Fibrillin-Rich Microfibrils—Structural and Instructive Determinants of Mammalian Development and Physiology

Child Health Institute of New Jersey, Robert W. Johnson Medical School, New Brunswick, New Jersey, USA.
Connective tissue research (Impact Factor: 1.61). 02/2008; 49(1):1-6. DOI: 10.1080/03008200701820708
Source: PubMed


Fibrillin-rich microfibrils have emerged recently as an informative model system in which to study fundamental questions related to extracellular matrix biology and connective tissue pathophysiology. As a result, these studies have yielded novel clinical concepts and promising therapeutic strategies. These achievements have been based on the realization from studies of genetically engineered mice that mutations in fibrillin-rich microfibrils impair both the structural integrity of connective tissues and signaling events by TGF-beta/BMP superfamily members. In this view, fibrillin-rich microfibrils represent architectural assemblies that specify the concentration and timely release of local effectors of morphogenesis and tissue remodeling, in addition to conferring structural integrity to individual organ systems. This review summarizes the evidence supporting our current understanding of the structural and instructive roles that fibrillin-rich microfibrils play during embryonic development and in human diseases.

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    • "Whilst the anisotropic nature of skin structure undoubtedly complicates the task of assigning specific mechanical properties to individual components [23] [24], the elastic fibre system is thought to be fundamental in mediating tissue resilience [25]. Elastic fibres may be composed of multiple components, including cross-linked elastin, fibrillin-rich microfibrils, microfibril-associated glycoproteins (MAGPs), fibulins and latent transforming growth factor ␤-binding proteins (LTBPs) (for reviews see [26] [27] [28]). In young skin, the elastic fibre system adopts a characteristic highly ordered architecture , in which perpendicularly oriented fibrillin-rich microfibrils (oxytalan fibres) at the DEJ merge with large diameter elastic fibres in the reticular dermis which are composed primarily of elastin [29] [30]. "
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    ABSTRACT: Ageing of human skin may result from both the passage of time (intrinsic ageing) and from cumulative exposure to external influences (extrinsic ageing) such as ultraviolet radiation (UVR) which promote wrinkle formation and loss of tissue elasticity. Whilst both ageing processes are associated with phenotypic changes in cutaneous cells, the major functional manifestations of ageing occur as a consequence of structural and compositional remodeling of normally long-lived dermal extracellular matrix proteins. This review briefly considers the effects of ageing on dermal collagens and proteoglycans before focusing on the mechanisms, functional consequences and treatment of elastic fibre remodeling in ageing skin. The early stages of photoageing are characterised by the differential degradation of elastic fibre proteins and whilst the activity of extracellular matrix proteases is increased in photoexposed skin, the substrate specificity of these enzymes is low. We have recently shown however, that isolated fibrillin microfibrils are susceptible to direct degradation by physiologically attainable doses of UV-B radiation and that elastic fibre proteins as a group are highly enriched in UV-absorbing amino acid residues. Functionally, elastic fibre remodeling events may adversely impact on: the mechanical properties of tissues, the recruitment and activation of immune cells, the expression of matrix metalloproteinases and cytokine signaling (by perturbing fibrillin microfibril sequestration of TGFβ). Finally, newly developed topical interventions appear to be capable of regenerating elements of the elastic fibre system in ageing skin, whilst systemic treatments may potentially prevent the pathological tissue remodeling events which occur in response to elastic fibre degradation.
    Maturitas 07/2011; 69(3):249-56. DOI:10.1016/j.maturitas.2011.04.011 · 2.94 Impact Factor
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    • "Although elastic fibers are progressively degraded during the course of life, leading to the loss of their original mechanical properties, they are considered to be highly stable polymers. Microfibrils which form a structural scaffold for tropoelastin aggregates are filamentous assemblies mainly composed of fibrillins -1 and -2 (Ramirez et al., 2008). Microfibrils can also form macroaggregates devoid of elastin. "
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    ABSTRACT: Extracellular matrix (ECM) is a complex network of various proteins and proteoglycans which provides tissues with structural strength and resilience. By harvesting signaling molecules like growth factors ECM has the capacity to control cellular functions including proliferation, differentiation and cell survival. Latent transforming growth factor β (TGF-β) binding proteins (LTBPs) associate fibrillar structures of the ECM and mediate the efficient secretion and ECM deposition of latent TGF-β. The current work was conducted to determine the regulatory regions of LTBP-3 and -4 genes to gain insight into their tissue-specific expression which also has impact on TGF-β biology. Furthermore, the current research aimed at defining the ECM targeting of the N-terminal variants of LTBP-4 (LTBP-4S and -4L), which is required to understand their functions in tissues and to gain insight into conditions in which TGF-β is activated. To characterize the regulatory regions of LTBP-3 and -4 genes in silico and functional promoter analysis techniques were employed. It was found that the expression of LTBP-4S and -4L are under control of two independent promoters. This finding was in accordance with the observed expression patterns of LTBP-4S and -4L in human tissues. All promoter regions characterized in this study were TATAless, GC-rich and highly conserved between human and mouse species. Putative binding sites for Sp1 and GATA family of transcription factors were recognized in all of these regulatory regions. It is possible that these transcription factors control the basal expression of LTBP-3 and -4 genes. Smad binding element was found within the LTBP-3 and -4S promoter regions, but it was not present in LTBP-4L promoter. Although this element important for TGF-β signaling was present in LTBP-4S promoter, TGF-β did not induce its transcriptional activity. LTBP-3 promoter activity and mRNA expression instead were stimulated by TGF-β1 in osteosarcoma cells. It was found that the stimulatory effect of TGF-β was mediated by Smad and Erk MAPK signaling pathways. The current work explored the ECM targeting of LTBP-4S and identified binding partners of this protein. It was found that the N-terminal end of LTBP-4S possesses fibronectin (FN) binding sites which are critical for its ECM targeting. FN deficient fibroblasts incorporated LTBP-4S into their ECM only after addition of exogenous FN. Furthermore, LTBP-4S was found to have heparin binding regions, of which the C-terminal binding site mediated fibroblast adhesion. Soluble heparin prevented the ECM association of LTBP-4S in fibroblast cultures. In the current work it was observed that there are significant differences in the secretion, processing and ECM targeting of LTBP-4S and -4L. Interestingly, it was observed that most of the secreted LTBP-4L was associated with latent TGF-β1, whereas LTBP-4S was mainly secreted as a free form from CHO cells. This thesis provides information on transcriptional regulation of LTBP-3 and -4 genes, which is required for the deeper understanding of their tissue-specific functions. Further, the current work elucidates the structural variability of LTBPs, which appears to have impact on secretion and ECM targeting of TGF-β. These findings may advance understanding the abnormal activation of TGF-β which is associated with connective tissue disorders and cancer. Soluväliaine on proteiineista muodostuvien säikeiden ja niitä ympäröivien proteoglykaanien sekä glykoproteiinien muodostama kokonaisuus, joka paitsi tukee kudosten soluja myös osallistuu niiden toimintojen säätelyyn kontrolloimalla signaalimolekyylien aktiivisuutta. Soluväliaineen tyypillisimpiä proteiineja ovat kollageenit, elastiini sekä fibrilliinit, jotka muodostavat säiemäisiä rakenteita. Näiden lisäksi soluväliaineessa on lukuisia muita proteiineja, jotka ovat oleellisia kudosten ja elinten normaalille toiminnalle. Soluväliaineen proteiinien ilmentymisessä tapahtuvat muutokset tai niiden rakenteellinen poikkeavuus saattavat siten vaikuttaa erilaisten sidekudossairauksien tai syövän syntyyn. LTBP-proteiinit (latent TGF-β binding protein), jotka olivat tämän tutkimuksen kohteena, ovat LTBP/fibrilliini-perheeseen kuuluvia soluväliaineen proteiineja. LTBP-1, -3 ja -4 erittyvät soluista sekä vapaina että liittyneenä TGF-β-kasvutekijän kanssa. TGF-β, joka puolestaan on tärkeä solujen kasvun ja erilaistumisen säätelijä, myös varastoituu soluväliaineen rakenteisiin LTBP-proteiinien välityksellä. LTBP-proteiineilla on osoitettu olevan tärkeä merkitys TGF-β kasvutekijän aktivoitumisessa, joten LTBP-proteiinien ilmentymiseen vaikuttavien tekijöiden sekä niiden rakenteellisten ominaisuuksien tunteminen on tärkeää TGF-β:n säätelyn kannalta. LTBP-proteiineilla on kudoksissa myös muita, TGF-β:sta riippumattomia tehtäviä, kuten avustaminen elastisten säikeiden muodostumisessa. Tämän väitöstutkimuksen tavoitteena oli tutkia LTBP-3 ja -4 geenien ilmentymiseen vaikuttavia tekijöitä sekä määrittää kyseisten geenien säätelystä vastaavat promoottorialueet. Tutkimuksessa löydettiin useita potentiaalisia transkriptiotekijöiden sitoutumiskohtia. TGF-β:n havaittiin lisäävän LTBP-3 geenin promoottoriaktiivisuutta osteosarkoomasoluissa. TGF-β:n vaikutusten välittäjiksi osoittautuivat Smad-ja Erk MAPK- signaalireitit, joiden kohdemolekyylit sitoutuvat Smad3/4 ja AP-1 elementteihin LTBP-3 geenin säätelyalueella. Tutkimuksessa osoitettiin myös, että LTBP-4-proteiinin N-terminaaliset varianttimuodot (LTBP-4S ja -4L) ovat kahden itsenäisen geeenisäätelyalueen alaisia. LTBP-3, -4S ja -4L promoottoreille yhteistä olivat GATA- ja Sp1-transkriptiotekijöiden sitoutumiskohdat, jotka mahdollisesti vastaavat kyseisten geenien perustranskriptiosta.Kaikki säätelyalueet olivat myös hyvin GC-rikkaita. Väitöstutkimuksessa selvitettiin myös LTBP-4S- ja -4L-proteiinien liittymistä soluväliaineen rakenteisiin. LTBP-4S:n N-terminaalisen alueen havaittiin sitoutuvan soluväliaineen fibronektiini-proteiiniin. Kyseisen vuorovaikutuksen osoitettiin olevan välttämätön LTBP-4S:n varhaiselle liittymiselle soluväliaineen rakenteisiin, kun taas kehittyneemmässä soluväliaineessa muut vuorovaikutukset näyttäisivät määrävän LTBP-4S:n sijainnin. Lisäksi tutkimuksessa löydettiin hepariinia sitovia alueita LTBP-4S-molekyylistä, jotka ainakin osittain toimivat soluadheesiossa tarttumispintana. Väitöstutkimuksen mukaan LTBP-4S- ja -4L-proteiinien erittymisessä soluista sekä niiden prosessoinnissa on merkittäviä eroja. Tärkeä havainto oli TGF-β1:n sitoutuminen LTBP-4L:n kanssa. LTBP-4S sen sijaan erittyi soluista pääasiassa vapaana muotona. Väitöstutkimuksessa tehdyt havainnot auttavat ymmärtämään LTBP-3 ja -4-proteiinien ilmentymistä kudoksissa. Lisäksi havaitut LTBP-proteiinien vuorovaikutukset muiden soluväliainemolekyylien kanssa selkeyttävät TGF-β-kasvutekijän sijoittumista soluväliaineen rakenteisiin ja ovat siten tärkeitä TGF-β-aktivaation ymmärtämiselle.
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    ABSTRACT: The assembly of elastic fibers in tissues that undergo repeated cycles of extension and recoil, such as the lungs and blood vessels, is dependent on the proper interaction and alignment of tropoelastin with a microfibrillar scaffold. Here, we describe in vivo histopathological effects of neuraminidase-1 (Neu1) deficiency on elastin assembly in the lungs and aorta of mice. These mice exhibited a tight-skin phenotype very similar to the Tsk mouse. Normal septation of Neu1-null mice did not occur in neonatal mice, resulting in enlarged alveoli that were maintained in adults. The abnormal development of elastic fibers was remarkable under electron microscopy and confirmed by the overlapping distribution of elastin, fibrillin-1, fibrillin-2, and fibulin-5 (Fib-5) by the light microscopy immunostainings. Fib-5 fibers appeared diffuse and unorganized around the alveolar walls and the apex of developing secondary septal crests. Fibrillin-2 deposition was also abnormal in neonatal and adult lungs. Dispersion of myofibroblasts appeared abnormal in developing lungs of Neu1-null mice, with a random distribution of myofibroblast around the alveolar walls, rather than concentrating at sites of elastin synthesis. The elastic lamellae in the aorta of the Neu1-null mice were thinner and separated by hypertrophic smooth muscle cells that were surrounded by an excess of the sialic acid-containing moieties. The concentration of elastin, as measure by desmosine levels, was significantly reduced in the aorta of Neu1-null mice. Message levels for tropoelastin and Fib-5 were normal, suggesting the elastic fiber defects in Neu1-null mice result from impaired extracellular assembly.
    AJP Lung Cellular and Molecular Physiology 08/2008; 295(4). DOI:10.1152/ajplung.90346.2008 · 4.08 Impact Factor
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