Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology.
Mol Ther
; 25(3): 705-714, 2017 03 01.
Article
en En
| MEDLINE
| ID: mdl-28162960
ABSTRACT
Mutations in cartilage oligomeric matrix protein cause pseudoachondroplasia, a severe disproportionate short stature disorder. Mutant cartilage oligomeric matrix protein produces massive intracellular retention of cartilage oligomeric matrix protein, stimulating ER and oxidative stresses and inflammation, culminating in post-natal loss of growth plate chondrocytes, which compromises linear bone growth. Treatments for pseudoachondroplasia are limited because cartilage is relatively avascular and considered inaccessible. Here we report successful delivery and treatment using antisense oligonucleotide technology in our transgenic pseudoachondroplasia mouse model. We demonstrate delivery of human cartilage oligomeric matrix protein-specific antisense oligonucleotides to cartilage and reduction of cartilage oligomeric matrix protein expression, which largely alleviates pseudoachondroplasia growth plate chondrocyte pathology. One antisense oligonucleotide reduced steady-state levels of cartilage oligomeric matrix protein mRNA and dampened intracellular retention of mutant cartilage oligomeric matrix protein, leading to a reduction of inflammatory markers and cell death and partial restoration of proliferation. This novel and exciting work demonstrates that antisense-based therapy is a viable approach for treating pseudoachondroplasia and other human cartilage disorders.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Oligonucleótidos Antisentido
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Condrocitos
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Proteína de la Matriz Oligomérica del Cartílago
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Placa de Crecimiento
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Mutación
Límite:
Animals
Idioma:
En
Revista:
Mol Ther
Asunto de la revista:
BIOLOGIA MOLECULAR
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TERAPEUTICA
Año:
2017
Tipo del documento:
Article