ADO2 is a heritable osteosclerotic disorder that usually results from heterozygous missense dominant negative mutations in the chloride channel 7 gene (CLCN7). ADO2 is characterized by a wide range of features and severity, including multiple fractures, impaired vision due to secondary bony overgrowth and/or the lack of the optical canal enlargement with growth, and osteonecrosis/osteomyelitis. The disease is presently incurable, although anecdotal evidence suggests that calcitriol and interferon gamma-1b (IFN-G) may have some beneficial effects. To identify the role of these drugs for the treatment of ADO2, we utilized a knock-in (G213R mutation in Clcn7) ADO2 mouse model that resembles the human disease. Six-week-old ADO2 heterozygous mice were administered vehicle (PBS) or calcitriol or IFN-G 5 times per week for 8 weeks. We determined bone phenotypes using DXA and μCT, and analyzed serum biochemistry and bone resorption markers. ADO2 mice treated with all doses of IFN-G significantly (p<0.05) attenuated the increase of whole body aBMD and distal femur BV/TV gain in both male and female compared to the vehicle group. In contrast, mice treated with low and medium doses of calcitriol showed a trend of higher aBMD and BV/TV whereas high dose calcitriol significantly (p<0.05) increased bone mass compared to the vehicle group. The calcium and phosphorus levels did not differ between vehicle and IFN-G or calcitriol treated mice; however, we detected significantly (p<0.05) elevated levels of CTX/TRAP5b ratio in IFN-G treated mice. Our findings indicate that while IFN-G at all doses substantially improved the osteopetrotic phenotypes in ADO2 heterozygous mice, calcitriol treatment at any dose did not improve the phenotype and at high dose further increased bone mass. Thus, use of high dose calcitriol therapy in ADO2 patients merits serious reconsideration. Importantly, our data support the prospect of a clinical trial of IFN-G in ADO2 patients.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/jbmr.2545 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Effect of Allele-Specific Clcn7 siRNA Delivered Via a Novel Nanocarrier on Bone Phenotypes in ADO2 Mice on 129S Background.
Calcif Tissue Int
July 2024
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Autosomal dominant osteopetrosis type 2 (ADO2) is a rare inherited bone disorder characterised by dense but brittle bones. It displays striking phenotypic variability, with the most severe symptoms, including blindness and bone marrow failure. Disease management largely relies on symptomatic treatment since there is no safe and effective treatment.
View Article and Find Full Text PDFThe PDE4 Inhibitors Roflumilast and Rolipram Rescue ADO2 Osteoclast Resorption Dysfunction.
Calcif Tissue Int
April 2024
Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, 1121 West Michigan Street, DS266, Indianapolis, IN, 46202, USA.
Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption caused by heterozygous missense mutations in the chloride channel 7 (CLCN7). Adenylate cyclase, which catalyzes the formation of cAMP, is critical for lysosomal acidification in osteoclasts. We found reduced cAMP levels in ADO2 osteoclasts compared to wild-type (WT) osteoclasts, leading us to examine whether regulating cAMP would improve ADO2 osteoclast activity.
View Article and Find Full Text PDFEffect of Roflumilast, a Selective PDE4 Inhibitor, on Bone Phenotypes in ADO2 Mice.
Calcif Tissue Int
April 2024
Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption that usually results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene. We previously created mouse models of ADO2 (p.G213R) with one of the most common mutations (G215R) as found in humans and demonstrated that this mutation in mice phenocopies the human disease of ADO2.
View Article and Find Full Text PDFNovel hybrid silicon-lipid nanoparticles deliver a siRNA to cure autosomal dominant osteopetrosis in mice. Implications for gene therapy in humans.
Mol Ther Nucleic Acids
September 2023
SiSaf Limited, Guildford, UK.
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.
View Article and Find Full Text PDFCLCN7, a gene shared by autosomal recessive and autosomal dominant osteopetrosis.
Bone
March 2023
Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany. Electronic address:
After the discovery of abundant v-ATPase complexes in the osteoclast ruffled membrane it was obvious that in parallel a negative counter-ion needs to be transported across this membrane to allow for efficient transport of protons into the resorption lacuna. While different candidate proteins were discussed the osteopetrosis phenotype of Clcn7 knockout mice suggested that the chloride/proton-exchanger ClC-7 might be responsible for transporting the negative charge. In the following, individuals with autosomal recessive osteopetrosis (ARO) were found to carry biallelic CLCN7 pathogenic variants.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!