in vitro evidence, in vivo data are missing. To better understand the physiopathology of OI, we used two zebrafish models: Chihuahua (Chi/+), carrying a dominant p.G736D substitution in the α1 chain of collagen type I, and the recessive p3h1, lacking prolyl 3-hydroxylase (P3h1) enzyme. Both models share the delay of collagen type I folding, resulting in its overmodification and partial intracellular retention. The regeneration of the bony caudal fin of Chi/+ and p3h1 was employed to investigate the impact of abnormal collagen synthesis on bone cell differentiation. Reduced regenerative ability was evident in both models, but it was associated to impaired osteoblast differentiation and osteoblastogenesis/adipogenesis switch only in Chi/+. On the contrary, reduced osteoclast number and activity were found in both models during regeneration. The dominant OI model showed a more detrimental effect in the extracellular matrix organization. Interestingly, the chemical chaperone 4-phenylbutyrate (4-PBA), known to reduce cellular stress and increase collagen secretion, improved bone formation only in p3h1 by favoring caudal fin growth without affecting bone cell markers expression. Taken together, our in vivo data proved the negative impact of structurally abnormal collagen type I on bone formation but revealed a gene mutation-specific effect on bone cell differentiation and matrix organization in OI. These, together with the distinct ability to respond to the chaperone treatment, underline the need for precision medicine approaches to properly treat the disease.
Topics: Animals; Collagen Type I; Osteogenesis Imperfecta; Osteogenesis; Zebrafish; Collagen; Molecular Chaperones; Mutation; Cell Differentiation
PubMed: 37336269
DOI: 10.1016/j.matbio.2023.06.003 -
Orthodontics & Craniofacial Research Apr 2024Cranio-cervical anomalies are significant complications of osteogenesis imperfecta (OI), a rare bone fragility disorder that is usually caused by mutations in collagen...
INTRODUCTION
Cranio-cervical anomalies are significant complications of osteogenesis imperfecta (OI), a rare bone fragility disorder that is usually caused by mutations in collagen type I encoding genes.
OBJECTIVE
To assess cranio-cervical anomalies and associated clinical findings in patients with moderate-to-severe OI using 3D cone beam computed tomography (CBCT) scans.
METHODS
Cross-sectional analysis of CBCT scans in 52 individuals with OI (age 10-37 years; 32 females) and 40 healthy controls (age 10-32 years; 26 females). Individuals with a diagnosis of OI type III (severe, n = 11), type IV (moderate, n = 33) and non-collagen OI (n = 8) were recruited through the Brittle Bone Disorders Consortium. Controls were recruited through the orthodontic clinic of the University of Missouri-Kansas City (UMKC).
RESULTS
OI and control groups were similar in mean age (OI: 18.4 [SD: 7.2] years, controls: 18.1 [SD: 6.3] years). The cranial base angle was increased in the OI group (OI: mean 148.6° [SD: 19.3], controls: mean 130.4° [SD: 5.7], P = .001), indicating a flatter cranial base. Protrusion of the odontoid process into the foramen magnum (n = 7, 14%) and abnormally located odontoid process (n = 19, 37%) were observed in the OI group but not in controls. Low stature, expressed as height z-score (P = .01), presence of DI (P = .04) and being male (P = .04) were strong predictors of platybasia, whereas height z-score (P = .049) alone was found as positive predictor for basilar impression as per the Chamberlain measurement.
CONCLUSION
The severity of the phenotype in OI, as expressed by the height z-score, correlates with the severity of cranial base anomalies such as platybasia and basilar impression in moderate-to-severe OI. Screening for cranial base anomalies is advisable in individuals with moderate-to-severe OI, with special regards to the individuals with a shorter stature and DI.
Topics: Female; Humans; Male; Adolescent; Child; Young Adult; Adult; Osteogenesis Imperfecta; Platybasia; Cross-Sectional Studies; Genotype; Phenotype; Mutation; Collagen Type I
PubMed: 37642979
DOI: 10.1111/ocr.12707 -
Healthcare (Basel, Switzerland) May 2024Only a few studies, mainly qualitative thematic analyses of interviews, have dealt with the psychological experience of parents of children and adolescents with...
Only a few studies, mainly qualitative thematic analyses of interviews, have dealt with the psychological experience of parents of children and adolescents with osteogenesis imperfecta (OI), a rare genetic syndrome involving skeletal fragility and increased exposure to bone fractures. The aim of the present study was to evaluate both negative (i.e., parental burden and parenting stress) and positive (i.e., coping strategies and perceived social support) experiences of parents related to their children's disease and behaviour. The participants were 34 parents of children and adolescents with OI who completed a specifically developed online survey assessing their psychological experience with caregiving, their perception of the severity level of their children's condition and any possible behavioural problems experienced by their children. Data analyses showed that 65% of the parents showed a clinical level of caregiver burden and nearly 30% a clinical level of parenting stress. Caregiver burden was related to the perceived severity level of the condition and the externalising problems shown by their children. Concerning the positive aspects of the parents' experience, a high level of perceived social support was connected to a lower level of parenting stress; the same did not happen for caregiver burden. Coping strategies were connected to stress and burden; in particular, a higher level of stress corresponded to a higher level of avoidance, and a higher level of burden corresponded to a higher level of positive attitude.
PubMed: 38786428
DOI: 10.3390/healthcare12101018 -
Current Osteoporosis Reports Aug 2023Here, we review issues regarding the transition from pediatric to adult-focused health care for individuals with osteogenesis imperfecta (OI). (Review)
Review
PURPOSE
Here, we review issues regarding the transition from pediatric to adult-focused health care for individuals with osteogenesis imperfecta (OI).
RECENT FINDINGS
The clinical consequences of OI change during the lifespan. Fracture rates are lower in adults than in children with OI, whereas other manifestations are typically becoming more prominent in adults. The evidence base for the transition to adult health care in OI is thin, as the literature on the topic is limited to qualitative investigations on a small number of participants. A few tools to help with transition, such as a program to improve self-management skills, have been developed. The transition process varies markedly between health care systems, which makes generalizations difficult. However, a better definition of follow-up requirements and care of adults with OI might be helpful for the transition from pediatric to adult health care.
Topics: Humans; Child; Adult; Osteogenesis Imperfecta; Fractures, Bone
PubMed: 37266843
DOI: 10.1007/s11914-023-00794-7 -
American Journal of Physiology. Heart... Oct 2023Osteogenesis imperfecta (OI) is an extracellular matrix disorder characterized by defects in collagen-1 transport or synthesis, resulting in bone abnormalities. Although...
Osteogenesis imperfecta (OI) is an extracellular matrix disorder characterized by defects in collagen-1 transport or synthesis, resulting in bone abnormalities. Although reduced collagen in OI hearts has been associated with reduced myocardial stiffness and left ventricular remodeling, its impact on cardiomyocyte (CM) function has not been studied. Here, we explore the tissue-level and CM-level properties of a heart from a deceased organ donor with OI type I. Proteomics and histology confirmed strikingly low expression of collagen 1. Trabecular stretch confirmed low stiffness on the tissue level. However, CMs retained normal viscoelastic properties as revealed by nanoindentation. Interestingly, OI CMs were hypercontractile relative to nonfailing controls after 24 h of culture. In response to 48 h of culture on surfaces with physiological (10 kPa) and pathological (50 kPa) stiffness, OI CMs demonstrated a greater reduction in contractility than nonfailing CMs, suggesting that OI CMs may have an impaired stress response. Levels of detyrosinated α-tubulin, known to be responsive to extracellular stiffness, were reduced in OI CMs. Together these data confirm multiple CM-level adaptations to low stiffness that extend our understanding of OI in the heart and how CMs respond to extracellular stiffness. In a rare donation of a heart from an individual with osteogenesis imperfecta (OI), we explored cardiomyocyte (CM) adaptations to low stiffness. This represents the first assessment of cardiomyocyte mechanics in OI. The data reveal the hypercontractility of OI CMs with rapid rundown when exposed to acute stiffness challenges, extending our understanding of OI. These data demonstrate that the impact of OI on myocardial mechanics includes cardiomyocyte adaptations beyond known direct effects on the extracellular matrix.
Topics: Humans; Adult; Osteogenesis Imperfecta; Myocytes, Cardiac; Collagen; Collagen Type I; Extracellular Matrix; Osteogenesis
PubMed: 37566108
DOI: 10.1152/ajpheart.00391.2023 -
Clinical Genetics Mar 2024Osteogenesis imperfecta (OI) is a group of genetic disorders of bone formation characterized by soft and shorter brittle bones in affected individuals. OI is generally...
Osteogenesis imperfecta (OI) is a group of genetic disorders of bone formation characterized by soft and shorter brittle bones in affected individuals. OI is generally considered a collagenopathy resulting from abnormal expression of type I collagen. As assay system to detect the cellular level and quality of type I collagen would help in rapid and correct detection of OI from the diagnostic perspectives. Here, we report an immunofluorescence assay for detection of type I collagen in fibroblast models of OI and represented them into two broad categories based on the expression level and aggregation characteristics of pro-α1(I). Cell phenotypic assays of pro-α1(I) in OI-related gene knocked down fibroblasts revealed aggregates of pro-α1(I) in conditions with knockdown of SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, TMEM38B, MESD, and KDELR2, whereas pro-α1(I) expression was very low in fibroblasts which had knockdown of IFITM5, SP7, BMP1, WNT1, CREB3L1, MBTPS2, and CCDC134. The expression of pro-α1(I) showed abundant and non-aggregated distribution in the fibroblasts with knockdown of non-OI skeletal disorder-related genes (RAB33B and IFT52). The in vitro assay accurately detected abnormally expressed pro-α1(I) levels in cellular models of various types of OI. Thus, this procedure represents a promising point-of-detection assay for potential diagnosis and therapeutic decisions in OI.
Topics: Humans; Collagen Type I; Osteogenesis Imperfecta; Genes, Recessive; Fibroblasts; Mutation; Vesicular Transport Proteins; Membrane Proteins
PubMed: 38014644
DOI: 10.1111/cge.14463