2020
Matrix Biol. 2020 Feb 26;S0945-053X(20)30013-5. doi: 10.1016/j.matbio.2020.02.003.
Substitution of Murine Type I Collagen A1 3-hydroxylation Site Alters Matrix Structure but Does Not Recapitulate Osteogenesis Imperfecta Bone Dysplasia
Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, MD, USA. Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria. Orthopaedic Research Laboratories, University of Washington, Seattle, WA, USA. Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA. Section on Physical Biochemistry, NICHD, NIH, Bethesda, MD, USA. Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy. Biomedical Mass Spectrometry Facility, NICHD, NIH, Bethesda, MD, USA. Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, MD,
Service type: Knock-in mice
Abstract
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.
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