New strategies for treating congenital musculoskeletal disorders are needed. Current treatments are limited and aim to prolong ambulation and survival.Cellular microenvironments such as stem cell niches in muscle and bone are defined by extracellular microfibrillar networks (EMFN) which are required for tissue structure and function. EMFN made of fibrillin-1 and -2, and collagen VI with associated ligands are of particular interest since human mutations in EMFN components result in disorders with overlapping clinical features.
The molecular mechanisms by which perturbed cellmatrix interactions lead to musculoskeletal disorders are not well understood, and common or shared pathogenetic mechanisms have not yet been uncovered. From genetic evidence in humans and mice it becomes clear that EMFN together with their associated ligands are controlling homeostasis of multiple tissues. However, the underlying molecular pathways remain obscure. Our previous investigations have identified EMFN consisting of fibrillins as regulators/ modulators of growth factor activity. This corroborates the emerging concept that extracellular matrix proteins are actively regulating growth factor activity and bioavailability.
This concept opens novel treatment avenues for a wide range of connective tissue diseases which were thought to be incurable due to defects in proteins of purely architecturalnature.
Elastin-Microfibril-Interface-Located-proteINs, the EMILIN, comprise a family of three structurally homologous extracellular matrix (ECM) glycol-proteins that serve as versatile regulators of cell adhesion, migration, and proliferation, but also as unique modulators of extracellular signalling pathways. EMILINs were found to influence pro-TGF-βprocessing, modulate Wnt and Hedgehog signaling, activate death receptor mediated apoptosis, and communicate with cells via α4β1 and α9β1 integrin mediated signalling. We recently found that EMILINs are targeted to fibrillin microfibrils implicating them in the disease pathogenesis of fibrillin-related disorders. Recently, we showed that EMILIN-1 directly interacts with fibulin-4 and is required for its ECM deposition within specialized cellular microenvironments (Schiavinato et al., 2017). Fibulin-4 mutations lead to flexion contractures in patients and mice. Mutations in fibrillin-2 also result in flexion contractures of the large joints in Beals Syndrome patients.
Mutations in building blocks of the EMFN manifest in connective tissue disorders such as Marfan syndrome (MFS) characterized by long bone overgrowth, aortic aneurysm formation, and muscle weakness. Understanding how structural changes induced by fibrillin-1 mutation impact the architecture of fibrillin microfibrils (FMF), which then translates into an altered activation state of targeted growth factors, represents a huge challenge in elucidating the genotype-phenotype correlations in MFS. In collaboration with the group of Katja Schenke-Layland (University of Tübingen) we could show that Raman microspectroscopy is able to reveal structural changes in fibrillin-1 microfibrils and elastic fiber networks and to discriminate between normal and diseased networks in vivo and in vitro (Brauchle et al., 2017).
For this purpose we analyzed a Marfan mouse model in which the C-terminal half of fibrillin-1 is truncated. Skin biopsies and organotypic co-cultures from isolated primary fibroblasts were utilized for Raman measurements. In our study, structural elements in an area of 400 × 700 nm were scanned based on the volume of the Raman laser spot. Given the length of fibrillin-1 monomers of 150 nm and a 50-80 nm periodicity Raman microspectroscopy is able to pick up structural changes of FMF on the molecular level. Therefore Raman microspectroscopy may be utilized as a non-invasive and sensitive diagnostic tool to identify connective tissue disorders and monitor their disease progression.
The short most C-terminal domain of the collagen VI α3 chain, was recently proposed to be released as an adipokine enhancing tumor progression, fibrosis, inflammation and insulin resistance, and therefore named “endotrophin”. We showed that the metalloproteinase BMP-1 is involved in the release of endotrophin. Moreover, we provided evidence that a variety of endotrophin-containing fragments are present in various tissues and body fluids (Heumüller et al., 2019). Among these, a large C2-C5 fragment containing endotrophin, is released by furin-like proprotein convertase cleavage. This detailed information on the processing of the collagen VI α3 chain therefore provides a basis to unravel the function of endotrophin (C5) and larger endotrophin-containing fragments and to refine their use as circulating biomarkers of disease progression.
In addition, we showed in collaboration with the group of Clair Baldock (University of Manchester) that genetic ablation of the metalloproteinase ADAMTS10 in mice ressembles recessive Weill-Marchesani syndrome (WMS). WMS mice have an increased skeletal muscle mass and more myofibres which correlated with increased expression of growth differentiation factor (GDF8) and BMPs (Mularczyk et al., 2018). Furthermore, our collaborative work addressed the question how modulators such as BMPER exert their function in the extracellular microenvironment (Lockhart-Cairns et al., 2019).
This project has the potential to provide a comprehensive and fundamental understanding of the molecular pathomechanisms caused by mutations in EMFN components which will lay the foundation for future translational approaches of congenital musculoskeletal disorders
1. Brauchle, E., Bauer, H., Fernes, P., Zuk, A., Schenke-Layland, K., and Sengle, G. (2017). Raman microspectroscopy as a diagnostic tool for the non-invasive analysis of fibrillin-1 deficiency in the skin and in the in vitro skin models.Acta Biomater. 52: 41-48.
2. Heumüller SE, Talantikite M, Napoli M, Armengaud J, Mörgelin M, Hartmann U, Sengle G, Paulsson M, Moali C, Wagener R. C-terminal proteolytic cleavage of the collagen VI α3 chain by BMP-1 and proprotein convertase(s): Endotrophin is released in fragments of different size, JBC 2019, in press.
3. Lockhart-Cairns MP, Lim KTW, Zuk A, Godwin ARF, Cain SA, Sengle G, Baldock C. Internal cleavage and synergy with twisted gastrulation enhance BMP inhibition by BMPER. Matrix Biol. (2019); 77: 73-86.
4. Mularczyk EJ, Singh M, Godwin ARF, Galli F, Humphreys N, Adamson AD, Mironov A, Cain SA, Sengle G, Boot-Handford RP, Cossu G, Kielty CM, Baldock C. ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome. Hum Mol Genet. (2018); 27: 3675-3687.
5. Schiavinato, A., Keene, D.R., Imhof, T., Doliana, R., Sasaki, T., and Sengle G. (2017). Fibulin-4 deposition requires EMILIN-1 in the extracellular matrix of osteoblasts. Sci Rep. 7: 5526.
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Chakkalakal SA, Heilig J, Baumann U, Paulsson M, and Zaucke F (2018). Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival. Int J Mol Sci 19.
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Lau D, Elezagic D, Hermes G, Morgelin M, Wohl AP, Koch M, Hartmann U, Hollriegl S, Wagener R, Paulsson M, Streichert T, and Klatt AR (2018). The cartilage-specific lectin C-type lectin domain family 3 member A (CLEC3A) enhances tissue plasminogen activator-mediated plasminogen activation. J Biol Chem 293, 203-214.
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Mularczyk EJ, Singh M, Godwin ARF, Galli F, Humphreys N, Adamson AD, Mironov A, Cain SA, Sengle G, Boot-Handford RP, Cossu G, Kielty CM, and Baldock C (2018). ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome. Hum Mol Genet 27, 3675-87.
Nuchel J, Ghatak S, Zuk AV, Illerhaus A, Morgelin M, Schonborn K, Blumbach K, Wickstrom SA, Krieg T, Sengle G, Plomann M, and Eckes B (2018). TGFB1 is secreted through an unconventional pathway dependent on the autophagic machinery and cytoskeletal regulators. Autophagy 14, 465-86.
Paulsson M, and Wagener R (2018). Matrilins. Methods Cell Biol 143, 429-46.
Schulz JN, Plomann M, Sengle G, Gullberg D, Krieg T, and Eckes B (2018). New developments on skin fibrosis - Essential signals emanating from the extracellular matrix for the control of myofibroblasts. Matrix Biol10.1016/j.matbio.2018.01.025.
van der Ven AT, Kobbe B, Kohl S, Shril S, Pogoda HM, Imhof T, Ityel H, Vivante A, Chen J, Hwang DY, Connaughton DM, Mann N, Widmeier E, Taglienti M, Schmidt JM, Nakayama M, Senguttuvan P, Kumar S, Tasic V, Kehinde EO, Mane SM, Lifton RP, Soliman N, Lu W, Bauer SB, Hammerschmidt M, Wagener R, and Hildebrandt F (2018). A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux. PLoS One 13, e0191224.
Wagener R, Lopez C, Kleinheinz K, Bausinger J, Aukema SM, Nagel I, Toprak UH, Seufert J, Altmuller J, Thiele H, Schneider C, Kolarova J, Park J, Hubschmann D, Murga Penas EM, Drexler HG, Attarbaschi A, Hovland R, Kjeldsen E, Kneba M, Kontny U, de Leval L, Nurnberg P, Oschlies I, Oscier D, Schlegelberger B, Stilgenbauer S, Wossmann W, Schlesner M, Burkhardt B, Klapper W, Jaffe ES, Kuppers R, and Siebert R (2018). IG-MYC (+) neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas. Blood 132, 2280-5.
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