We are studying how collagen cross-links have evolved to adapt human bone, cartilage and other supporting tissues for their distinctive functions. We have raised the structure which predicts a novel chemistry and critical role for pyrrole cross-links in bone collagen and identified a previously unknown cross-link, arginoline, in cartilage collagen. We propose and will seek to validate a unified theory of oxidative maturation for cross-links in the fibrillar collagens of all tissues. Though the lysyl oxidase cross-linking mechanism was discovered in the 1970s, much is still unknown. Post-translational differences in collagen quality between individuals, notably in the cross-linking chemistry of bone and cartilages, are potential risk factors for osteoporotic fracture and joint failure. They result from cumulative environmental influences rather than a direct genetic basis. We are pursuing this through analyses of bone, cartilage and other skeletal tissue collagens using advanced mass spectrometric protein techniques. The clinical significance is the promise of new molecular targets in the effort to meet the public health challenges of osteoporosis and osteoarthritis. Skeletal tissues depend heavily on the cross-linking of highly specialized collagens for their unique strengths, properties and longevity. The translational aim, therefore, is to seek new molecular targets for therapy and non- invasive biomarkers based on urinary collagen peptides that can index a patient's bone quality, joint cartilage breakdown rate and other measures of skeletal health.

Public Health Relevance

Using the power of protein mass spectrometry the goal is to complete a basic scientific understanding of how different skeletal collagens are covalently cross-linked. Qualitative differences in bone collagen cross-linking that develop with age and may to be linked to risk of osteoporotic fracture independent of bone density are of particular interest. In parallel with basic tissue studies, collagen fragments in urine are being examined by similar methods as potential non-invasive biomarkers of a patient's bone and joint health.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Tyree, Bernadette
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University of Washington
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Hudson, David M; Archer, Marilyn; King, Karen B et al. (2018) Glycation of type I collagen selectively targets the same helical domain lysine sites as lysyl oxidase-mediated cross-linking. J Biol Chem 293:15620-15627
Cundy, Tim; Dray, Michael; Delahunt, John et al. (2018) Mutations That Alter the Carboxy-Terminal-Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype. J Bone Miner Res 33:1260-1271
Gistelinck, Charlotte; Kwon, Ronald Y; Malfait, Fransiska et al. (2018) Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies. Proc Natl Acad Sci U S A 115:E8037-E8046
Duran, Ivan; Martin, Jorge H; Weis, Mary Ann et al. (2017) A Chaperone Complex Formed by HSP47, FKBP65, and BiP Modulates Telopeptide Lysyl Hydroxylation of Type I Procollagen. J Bone Miner Res 32:1309-1319
Hudson, David M; Weis, MaryAnn; Rai, Jyoti et al. (2017) P3h3-null and Sc65-null Mice Phenocopy the Collagen Lysine Under-hydroxylation and Cross-linking Abnormality of Ehlers-Danlos Syndrome Type VIA. J Biol Chem 292:3877-3887
Maccarana, Marco; Svensson, René B; Knutsson, Anki et al. (2017) Asporin-deficient mice have tougher skin and altered skin glycosaminoglycan content and structure. PLoS One 12:e0184028
Hudson, D M; Garibov, M; Dixon, D R et al. (2017) Distinct post-translational features of type I collagen are conserved in mouse and human periodontal ligament. J Periodontal Res 52:1042-1049
Lietman, Caressa D; Lim, Joohyun; Grafe, Ingo et al. (2017) Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone. J Bone Miner Res 32:1354-1367
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
Fratzl-Zelman, Nadja; Barnes, Aileen M; Weis, MaryAnn et al. (2016) Non-Lethal Type VIII Osteogenesis Imperfecta Has Elevated Bone Matrix Mineralization. J Clin Endocrinol Metab 101:3516-25

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