Fibrillin assemblies: Extracellular determinants of tissue formation and fibrosis

Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, USA. .
Fibrogenesis & Tissue Repair 12/2010; 3(1):24. DOI: 10.1186/1755-1536-3-24
Source: PubMed


The extracellular matrix (ECM) plays a key role in tissue formation, homeostasis and repair, mutations in ECM components have catastrophic consequences for organ function and therefore, for the fitness and survival of the organism. Collagen, fibrillin and elastin polymers represent the architectural scaffolds that impart specific mechanic properties to tissues and organs. Fibrillin assemblies (microfibrils) have the additional function of distributing, concentrating and modulating local transforming growth factor (TGF)-β and bone morphogenetic protein (BMP) signals that regulate a plethora of cellular activities, including ECM formation and remodeling. Fibrillins also contain binding sites for integrin receptors, which induce adaptive responses to changes in the extracellular microenvironment by reorganizing the cytoskeleton, controlling gene expression, and releasing and activating matrix-bound latent TGF-β complexes. Genetic evidence has indicated that fibrillin-1 and fibrillin-2 contribute differently to the organization and structural properties of non-collagenous architectural scaffolds, which in turn translate into discrete regulatory outcomes of locally released TGF-β and BMP signals. Additionally, the study of congenital dysfunctions of fibrillin-1 has yielded insights into the pathogenesis of acquired connective tissue disorders of the connective tissue, such as scleroderma. On the one hand, mutations that affect the structure or expression of fibrillin-1 perturb microfibril biogenesis, stimulate improper latent TGF-β activation, and give rise to the pleiotropic manifestations in Marfan syndrome (MFS). On the other hand, mutations located around the integrin-binding site of fibrillin-1 perturb cell matrix interactions, architectural matrix assembly and extracellular distribution of latent TGF-β complexes, and lead to the highly restricted fibrotic phenotype of Stiff Skin syndrome. Understanding the molecular similarities and differences between congenital and acquired forms of skin fibrosis may therefore provide new therapeutic tools to mitigate or even prevent disease progression in scleroderma and perhaps other fibrotic conditions.

Download full-text


Available from: Jacopo Olivieri, Oct 01, 2015
  • Source
    • "Absence of tenascin C alters neural stem cell number and function in the subventricular zone [27]; tenascin C deletion has also been shown to affect primitive cell populations in the hematopoietic system, raising the possibility that it participates in several stem cell niches as a modulator of growth factor signaling [28]. Despite the fact that both are largely restricted to developing fetal tissues [29], enhanced expression of fibrillin-2 and tenascin C has been observed in adults with fibroproliferative conditions, such as wound healing and sclerosis [23] [25] [30]. Moreover, a fair amount of clusterin was found in FE while none was detected in AE, which might be responsible for less apoptosis observed in FE expanded ASDSCs since clusterin could inhibit apoptosis by interacting with activated Bax [31]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autologous cells suffer from limited cell number and senescence during ex vivo expansion for cartilage repair. Here we found that expansion on extracellular matrix (ECM) deposited by fetal synovium-derived stem cells (SDSCs) (FE) was superior to ECM deposited by adult SDSCs (AE) in promoting cell proliferation and chondrogenic potential. Unique proteins in FE might be responsible for the rejuvenation effect of FE while advantageous proteins in AE might contribute to differentiation more than to proliferation. Compared to AE, the lower elasticity of FE yielded expanded adult SDSCs with lower elasticity which could be responsible for the enhancement of chondrogenic and adipogenic differentiation. MAPK and noncanonical Wnt signals were actively involved in ECM-mediated adult SDSC rejuvenation.
    Biomaterials 10/2013; 35(2). DOI:10.1016/j.biomaterials.2013.09.099 · 8.56 Impact Factor
  • Source
    • "Fibrillins play an important role in maintaining tissue integrity and homeostasis through the modulation of TGF-β and bone morphogenetic protein signaling [8]. Fibrillin-2 binds to other ECM proteins, forming microfibrils, and is mostly expressed during embryogenesis [9]. Tenascin-C is a hexameric ECM glycoprotein, and its expression is restricted to the fetal period of development [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To determine the extracellular matrix proteins involved in the formation of human granular and lattice type I corneal stromal dystrophies, the expression patterns of fibrillin-2, tenascin-C, matrilin-2, and matrilin-4 were compared in human corneal stromal dystrophy samples. Ten cases of granular dystrophy, 7 cases of lattice dystrophy, and 6 normal corneal buttons collected during corneal transplantation were examined for their expression patterns of fibrillin-2, tenascin-C, matrilin-2, and matrilin-4 by immunohistochemistry. Highly elevated fibrillin-2, tenascin-C, matrilin-2, and matrilin-4 were observed in the epithelial layer of both granular and lattice type I dystrophies. Fibrillin-2, tenascin-C, and matrilin-4 in the granular dystrophy and all antibodies in the lattice dystrophy showed statistically significant staining in the corneal stroma (p<0.05). Interestingly, fibrillin-2, matrilin-2, and matrilin-4 stained significantly in amyloid plaques of lattice type 1 dystrophy. Fibrillin-2, tenascin-C, matrilin-2, and matrilin-4 may be markers of the pathogenesis of either granular or lattice type I corneal dystrophy, as revealed by immunohistochemical analysis. Each molecule seems to be involved in the regeneration and reorganization of the corneal matrix in granular and lattice type I dystrophies.
    Molecular vision 07/2012; 18:1927-36. · 1.99 Impact Factor
  • Source
    • "Collectively, the human and mouse findings imply that LTBP4 may perform two roles: 1) a structural role in promoting elastogenesis and 2) a functional role in regulating TGF-β activity. However, it is possible that LTBP4 plays exclusively a structural role and that increased TFG-β activity is actually a consequence of abnormal elastic fibers and perturbed extracellular milieu, which, in turn, leads to a promiscuous activation of latent TGF-β, similarly to what is seen in human and mouse mutants for fibrillin-1 (reviewed in[Olivieri et al., 2010]). The fact that attenuation of TFG-β2 activity, a TFG-β isoform that does not interact directly with LTBP4, partially rescues abnormal lung development in Ltbp4S −/− mice, favors the latter hypothesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Latent transforming growth factor beta (TGF-β) binding proteins (LTBPs) are large extracellular glycoproteins structurally similar to fibrillins. They perform intricate and important roles in the extracellular matrix (ECM) and perturbations of their function manifest as a wide range of diseases. LTBPs are major regulators of TGF-β bioavailability and action. In addition, LTBPs interact with other ECM proteins-from cytokines to large multi-factorial aggregates like microfibrils and elastic fibers, affecting their genesis, structure, and performance. In the present article, we review recent advancements in the field and relate the complex roles of LTBP in development and homeostasis.
    Journal of Cellular Biochemistry 02/2012; 113(2):410-8. DOI:10.1002/jcb.23385 · 3.26 Impact Factor
Show more