LTBP-2 competes with tropoelastin for binding to fibulin-5 and heparin, and is a negative modulator of elastinogenesis

Sideek, Mohamed Arshad Mohamed; Menz, Clementine; Parsi, Mahroo K.; Gibson, Mark

doi:10.1016/j.matbio.2013.10.007

Cited by 30 publications

(25 citation statements)

References 44 publications

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“…Strongly upregulated Ltbp2 is also an ECM protein principally expressed by all cells of mesenchymal origin. Its function is largely unknown, but it has been found to surround chondrocytes (63), and Ltbp2 might have a negative regulatory impact on the assembly of elastic fibers (54).…”

Section: Discussionmentioning

confidence: 99%

Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing

Rukov

Gravesen

Mace

et al. 2016

American Journal of Physiology-Renal Physiology

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Rukov JL, Gravesen E, Mace ML, Hofman-Bang J, Vinther J, Andersen CB, Lewin E, Olgaard K. Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing. Am J Physiol Renal Physiol 310: F477-F491, 2016. First published January 6, 2016 doi:10.1152/ajprenal.00472.2015.-The development of vascular calcification (VC) in chronic uremia (CU) is a tightly regulated process controlled by factors promoting and inhibiting mineralization. Next-generation high-throughput RNA sequencing (RNA-seq) is a powerful and sensitive tool for quantitative gene expression profiling and the detection of differentially expressed genes. In the present study, we, for the first time, used RNA-seq to examine rat aorta transcriptomes from CU rats compared with control rats. Severe VC was induced in CU rats, which lead to extensive changes in the transcriptional profile. Among the 10,153 genes with an expression level of Ͼ1 reads/kilobase transcript/million mapped reads, 2,663 genes were differentially expressed with 47% upregulated genes and 53% downregulated genes in uremic rats. Significantly deregulated genes were enriched for ontologies related to the extracellular matrix, response to wounding, organic substance, and ossification. The individually affected genes were of relevance to osteogenic transformation, tissue calcification, and Wnt modulation. Downregulation of the Klotho gene in uremia is believed to be involved in the development of VC, but it is debated whether the effect is caused by circulating Klotho only or if Klotho is produced locally in the vasculature. We found that Klotho was neither expressed in the normal aorta nor calcified aorta by RNA-seq. In conclusion, we demonstrated extensive changes in the transcriptional profile of the uremic calcified aorta, which were consistent with a shift in phenotype from vascular tissue toward an osteochondrocytic transcriptome profile. Moreover, neither the normal vasculature nor calcified vasculature in CU expresses Klotho.

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Section: Discussionmentioning

confidence: 99%

Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing

Rukov

Gravesen

Mace

et al. 2016

American Journal of Physiology-Renal Physiology

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“…This interaction might help provide additional anchoring of microfibrils to basal membranes. A recent paper also suggested that LTBP-2 might negatively regulate elastogenesis in cultured ear cartilage cells through its interactions with fibulin-5, heparin, and elastin (Sideek et al 2014). …”

Section: Ltbp-2mentioning

confidence: 99%

Latent TGF-β-binding proteins

et al. 2015

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The LTBPs (or latent transforming growth factor β binding proteins) are important components of the extracellular matrix (ECM) that interact with fibrillin microfibrils and have a number of different roles in microfibril biology. There are four LTBPs isoforms in the human genome (LTBP-1, -2, -3, and -4), all of which appear to associate with fibrillin and the biology of each isoform is reviewed here. The LTBPs were first identified as forming latent complexes with TGFβ by covalently binding the TGFβ propeptide (LAP) via disulfide bonds in the endoplasmic reticulum. LAP in turn is cleaved from the mature TGFβ precursor in the trans golgi network but LAP and TGFβ remain strongly bound through non-covalent interactions. LAP, TGFβ, and LTBP together form the large latent complex (LLC). LTBPs were originally thought to primarily play a role in maintaining TGFβ latency and targeting the latent growth factor to the extracellular matrix (ECM), but it has also been shown that LTBP-1 participates in TGFβ activation by integrins and may also regulate activation by proteases and other factors. LTBP-3 appears to have a role in skeletal formation including tooth development. As well as having important functions in TGFβ regulation, TGFβ-independent activities have recently been identified for LTBP-2 and LTBP-4 in stabilizing microfibril bundles and regulating elastic fiber assembly.

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“…When LTBP-2 is knocked down, elastin preferentially deposits onto fibrillin-2 microfibrils. Another study showed that LTBP-2 binds fibulin-5 and inhibits tropoelastin-fibulin-5 interaction (Sideek et al, 2013). LTBP-1 binds strongly to fibulin-4 and forms a ternary complex involving LTBP-1, fibrillin-1 and fibulin-4 (Massam-Wu et al, 2010).…”

Section: Fibulin-4 and Fibulin-5 During Elastic Fiber Assemblymentioning

confidence: 99%

Fibulin-4 and fibulin-5 in elastogenesis and beyond: Insights from mouse and human studies

Papke

Yanagisawa²

2014

Matrix Biology

124

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The fibulin family of extracellular matrix/matricellular proteins is comprised of long fibulins (fibulins-1, -2, -6) and short fibulins (fibulins-3, -4, -5, -7) and is involved in protein-protein interaction with the components of basement membrane and extracellular matrix proteins. Fibulins-1, -2, -3, -4, and -5 bind the monomeric form of elastin (tropoelastin) in vitro and fibulins-2, -3, -4, and -5 are shown to be involved in various aspects of elastic fiber development in vivo. In particular, fibulins-4 and -5 are critical molecules for elastic fiber assembly and play a non-redundant role during elastic fiber formation. Despite manifestation of systemic elastic fiber defects in all elastogenic tissues, fibulin-5 null (Fbln5−/−) mice have a normal lifespan. In contrast, fibulin-4 null (Fbln4−/−) mice die during the perinatal period due to rupture of aortic aneurysms, indicating differential functions of fibulin-4 and fibulin-5 in normal development. In this review, we will update biochemical characterization of fibulin-4 and fibulin-5 and discuss their roles in elastogenesis and outside of elastogenesis based on knowledge obtained from loss-of-function studies in mouse and in human patients with FBLN4 or FBLN5 mutations. Finally, we will evaluate therapeutic options for matrix-related diseases.

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LTBP-2 competes with tropoelastin for binding to fibulin-5 and heparin, and is a negative modulator of elastinogenesis

Cited by 30 publications

References 44 publications

Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing

Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing

Latent TGF-β-binding proteins

Fibulin-4 and fibulin-5 in elastogenesis and beyond: Insights from mouse and human studies

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