In this competing renewal of AR036794 (title updated to reflect the evolution in specific aims and scope), we focus on a newly discovered mechanism of regulation of collagen fibril diversity that is important for understanding skeletal tissue differentiation and pathobiology. We have evidence that 3-hydroxproline (3Hyp) residues play a fundamental role in directing the manner of fibrillar collagen supramolecular assembly. The first hint came from our demonstration by mass spectrometry that the single, fully occupied 3Hyp site (P986) near the C-terminus of collagen a1(I) and a1(II) chains fails to be hydroxylated in collagens of the crtap mouse and recessive forms of human osteogenesis imperfecta (O.I.) caused by CRTAP or LEPRE1 mutations. We now have evidence for three classes of 3Hyp site in fibril-forming collagens. For example, a second site in type II collagen is highly hydroxylated in vitreous, meniscus and intervertebral disc but not in hyaline cartilage. The sequence motif of this second site is reproduced at D-periodic intervals in a2(V), with 3Hyp present, and shows similarities to a 3Hyp motif in type IV collagen. Tendon collagen uniquely contains a third type of 3Hyp motif, which we believe is characteristic and functionally important in tendon, ligament and related highly tensile tissues. Under 4 aims, we intend to pursue this concept aggressively since it is central to understanding how different cell types regulate the diversity of heteropolymeric collagen assemblies between different cartilages, bone, tendon and other connective tissues. If correct, it also has concept- changing implications for the field of vertebrate collagen biology. The clinical significance is in providing a molecular basis for understanding processes that cause cartilages and other collagenous tissues of low turnover to degenerate in the adult musculoskeleton in osteoarthritis, disc degeneration and related disorders of collagen framework failure. In addition, a full understanding of the effects of disrupting prolyl 3-hydroxylation in recessive forms of osteogenesis imperfecta we believe will reveal a molecular mechanism for brittle bone common to all forms of O.I. Such findings will also be significant for understanding qualitative changes in bone matrix that add significant risk of osteoporotic fracture in the population as a whole and a potential for novel biomarkers and therapeutic targets.

Public Health Relevance

The goal is to understand molecular mechanisms that govern the diversity in properties of collagen, the protein that forms the structural framework of all major skeletal tissues in the body including bone, cartilages, tendons and ligaments. Specifically, we aim to define the biochemical pathways that equip bone collagen to mineralize, cartilage to last a lifetime as the bearing surfaces of joints and tendons and ligaments to transmit or restrain high mechanical loads without failing. With this knowledge new targets for therapy and prevention of genetic and acquired human disorders of bones and joints are predicted.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR036794-27
Application #
8475425
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Tyree, Bernadette
Project Start
1986-01-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
27
Fiscal Year
2013
Total Cost
$320,112
Indirect Cost
$114,912
Name
University of Washington
Department
Orthopedics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Lindert, Uschi; Cabral, Wayne A; Ausavarat, Surasawadee et al. (2016) MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nat Commun 7:11920
Hosseininia, S; Weis, M A; Rai, J et al. (2016) Evidence for enhanced collagen type III deposition focally in the territorial matrix of osteoarthritic hip articular cartilage. Osteoarthritis Cartilage 24:1029-35
Heard, Melissa E; Besio, Roberta; Weis, MaryAnn et al. (2016) Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation. PLoS Genet 12:e1006002
Lietman, Caressa D; Marom, Ronit; Munivez, Elda et al. (2015) A transgenic mouse model of OI type V supports a neomorphic mechanism of the IFITM5 mutation. J Bone Miner Res 30:489-98
Duran, Ivan; Nevarez, Lisette; Sarukhanov, Anna et al. (2015) HSP47 and FKBP65 cooperate in the synthesis of type I procollagen. Hum Mol Genet 24:1918-28
Hudson, David M; Joeng, Kyu Sang; Werther, Rachel et al. (2015) Post-translationally abnormal collagens of prolyl 3-hydroxylase-2 null mice offer a pathobiological mechanism for the high myopia linked to human LEPREL1 mutations. J Biol Chem 290:8613-22
Lindert, Uschi; Weis, Mary Ann; Rai, Jyoti et al. (2015) Molecular Consequences of the SERPINH1/HSP47 Mutation in the Dachshund Natural Model of Osteogenesis Imperfecta. J Biol Chem 290:17679-89
Herchenhan, Andreas; Uhlenbrock, Franziska; Eliasson, Pernilla et al. (2015) Lysyl Oxidase Activity Is Required for Ordered Collagen Fibrillogenesis by Tendon Cells. J Biol Chem 290:16440-50
McAlinden, Audrey; Traeger, Geoffrey; Hansen, Uwe et al. (2014) Molecular properties and fibril ultrastructure of types II and XI collagens in cartilage of mice expressing exclusively the *1(IIA) collagen isoform. Matrix Biol 34:105-13
Cabral, Wayne A; Perdivara, Irina; Weis, MaryAnn et al. (2014) Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta. PLoS Genet 10:e1004465

Showing the most recent 10 out of 87 publications