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Effect of rapamycin on bone mass and strength in the α2(I)-G610C mouse model of osteogenesis imperfecta.
- Source :
-
Journal of cellular and molecular medicine [J Cell Mol Med] 2019 Mar; Vol. 23 (3), pp. 1735-1745. Date of Electronic Publication: 2018 Dec 30. - Publication Year :
- 2019
-
Abstract
- Osteogenesis imperfecta (OI) is commonly caused by heterozygous type I collagen structural mutations that disturb triple helix folding and integrity. This mutant-containing misfolded collagen accumulates in the endoplasmic reticulum (ER) and induces a form of ER stress associated with negative effects on osteoblast differentiation and maturation. Therapeutic induction of autophagy to degrade the mutant collagens could therefore be useful in ameliorating the ER stress and deleterious downstream consequences. To test this, we treated a mouse model of mild to moderate OI (α2(I) G610C) with dietary rapamycin from 3 to 8 weeks of age and effects on bone mass and mechanical properties were determined. OI bone mass and mechanics were, as previously reported, compromised compared to WT. While rapamycin treatment improved the trabecular parameters of WT and OI bones, the biomechanical deficits of OI bones were not rescued. Importantly, we show that rapamycin treatment suppressed the longitudinal and transverse growth of OI, but not WT, long bones. Our work demonstrates that dietary rapamycin offers no clinical benefit in this OI model and furthermore, the impact of rapamycin on OI bone growth could exacerbate the clinical consequences during periods of active bone growth in patients with OI caused by collagen misfolding mutations.<br /> (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Subjects :
- Animals
Apoptosis
Collagen Type I, alpha 1 Chain
Female
Male
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Osteoblasts cytology
Osteogenesis
Osteogenesis Imperfecta metabolism
Osteogenesis Imperfecta pathology
Bone Density drug effects
Collagen Type I physiology
Disease Models, Animal
Immunosuppressive Agents pharmacology
Osteoblasts drug effects
Osteogenesis Imperfecta drug therapy
Sirolimus pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 23
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 30597759
- Full Text :
- https://doi.org/10.1111/jcmm.14072