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.
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.
|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|
|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|
|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|
|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|
|Gistelinck, Charlotte; Witten, Paul Eckhard; Huysseune, Ann et al. (2016) Loss of Type I Collagen Telopeptide Lysyl Hydroxylation Causes Musculoskeletal Abnormalities in a Zebrafish Model of Bruck Syndrome. J Bone Miner Res 31:1930-1942|
|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|
|Cabral, Wayne A; Ishikawa, Masaki; Garten, Matthias et al. (2016) Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. PLoS Genet 12:e1006156|
|Murdoch, Alan D; Hardingham, Timothy E; Eyre, David R et al. (2016) The development of a mature collagen network in cartilage from human bone marrow stem cells in Transwell culture. Matrix Biol 50:16-26|
|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|
Showing the most recent 10 out of 51 publications