Journal
MATRIX BIOLOGY
Volume 90, Issue -, Pages 20-39Publisher
ELSEVIER
DOI: 10.1016/j.matbio.2020.02.003
Keywords
Osteogenesis imperfecta; Prolyl 3-hydroxylase; Prolyl 3-hydroxylation complex; Crosslinking; Type I collagen; Murine skeletal disease model
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Funding
- NICHD Intramural Funds
- AUVA (Research Funds of the Austrian workers ' compensation board)
- NIH [AR062522, AR037318, HD070394]
- OEGK (Austrian Social Health Insurance Fund)
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [ZIAHD000256, ZIAHD000408] Funding Source: NIH RePORTER
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Null mutations in CRTAP or P3H1, encoding cartilage-associated protein and prolyl 3-hydroxylase 1, cause the severe bone dysplasias, types VII and VIII osteogenesis imperfecta. Lack of either protein prevents formation of the ER prolyl 3-hydroxylation complex, which catalyzes 3Hyp modification of types I and II collagen and also acts as a collagen chaperone. To clarify the role of the A1 3Hyp substrate site in recessive bone dysplasia, we generated knock-in mice with an alpha 1(I)P986A substitution that cannot be 3-hydroxylated. Mutant mice have normal survival, growth, femoral breaking strength and mean bone mineralization. However, the bone collagen HP/LP crosslink ratio is nearly doubled in mutant mice, while collagen fibril diameter and bone yield energy are decreased. Thus, 3-hydroxylation of the A1 site alpha 1(I)P986 affects collagen crosslinking and structural organization, but its absence does not directly cause recessive bone dysplasia. Our study suggests that the functions of the modification complex as a collagen chaperone are thus distinct from its role as prolyl 3-hydroxylase. Published by Elsevier B.V.
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