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3. Single cell RNA sequencing identifies mitochondrial respiration as a key factor contributing to extracellular matrix integrity

Author

Bubb, K, additional, Holzer, T, additional, Nolte, J L, additional, Krüger, M, additional, Wilson, R, additional, Schlötzer-Schrehardt, U, additional, Brinckmann, J, additional, Altmüller, J, additional, Aszodi, A, additional, Fleischhauer, L, additional, Clausen-Schaumann, H, additional, Probst, K, additional, and Brachvogel, B, additional

Published
2021
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5. Homozygous EMILIN1 loss-of-function variants impair both elastin and collagen fiber formation and cause a novel entity with arterial tortuosity and osteopenia

Author

Beyens, A., Adamo, C., Gulec, E. Yilmaz, Gezdirici, A., Bonaldo, P., Bornaun, H., Brauchle, E., Brinckmann, J., Devine, W. P., Gangaram, B., Sasaki, T., Schenke-Layland, K., Symoens, S., Tam, A., Sengle, G., Callewaert, B., Beyens, A., Adamo, C., Gulec, E. Yilmaz, Gezdirici, A., Bonaldo, P., Bornaun, H., Brauchle, E., Brinckmann, J., Devine, W. P., Gangaram, B., Sasaki, T., Schenke-Layland, K., Symoens, S., Tam, A., Sengle, G., and Callewaert, B.

Published
2020

11. A comprehensive map of human elastin cross-linking during elastogenesis

Author

Hedtke, T., Schräder, C.U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., Schmelzer, C.E.H., and Publica

Abstract

Elastin is an essential structural protein in the extracellular matrix of vertebrates. It is the core component of elastic fibers, which enable connective tissues such as those of the skin, lungs or blood vessels to stretch and recoil. This function is provided by elastin's exceptional properties, which mainly derive from a unique covalent cross-linking between hydrophilic lysine-rich motifs of units of the monomeric precursor tropoelastin. To date, elastin's cross-linking is poorly investigated. Here, we purified elastin from human tissue and cleaved it into soluble peptides using proteases with different specificities. We then analyzed elastin's molecular structure by identifying unmodified residues, post-translational modifications and cross-linked peptides by high-resolution mass spectrometry and amino acid analysis. The data revealed the presence of multiple isoforms in parallel and a complex and heterogeneous molecular interconnection. We discovered that the same lysine residues in different monomers were simultaneously involved in various cross-link types or remained unmodified. Furthermore, both types of cross-linking domains, Lys-Pro and Lys-Ala domains, participate not only in bifunctional inter- but also in intra-domain cross-links. We elucidated the sequences of several desmosine-containing peptides and the contribution of distinct domains such as 6, 14 and 25. In contrast to earlier assumptions proposing that desmosine cross-links are formed solely between two domains, we elucidated the structure of a peptide that proves a desmosine formation with participation of three Lys-Ala domains. In summary, these results provide new and detailed insights into the cross-linking process, which takes place within and between human tropoelastin units in a stochastic manner.

Published
2019

19. Elastin is heterogeneously cross-linked

Author

Schräder, C.U., Heinz, A., Majovsky, P., Mayack, B.K., Brinckmann, J., Sippl, W., Schmelzer, C.E.H., and Publica

Abstract

Elastin is an essential vertebrate protein responsible for the elasticity of force-bearing tissues such as those of the lungs, blood vessels, and skin. One of the key features required for the exceptional properties of this durable biopolymer is the extensive covalent cross-linking between domains of its monomer molecule tropoelastin. To date, elastin's exact molecular assembly and mechanical properties are poorly understood. Here, using bovine elastin, we investigated the different types of cross-links in mature elastin to gain insight into its structure. We purified and proteolytically cleaved elastin from a single tissue sample into soluble cross-linked and noncross-linked peptides that we studied by high-resolution MS. This analysis enabled the elucidation of cross-links and other elastin modifications. We found that the lysine residues within the tropoelastin sequence were simultaneously unmodified and involved in various types of cross-links with different other domains. The Lys-Pro domains were almost exclusively linked via lysinonorleucine, whereas Lys-Ala domains were found to be cross-linked via lysinonorleucine, allysine aldol, and desmosine. Unexpectedly, we identified a high number of intramolecular cross-links between lysine residues in close proximity. In summary, we show on the molecular level that elastin formation involves random cross-linking of tropoelastin monomers resulting in an unordered network, an unexpected finding compared with previous assumptions of an overall beaded structure.

Published
2018

24. Production from both wild harvest and cultivation:The cross-border Swertia chirayita (Gentianaceae) trade

Author

Cunningham, A. B., Brinckmann, J. A., Schippmann, U., Pyakurel, D., Cunningham, A. B., Brinckmann, J. A., Schippmann, U., and Pyakurel, D.

Abstract

Ethnopharmacological relevance: Swertia chirayita is the most widely traded species in a genus of 150 species, many of which are used in traditional medicine. S. chirayita is used mainly in Ayurvedic and Tibetan systems of medicine and the homoeopathic system of medicine as well as in regional folk medicine. Primarily wild collected, with some cultivation. S. chirayita is traded as a medicinal substance and exported in the forms of dried whole plant or extract of whole plant individually and/or as active ingredients of Ayurvedic medicines. S. chirayita export valuations continue to make S. chirayita one of Nepal's highest foreign exchange earning medicinal plant species. Aims of the review: The aims of this review were first, to assess the scale of the global trade in S. chirayita, second, to review evidence from plant population biology and from studies on the impacts of wild harvest on S. chirayita populations and cultivation as an alternative source of supply. Methods: The taxonomy and trade names for S. chirayita were reviewed, followed by a synthesis of published information on Swertia population biology and studies on impacts of wild S. chirayita harvest from across the geographic range of this species. Data on the prices paid for S. chirayita were then compiled for the period 2001–2017, followed by an analysis of global trade data for S. chirayita. Results and conclusions: Based on India import data and assuming an estimate in an earlier study that 60% of Nepal's S. chirayita production goes to India and 35% to Tibet, then Nepal's 2013 annual production was about 711 metric tonnes (MT) of which about 675.6 MT would be exported (India + Tibet). Nepal's 2014 annual production would be an estimated 503.25 MT of which about 478 MT would be exported. Declines in S. chirayita populations have been widely noted across its range. In India, since, Ethnopharmacological relevance: Swertia chirayita is the most widely traded species in a genus of 150 species, many of which are used in traditional medicine. S. chirayita is used mainly in Ayurvedic and Tibetan systems of medicine and the homoeopathic system of medicine as well as in regional folk medicine. Primarily wild collected, with some cultivation. S. chirayita is traded as a medicinal substance and exported in the forms of dried whole plant or extract of whole plant individually and/or as active ingredients of Ayurvedic medicines. S. chirayita export valuations continue to make S. chirayita one of Nepal's highest foreign exchange earning medicinal plant species. Aims of the review: The aims of this review were first, to assess the scale of the global trade in S. chirayita, second, to review evidence from plant population biology and from studies on the impacts of wild harvest on S. chirayita populations and cultivation as an alternative source of supply. Methods: The taxonomy and trade names for S. chirayita were reviewed, followed by a synthesis of published information on Swertia population biology and studies on impacts of wild S. chirayita harvest from across the geographic range of this species. Data on the prices paid for S. chirayita were then compiled for the period 2001–2017, followed by an analysis of global trade data for S. chirayita. Results and conclusions: Based on India import data and assuming an estimate in an earlier study that 60% of Nepal's S. chirayita production goes to India and 35% to Tibet, then Nepal's 2013 annual production was about 711 metric tonnes (MT) of which about 675.6 MT would be exported (India + Tibet). Nepal's 2014 annual production would be an estimated 503.25 MT of which about 478 MT would be exported. Declines in S. chirayita populations have been widely noted across

Published
2018

26. Novel insights in the link between type 2 innate signals and initiation of profibrotic pathways

Author

Willenborg, S., Knipper, J. A., Brinckmann, J., Bloch, W., Maass, T., Wagener, R., Krieg, T., Sutherland, T., Munitz, A., Rothenberg, M. E., Niehoff, A., Richardson, R., Hammerschmidt, M., Allen, E., Eming, S. A., Willenborg, S., Knipper, J. A., Brinckmann, J., Bloch, W., Maass, T., Wagener, R., Krieg, T., Sutherland, T., Munitz, A., Rothenberg, M. E., Niehoff, A., Richardson, R., Hammerschmidt, M., Allen, E., and Eming, S. A.

Published
2016

30. Identification of PLOD2 as Telopeptide Lysyl Hydroxylase, an Important Enzyme in Fibrosis

Author

Slot, A.J. van der, Zuurmond, A.M., Bardoel, A.F.J., Wijmenga, C., Pruijs, H.E.H., Sillence, D.O., Brinckmann, J., Abraham, D.J., Black, C.M., Verzijl, N., Groot, J. de, Hanemaaijer, R., Koppele, J.M. te, Huizinga, T.W.J., Bank, R.A., and TNO Preventie en Gezondheid

Subjects
Biomedical Research, DNA, Complementary, Unclassified drug, Genotype, Clinical article, DNA Mutational Analysis, Molecular Sequence Data, Mutation, Missense, Hydroxylation, Bone and Bones, Enzyme analysis, Telopeptides, Animals, Humans, Amino Acid Sequence, RNA, Messenger, Biology, Genetic disorder, Skin, Tissue, Scleroderma, Systemic, Telopeptide lysyl hydroxylase, Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, Reverse Transcriptase Polymerase Chain Reaction, Messenger RNA, Linkage (Genetics), Exons, Syndrome, Fibroblasts, Complementary DNA, Fibrosis, Enzymes, Polymerase chain reaction, Procollagen lysine 2 oxoglutarate 5 dioxygenase, Fibrogenesis, Fibroblast culture, Cross-Linking Reagents, Human cell, Mutation, RNA, Systemic sclerosis, Osteogenesis imperfecta, Collagen, Peptides, Nucleotide sequence
Abstract

The hallmark of fibrotic processes is an excessive accumulation of collagen. The deposited collagen shows an increase in pyridinoline cross-links, which are derived from hydroxylated lysine residues within the telopeptides. This change in cross-linking is related to irreversible accumulation of collagen in fibrotic tissues. The increase in pyridinoline cross-links is likely to be the result of increased activity of the enzyme responsible for the hydroxylation of the telopeptides (telopeptide lysyl hydroxylase, or TLH). Although the existence of TLH has been postulated, the gene encoding TLH has not been identified. By analyzing the genetic defect of Bruck syndrome, which is characterized by a pyridinoline deficiency in bone collagen, we found two missense mutations in exon 17 of PLOD2, thereby identifying PLOD2 as a putative TLH gene. Subsequently, we investigated fibroblasts derived from fibrotic skin of systemic sclerosis (SSc) patients and found that PLOD2 mRNA is highly increased indeed. Furthermore, increased pyridinoline cross-link levels were found in the matrix deposited by SSc fibroblasts, demonstrating a clear link between mRNA levels of the putative TLH gene (PLOD2) and the hydroxylation of lysine residues within the telopeptides. These data underscore the significance of PLOD2 in fibrotic processes. Chemicals/CAS: collagen, 9007-34-5; procollagen lysine 2 oxoglutarate 5 dioxygenase, 9059-25-0; Collagen, 9007-34-5; Cross-Linking Reagents; DNA, Complementary; Peptides; PLOD2 protein, human, EC 1.14.11.4; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, EC 1.14.11.4; RNA, Messenger

Published
2003

33. Scleroderma and related disorders: 223. Long Term Outcome in a Contemporary Systemic Sclerosis Cohort

Author

Nihtyanova, S., primary, Ong, V., additional, Black, C., additional, Denton, C., additional, Lutalo, P., additional, Shattles, W., additional, Jones, H., additional, Nouri, R., additional, Hepburn, A., additional, Chard, M., additional, Horwood, N., additional, Lynn, M., additional, Duke, O., additional, Kiely, P., additional, Zouita, L., additional, Davies, U., additional, Hughes, R., additional, Lloyd, M., additional, Nikitorowicz Buniak, J., additional, Shiwen, X., additional, Abraham, D., additional, Stratton, R., additional, Hugle, T., additional, Schuetz, P., additional, Daikeler, T., additional, Tyndall, A., additional, Matucci-Cerinic, M., additional, Walker, U. A., additional, van Laar, J. M., additional, Pauling, J. D., additional, Flower, V., additional, McHugh, N., additional, Liu, S., additional, Leask, A., additional, Aden, N., additional, Khan, K., additional, Hoyles, R., additional, Bhagat, S., additional, Drummond, T., additional, Goh, C., additional, Busch, R., additional, Hall, F., additional, Meyer, P., additional, Moinzadeh, P., additional, Krieg, T., additional, Hellmich, M., additional, Brinckmann, J., additional, Neumann, E., additional, Mueller-Ladner, U., additional, Kreuter, A., additional, Dumitresco, D., additional, Rosenkranz, S., additional, Hunzelmann, N., additional, Binai, N., additional, Huegle, T., additional, van Laar, J., additional, Sonnylal, S., additional, Tam, A., additional, Norman, J., additional, de Crombrugghe, B., additional, Chighizola, C. B., additional, Luigi Meroni, P., additional, Coghlan, G., additional, Newton, F., additional, Derrett-Smith, E. C., additional, Dooley, A., additional, Baliga, R., additional, Hobbs, A., additional, MacAllister, R., additional, Futema, M., additional, Pantelidis, P., additional, Renzoni, E., additional, Schreiber, B. E., additional, Coghlan, G. J., additional, Wells, A. U., additional, Welsh, K., additional, Fonseca, C., additional, Ponticos, M., additional, Wells, A., additional, Guillevin, L., additional, Schwierin, B., additional, Rosenberg, D., additional, Silkey, M., additional, Parapuram, S., additional, Shi-wen, X., additional, Nihtyanova, S., additional, Ahmed Abdi, B., additional, and Xu, S., additional

Published
2011
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37. Interleukin 4 and prolonged hypoxia induce a higher gene expression of lysyl hydroxylase 2 and an altered cross-link pattern: Important pathogenetic steps in early and late stage of systemic scleroderma?

Author

Brinckmann, J., primary, Kim, S., additional, Wu, J., additional, Reinhardt, D.P., additional, Batmunkh, C., additional, Metzen, E., additional, Notbohm, H., additional, Bank, R.A., additional, Krieg, T., additional, and Hunzelmann, N., additional

Published
2005
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