Transforming growth factor-s (TGF-s) are multifunctional growth factors that are secreted as inactive (latent) precursors in large protein complexes. These complexes include the latency-associated propeptide (LAP) and a latent transforming growth factor- binding protein (LTBP). Four isoforms of LTBPs (LTBP-1-LTBP-4) have been cloned and are believed to be structural components of connective tissue microfibrils and local regulators of TGF- tissue deposition and signaling. By using a gene trap strategy that selects for integrations into genes induced transiently during early mouse development, we have disrupted the mouse homolog of the human LTBP-4 gene. Mice homozygous for the disrupted allele develop severe pulmonary emphysema, cardiomyopathy, and colorectal cancer. These highly tissue-specific abnormalities are associated with profound defects in the elastic fiber structure and with a reduced deposition of TGF- in the extracellular space. As a consequence, epithelial cells have reduced levels of phosphorylated Smad2 proteins, overexpress c-myc, and undergo uncontrolled proliferation. This phenotype supports the predicted dual role of LTBP-4 as a structural component of the extracellular matrix and as a local regulator of TGF- tissue deposition and signaling.
The TGF‐β superfamily of growth factors consists of an increasing number of different polypeptide modulators of cell growth, differentiation, and morphogenesis. Three mammalian isoforms have been molecularly cloned. Numerous ways to regulate the expression of the TGF‐β genes have been identified. TGF‐βs are, for example, subject to regulation by retinoids, steroid hormones, and vitamin D. A characteristic feature in the biology of TGF‐βs is that they are usually secreted from cells in latent forms. The large latent complex consists of the small latent complex (TGF‐β and its propeptide) and a high molecular weight protease resistant binding protein, latent TGF‐β binding protein (LTBP). LTBPs are required for the proper folding and secretion of TGF‐β. TGF‐β is not just secreted from cultured cells but is deposited via LTBPs to the pericellular space, namely to the extracellular matrix. Release of these complexes and activation by proteases is under tight regulation and provides a means to rapidly increase local concentrations of TGF‐β. Biological events, where enhanced or focal proteolysis and activation of latent TGF‐β takes place, include cell invasion, tissue remodeling, and wound healing. Microsc. Res. Tech. 52:354–362, 2001. © 2001 Wiley‐Liss, Inc.
Idiopathic pulmonary fibrosis (IPF), ie, usual interstitial pneumonia in histopathology, is a disease characterized by tissue destruction and active areas of fibroproliferation in the lung. Gremlin (Drm), a member of the cysteine knot family of bone morphogenetic protein (BMP) inhibitors, functions to antagonize BMP-4-mediated signals during lung development. We describe here consistent overexpression of gremlin in the lung interstitium of IPF patients. Quantitative real-time reverse transcriptase-polymerase chain reaction analyses revealed considerably higher levels of gremlin mRNA in lung biopsies from IPF patients, the highest level being 35-fold higher compared to controls. Lung fibroblasts isolated from IPF patients also expressed elevated levels of gremlin, which was associated with impaired responsiveness to endogenous and exogenous BMP-4. Transforming growth factor--induced epithelial-tomesenchymal transition of A549 lung epithelial cells in culture was also associated with induction of gremlin mRNA expression. In addition, A549 cells transfected to overexpress gremlin were more susceptible to transforming growth factor--induced epithelial-to-mesenchymal transition. Gremlin-mediated inhibition of BMP-4 signaling pathways is likely to enhance the fibrotic response and reduce epithelial regeneration in the lung. The overexpression of this developmental gene in IPF may be a key event in the persistence of myofibroblasts in the lung interstitium and provides a potential target for therapeutic intervention. (Am J
Elastic fiber assembly requires deposition of elastin monomers onto microfibrils, the mechanism of which is incompletely understood. Here we show that latent TGF-β binding protein 4 (LTBP-4) potentiates formation of elastic fibers through interacting with fibulin-5, a tropoelastin-binding protein necessary for elastogenesis. Decreased expression of LTBP-4 in human dermal fibroblast cells by siRNA treatment abolished the linear deposition of fibulin-5 and tropoelastin on microfibrils. It is notable that the addition of recombinant LTBP-4 to cell culture medium promoted elastin deposition on microfibrils without changing the expression of elastic fiber components. This elastogenic property of LTBP-4 is independent of bound TGF-β because TGF-β-free recombinant LTBP-4 was as potent an elastogenic inducer as TGF-β-bound recombinant LTBP-4. Without LTBP-4, fibulin-5 and tropoelastin deposition was discontinuous and punctate in vitro and in vivo. These data suggest a unique function for LTBP-4 during elastic fibrogenesis, making it a potential therapeutic target for elastic fiber regeneration.connective tissue | development | extracellular matrix
Rationale: Members of the transforming growth factor (TGF)-b superfamily, including TGF-bs and bone morphogenetic proteins (BMPs), are essential for the maintenance of tissue homeostasis and regeneration after injury. We have observed that the BMP antagonist, gremlin, is highly up-regulated in idiopathic pulmonary fibrosis (IPF). Objectives: To investigate the role of gremlin in the regulation of BMP signaling in pulmonary fibrosis. Methods: Progressive asbestos-induced fibrosis in the mouse was used as a model of human IPF. TGF-b and BMP expression and signaling activities were measured from murine and human fibrotic lungs. The mechanism of gremlin induction was analyzed in cultured lung epithelial cells. In addition, the possible therapeutic role of gremlin inhibition was tested by administration of BMP-7 to mice after asbestos exposure. Measurements and Main Results: Gremlin mRNA levels were upregulated in the asbestos-exposed mouse lungs, which is in agreement with the human IPF biopsy data. Down-regulation of BMP signaling was demonstrated by reduced levels of Smad1/5/8 and enhanced Smad2 phosphorylation in asbestos-treated lungs. Accordingly, analyses of cultured human bronchial epithelial cells indicated that asbestos-induced gremlin expression could be prevented by inhibitors of the TGF-b receptor and also by inhibitors of the mitogenactivated protein kinase kinase/extracellular signal-regulated protein kinase pathways. BMP-7 treatment significantly reduced hydroxyproline contents in the asbestos-treated mice. Conclusions: The TGF-b and BMP signaling balance is important for lung regenerative events and is significantly perturbed in pulmonary fibrosis. Rescue of BMP signaling activity may represent a potential beneficial strategy for treating human pulmonary fibrosis.
Transforming growth factor-betas (TGF-beta) regulate a wide variety of cellular functions in normal development and are involved in both tissue homeostasis and disease pathogenesis. The regulation of the TGF-beta family of growth factors is unique because they are targeted to the extracellular matrix in a biologically inactive form. The release from pericellular matrices and the activation of TGF-beta are important mechanisms in several pathophysiologic conditions. Reactive oxygen species (ROS) can activate TGF-beta either directly or indirectly via the activation of proteases. In addition, TGF-beta itself induces ROS production as part of its signal-transduction pathway. The lung is a unique organ, because its structures act as boundaries between gaseous and aqueous phases, allowing the utilization of inhaled oxygen. However, this renders pulmonary tissues vulnerable to the toxic effects of inhaled air. The oxidant pathways are especially relevant in the lung, where TGF-beta is known to have a role in tissue repair and connective tissue turnover. In pulmonary fibrosis, TGF-beta activation is considered as a hallmark of disease progression. More recently, the oxidative effects of cigarette smoking have been found to activate TGF-beta in chronic obstructive pulmonary disease (COPD), a disease consisting of emphysema, airway fibrosis, and focal lung fibrosis.
ABSTRACT.Purpose: Angiogenesis in diabetic retinopathy (DR) is a multifactorial process regulated by hypoxia-induced growth factors and inflammatory cytokines. In addition to the angiogenic switch, the proteolytic processing and altered synthesis of the extracellular matrix are critical steps in this disease. This study was performed to evaluate the levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and MMP-9), angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), vascular endothelial growth factor (VEGF), erythropoietin (EPO) and transforming growth factor-b1 (totalTGFb1) in the vitreous of diabetic eyes undergoing vitrectomy compared with control eyes operated because of macular hole or pucker. Methods: Prospective consecutive controlled observational study performed in the unit of vitreoretinal surgery in Finland during the years 2006-2008. Vitreous samples were collected before the start of the conventional 3-ppp vitrectomy. Vitreous MMP-2 and MMP-9, Ang-1 and Ang-2, VEGF, EPO and TGFb1 concentrations were measured from 69 patients with Type 1 or 2 diabetes and 40 controls. Results: Comparison of eyes with DR with controls revealed that the mean vitreous concentrations of proMMP-2 (p = 0.0015), totalMMP-2 (p = 0.0011), proMMP-9 (p = 0.00001), total-MMP-9 (p < 0.00001), Ang-2 (p < 0.00001), VEGF (p < 0.00001), EPO (p < 0.00001) and totalTGFb1 (p = 0.000026) were significantly higher in the former group. A multivariate logistic regression analysis suggested intravitreal Ang-2 concentration being the key marker of PDR (p = 0.00025) (OR = 1507.9). Conclusion: The main new finding is that the intravitreal concentrations of Ang-2 correlated significantly with MMP-9, VEGF, EPO and TGFb1 levels in diabetic eyes undergoing vitrectomy. Thus, these factors could promote retinal angiogenesis synergistically.Key words: angiogenesis -angiopoietin-1 -angiopoietin-2 -diabetic retinopathy -erythropoietin -matrix metalloproteinases -proliferative diabetic retinopathy -proliferative diabetic vitreoretinopathy -traction retinal detachment -transforming growth factor-b1 -vascular endothelial growth factor -vitrectomy Acta Ophthalmol. 2013: 91: 531-539
Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S−/−), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S−/− and Ltbp4-null (Ltbp4−/−) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C.
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