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Molecular Therapy. Nucleic Acids Sep 2023Rare skeletal diseases are still in need of proper clinically available transfection agents as the major challenge for first-in-human translation relates to intrinsic...
Rare skeletal diseases are still in need of proper clinically available transfection agents as the major challenge for first-in-human translation relates to intrinsic difficulty in targeting bone without exacerbating any inherent toxicity due to used vector. SiSaf's silicon stabilized hybrid lipid nanoparticles (sshLNPs) constitute next-generation non-viral vectors able to retain the integrity and stability of constructs and to accommodate considerable payloads of biologicals, without requiring cold-chain storage. sshLNP was complexed with a small interfering RNA (siRNA) specifically designed against the human mRNA. When tested via single intraperitoneal injection in pre-puberal autosomal dominant osteopetrosis type 2 (ADO2) mice, carrying a heterozygous mutation of the gene (), sshLNP, this significantly downregulated the related mRNA levels in femurs at 48 h. Confirmatory results were observed at 2 weeks and 4 weeks after treatments (3 intraperitoneal injections/week), with rescue of the bone phenotype and demonstrating safety. The pre-clinical results will enable advanced preclinical development of RNA-based therapy for orphan and genetic skeletal disorders by safely and effectively delivering biologicals of interest to cure human systemic conditions.
PubMed: 37680985
DOI: 10.1016/j.omtn.2023.08.020 -
Intractable & Rare Diseases Research Aug 2023We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome....
We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome. Medical records were reviewed, and oral examination was performed. Sanger sequencing was undertaken for molecular diagnosis. The patient presented with osteopetrosis, renal tubular acidosis, cerebral calcification, blindness, deafness, and development delay. The oral manifestations included anterior open bite, posterior crossbite, tooth eruption impairment, and hypoplastic amelogenesis imperfecta (AI). Molecular analysis revealed a homozygous deletion (c.753delG, p.Asn252Thrfs*14) and confirmed the clinical diagnosis. This study suggests that AI can be another feature of CAII deficiency syndrome. For the first time, a disease-causing variant is reported to be associated with syndromic AI.
PubMed: 37662627
DOI: 10.5582/irdr.2023.01033 -
International Journal of Molecular... Aug 2023Myocyte enhancement factor 2C (MEF2C) is a transcription factor studied in the development of skeletal and smooth muscles. Bone resorption studies have exhibited that...
Myocyte enhancement factor 2C (MEF2C) is a transcription factor studied in the development of skeletal and smooth muscles. Bone resorption studies have exhibited that the reduced expression of MEF2C contributes to osteopetrosis and the dysregulation of pathological bone remodeling. Our current study aims to determine how MEF2C contributes to osteoclast differentiation and to analyze the skeletal phenotype of cKO mice (; ). qRT-PCR and Western blot demonstrated that expression is highest during the early days of osteoclast differentiation. Osteoclast genes, including c, , , and , had a significant reduction in expression, along with a reduction in osteoclast size. Despite reduced CTX activity, female cKO mice were osteopenic, with decreased bone formation as determined via a P1NP ELISA, and a reduced number of osteoblasts. There was no difference between male WT and cKO mice. Our results suggest that is critical for osteoclastogenesis, and that its dysregulation leads to a sex-specific osteopenic phenotype.
Topics: Animals; Female; Male; Mice; Osteoclasts; Osteogenesis; Bone Diseases, Metabolic; MEF2 Transcription Factors; Cell Differentiation
PubMed: 37628864
DOI: 10.3390/ijms241612686 -
JBMR Plus Aug 2023Osteosclerotic metaphyseal dysplasia (OSMD) is a very rare autosomal-recessive disease caused by mutations in the leucine-rich repeat kinase 1 (LRRK1) gene. It is a...
Osteosclerotic metaphyseal dysplasia (OSMD) is a very rare autosomal-recessive disease caused by mutations in the leucine-rich repeat kinase 1 (LRRK1) gene. It is a sclerosing skeletal dysplasia characterized by osteosclerosis of the long bones, predominantly at the metaphyses and vertebrae. Phenotypic features can be short stature, pathological fractures, delayed development, and hypotonia, but they are not uniformly present, and relatively few cases are known from the literature. A 40-year-old man was seen at our bone center because of nonspontaneous multiple peripheral low-energy trauma fractures since puberty. He had no other complaints and his family history was negative. Except for a relatively short stature (167 cm; -1.5 SD), there were no abnormalities on examination, including laboratory tests. Initially, a suspicion was raised of osteogenesis imperfecta, but bone mineral density was high and X-rays of the whole skeleton showed osteosclerosis of the metaphyses of long bones and vertebrae. Whole-exome sequencing showed a homozygous, likely pathogenic, variant (American College of Medical Genetics and Genomics criteria class 4) in the LRRK1 gene, fitting the diagnosis of OSMD. In conclusion, we described a 40-year-old patient with osteosclerotic metaphyseal dysplasia caused by a homozygous variant in the LRRK1 gene, resulting in multiple fractures of the long bones without other features of the disease, adding to the phenotypic variation of OSMD. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
PubMed: 37614307
DOI: 10.1002/jbm4.10755 -
International Journal of Oral Science Aug 2023The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood. We found that Atp6i deficient mice (Atp6i)...
The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood. We found that Atp6i deficient mice (Atp6i) arrested tooth root formation, indicated by truncated Hertwig's epithelial root sheath (HERS) progression. Furthermore, Atp6i deficiency significantly reduced the proliferation and differentiation of radicular odontogenic cells responsible for root formation. Atp6i mice had largely decreased expression of odontoblast differentiation marker gene expression profiles (Col1a1, Nfic, Dspp, and Osx) in the alveolar bone. Atp6i mice sample RNA-seq analysis results showed decreased expression levels of odontoblast markers. Additionally, there was a significant reduction in Smad2/3 activation, inhibiting transforming growth factor-β (TGF-β) signaling in Atp6i odontoblasts. Through treating pulp precursor cells with Atp6i or wild-type OC bone resorption-conditioned medium, we found the latter medium to promote odontoblast differentiation, as shown by increased odontoblast differentiation marker genes expression (Nfic, Dspp, Osx, and Runx2). This increased expression was significantly blocked by anti-TGF-β1 antibody neutralization, whereas odontoblast differentiation and Smad2/3 activation were significantly attenuated by Atp6i OC conditioned medium. Importantly, ectopic TGF-β1 partially rescued root development and root dentin deposition of Atp6i mice tooth germs were transplanted under mouse kidney capsules. Collectively, our novel data shows that the prevention of TGF-β1 release from the alveolar bone matrix due to OC dysfunction may lead to osteopetrosis-associated root formation via impaired radicular odontoblast differentiation. As such, this study uncovers TGF-β1 /Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation and may contribute to future therapeutic approaches to tooth root regeneration.
Topics: Female; Animals; Mice; Transforming Growth Factor beta1; Odontoblasts; Culture Media, Conditioned; Cell Differentiation; Signal Transduction; Disease Models, Animal; Tooth Root
PubMed: 37599332
DOI: 10.1038/s41368-023-00235-2 -
International Journal of Surgery Case... Aug 2023Femoral fractures are common in the patients with osteopetrosis and multiple treatment strategies have been described with varying results. However, there is a paucity...
Application of femoral nail, reconstruction locked plate and bone morphogenic protein - 7 in an osteopetrosis patient with a recurrent femoral shaft fracture: A case report.
INTRODUCTION AND IMPORTANCE
Femoral fractures are common in the patients with osteopetrosis and multiple treatment strategies have been described with varying results. However, there is a paucity of literature describing the treatment of recurrent fractures and subsequent deformity.
CASE PRESENTATION
We present detailed revision strategies and long-term follow-up results of a patient with osteopetrosis who suffered unsuccessful operative treatment using the plate-screw system (recurrent femoral shaft fracture and implant failure).
CLINICAL DISCUSSION
The success of revision surgery of osteopetrosis is based on good preoperative planning, appropriate selection of fixation methods, and a meticulous approach during surgery. The combined application of the expert adolescent lateral femoral nail, the reconstruction locked plate, and bone morphogenic protein (BMP)-7 in this patient achieved good clinical results.
CONCLUSION
In the treatment of failed plated and recurrent osteopetrotic femoral shaft fractures, the combination of nails and plating presents an alternative, potentially more successful, revision strategy.
PubMed: 37562280
DOI: 10.1016/j.ijscr.2023.108628 -
Genes Jul 2023Mutations in the mouse microphthalmia-associated transcription factor () gene affect retinal pigment epithelium (RPE) differentiation and development and can lead to...
Mutations in the mouse microphthalmia-associated transcription factor () gene affect retinal pigment epithelium (RPE) differentiation and development and can lead to hypopigmentation, microphthalmia, deafness, and blindness. For instance, an association has been established between loss-of-function mutations in the mouse gene and a variety of human retinal diseases, including Waardenburg type 2 and Tietz syndromes. Although there is evidence showing that mice with the homozygous mutation manifest microphthalmia and osteopetrosis, there are limited or no data on the effects of the heterozygous condition in the eye. mice can therefore be regarded as an important model system for the study of human disease. Thus, we characterized mice at 1, 3, 12, and 18 months old in comparison with age-matched wild-type mice. The light- and dark-adapted electroretinogram (ERG) recordings showed progressive cone-rod dystrophy in mice. The RPE response was reduced in the mutant in all age groups studied. Progressive loss of pigmentation was found in mice. Histological retinal sections revealed evidence of retinal degeneration in mice at older ages. For the first time, we report a mouse model of progressive cone-rod dystrophy and RPE dysfunction with a mutation in the gene.
Topics: Animals; Mice; Cone-Rod Dystrophies; Microphthalmia-Associated Transcription Factor; Microphthalmos; Retinal Dystrophies; Retinal Pigment Epithelium
PubMed: 37510362
DOI: 10.3390/genes14071458 -
Journal of Clinical and Translational... Aug 2023We report a patient with refractory ascites because of portal hypertension caused by hemochromatosis secondary to osteopetrosis. To our knowledge, this is the first...
We report a patient with refractory ascites because of portal hypertension caused by hemochromatosis secondary to osteopetrosis. To our knowledge, this is the first well-documented case of this association. A 46-year-old male patient who was repeatedly infused with red blood cells for anemia secondary to osteopetrosis suffered from refractory ascites. The serum-ascites albumin gradient was 29.9 g/L. Abdominal computed tomography (CT) showed a large amount of ascites, hepatomegaly, and splenomegaly. Bone marrow biopsy showed a small bone marrow cavity with no hematopoietic tissue. A peripheral blood smear showed tear drop red blood cells and metarubricytes. Serum ferritin was 8,855.0 ng/mL. Therefore, we considered that the ascites resulted from portal hypertension caused by hemochromatosis secondary to osteopetrosis. We simultaneously performed the transjungular intrahepatic portal-systemic shunt (TIPS) and obtained a transjungular liver biopsy. The portal pressure gradient before TIPS was 28 mmHg, and iron staining was strongly positive on liver biopsy, which confirmed our diagnosis. After TIPS, both abdominal distention and ascites gradually resolved, and no recurrence as observed after the 12-month postoperative follow-up was observed. This case indicated that regular monitoring of iron load is important for patients with osteopetrosis. TIPS is safe and effective for portal hypertension complications due to osteopetrosis.
PubMed: 37408812
DOI: 10.14218/JCTH.2022.00418