Interactions of growth factors with the extracellular matrix
Growth factors of the TGF-β superfamily have been identified to be key inducers of important cellular events such as proliferation, differentiation, apoptosis, and specification of developmental fate, during embryogenesis as well as in adult life. Recent findings in fibrillin-1 deficient mice demonstrated that fibrillin containing microfibrils, small diameter (10-12 nm) architectural elements that are ubiquitously found in the connective tissue space, act as structural platforms important for the regulation of TGF-β signalling [1, 2].
These findings are underpinned by genetic evidence provided by human mutations in the fibrillin genes (FBN1 and FBN2) which result in a spectrum of congenital disorders (fibrillinopathies) including Marfan Syndrome characterized by phenotypes ranging from tall to short stature, from hyper- to hypomuscularity, and from hyperelastic and fragile skin to stiff skin. To date, it is unclear how fibrillins exert control over the growth and differentiation processes resulting in this spectrum of phenotypes. However, the most plausible explanation is that fibrillins regulate growth factor signaling essential for proper growth and homeostasis in multiple organ systems.
We have shown that fibrillin microfibrils also target and sequester bone morphogenetic proteins (BMPs) through specific molecular interactions between fibrillins and BMP propeptides. This work contributed significantly to the establishment of a new model of microfibril function which forms the basis for the current thinking about the fibrillinopathies . In this model, fibrillin microfibrils serve as spatio-temporal scaffolds actively targeting and sequestering growth factor signals. This way, microfibrils are viewed as informational highways where sequestered growth factor signals serve as interactive signposts utilized by cells traversing through the connective tissue space.
However, the exact function of interactions of growth factors of the TGF-β superfamily and fibrillin is not fully understood. Therefore our focus is to gain a detailed understanding of how the fibrillin microfibril scaffold, with its multiple sequestered growth factors, coordinates growth factor activity and bioavailability. This may lead to new therapies for Marfan Syndrome and related disorders and give rise to novel opportunities for tissue engineering.
Working model of multifunctional microfibril networks. Fibrillin microfibril networks with associated LTBPs sequester latent complexes of TGF-β. In addition, BMP molecules (butterflies) with their associated propeptides interact directly with fibrillin. Growth factor receptors may interact with their ligands while the ligands are positioned on the microfibril, or proteases may be secreted by the cell in order to release growth factor complexes positioned on the microfibril. Cells may determine where they are by information received directly from the microfibril through integrin or other receptors, or indirectly through other microfibril associated molecules
1. Neptune, E.R., Frischmeyer, P.A., Arking, D.E., Myers, L., Bunton, T.E., Gayraud, B., Ramirez, F., Sakai, L.Y., and Dietz, H.C. Dysregulation of TGFβ activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407-411 (2003)
2. Habashi, J.P., Judge, D.P., Holm, T.M., Cohn, R.D., Loeys, B.L., Cooper, T.K., Myers, L., Klein, E.C., Liu, G., Calvi, C., Podowski, M., Neptune, E.R., Halushka, M.K., Bedja, D., Gabrielson, K., Rifkin, D.B., Carta, L., Ramirez, F., Huso, D.L., and Dietz, H.C. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312,117-121 (2006)
3. Hynes, R.O. The extracellular matrix: not just pretty fibrils. Science 326, 1216-9 (2009)
16 Februar 2016
Institute for Biochemistry II, Joseph-Stelzmann-Strasse 52, D50931 Cologne
Suggestions and wishes: Gudrun Konertz