Substitution of murine type I collagen A1 3-hydroxylation site alters matrix structure but does not recapitulate osteogenesis imperfecta bone dysplasia
| Autor: | MaryAnn Weis, Nadja Fratzl-Zelman, Paul Roschger, Joseph E. Perosky, Sergey Leikin, Wayne A. Cabral, David R. Eyre, Kenneth M. Kozloff, Heeseog Kang, Peter S. Backlund, Elena Makareeva, Antonella Forlino, Joan C. Marini, Adrienne Alimasa, Rachel Harris, Klaus Klaushofer, Aileen M. Barnes |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Mutant Bone Dysplasias Hydroxylation Collagen Type I Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Humans Gene Knock-In Techniques Molecular Biology Cells Cultured Osteoblasts Structural organization biology Fibroblasts Osteogenesis Imperfecta medicine.disease Cell biology Collagen Type I alpha 1 Chain Disease Models Animal Phenotype 030104 developmental biology Amino Acid Substitution chemistry Dysplasia Osteogenesis imperfecta 030220 oncology & carcinogenesis Chaperone (protein) biology.protein Type I collagen |
| Zdroj: | Matrix Biol |
| ISSN: | 0945-053X |
| Popis: | 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 α1(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 α1(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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect