Latent Transforming Growth Factor-β Binding Protein 2 Negatively Regulates Coalescence of Oxytalan Fibers Induced by Stretching Stress

Tsuruga, Eichi; Oka, Kyoko; Hatakeyama, Yuji; Isokawa, Keitaro; Sawa, Yoshihiko

doi:10.3109/03008207.2012.702816

Cited by 6 publications

(2 citation statements)

References 24 publications

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“…Thus LTBP-2 can inhibit fibrillin-1-independent deposition of elastin and may facilitate the specific association of elastin and fibulin-5 with fibrillin-1 in fibroblast cultures (Hirai et al 2007). In the periodontal membrane, LTBP-2 also controls the maturation of oxytalan fibers, which consist of elastin-free microfibril bundles, by regulating their coalescence through interaction with fibulin-5 (Tsuruga et al 2012). …”

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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Section: Ltbp-2mentioning

confidence: 99%

Latent TGF-β-binding proteins

et al. 2015

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“…Moreover, latent transforming growth factor-β binding protein-2 controls the capacity of fibulin-5 for coalescence [18]. In this study, irrespective of the application of stretching stress, the oxytalan fibers tended were oriented at almost a right angle to the long cell axis.…”

Section: Non-stretch Stretchmentioning

confidence: 57%

Stretching Induces the Rearrangement of the Periodontal Ligament Cells without Altering the Orientation of Oxytalan Fibers Relative to the Cell Axis <i>in Vitro</i>

Tamaoki¹,

Nakashima²,

Yamauchi³

et al. 2016

OJST

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The periodontal ligament (PDL) contains oxytalan fibers as well as collagen fibers, which helps it to withstand the mechanical stress to which it is constantly exposed. The oxytalan fibers are produced by PDL fibroblasts. However, the arrangement of PDL fibroblasts and the orientation of oxytalan fibers relative to the fibroblast cell axis have not been investigated under the condition of mechanical stress. We hypothesized that such stress would alter the arrangement and orientation of these cells and their oxytalan fibers. The aim of this study was to evaluate the effects of stretching strain on PDL fibroblasts, focusing on the cellular arrangement and orientation of oxytalan fibers relative to the long cell axis in cell/matrix layers by staining the major component of the fibers, fibrillin-1. The angle between the long cell axis and the oxytalan fibers was approximately 70 degrees under both non-stretching and stretching conditions. Moreover, stretching induced the rearrangement of the cells. This is the first study to demonstrate that stretching induces the rearrangement of the PDL fibroblasts without altering the angle between the long cell axis and the oxytalan fibers. These results may reflect the orientation of oxytalan fibers in the PDL under the condition of mechanical stress.

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

et al. 2014

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Latent transforming growth factor-beta-1 binding protein-2 (LTBP-2) is a protein of ill-defined function associated with elastic fibers during elastinogenesis. Although LTBP-2 binds fibrillin-1, fibulin-5, and heparin/heparan sulfate, molecules critical for normal elastic fiber assembly, it does not interact directly with elastin or its precursor, tropoelastin. We investigated the modulating effect of LTBP-2 on two key interactions of tropoelastin during elastinogenesis a) with fibulin-5 and b) with heparan sulfate (using heparin). Firstly, using solid phase assays we showed that LTBP-2 bound fibulin-5 (Kd=26.47±5.68 nM) with an affinity similar to that of the tropoelastin-fibulin-5 interaction (Kd=24.66±5.64 nM). Then using a competitive binding assay we showed that LTBP-2 inhibited the tropoelastin-fibulin-5 interaction in a dose dependent manner with almost complete inhibition obtained with 5-fold molar excess of LTBP-2. Interestingly, a fragment of LTBP-2 containing the fibulin-5 binding sequence only partially inhibited the tropoelasin-fibulin-5 interaction suggesting that LTBP-2 was directly blocking only the C-terminal tropoelastin binding site on fibulin-5 and indirectly blocking tropoelastin binding to the N-terminal region. In parallel experiments heparin was shown to have minor inhibitory effects on fibulin-5 interactions with tropoelastin and LTBP-2. However, LTBP-2 was shown to significantly inhibit the binding of heparin to tropoelastin with 50% inhibition achieved with 10 fold molar excess of LTBP-2. Confocal microscopy of fibroblast matrix showed strong co-distribution of LTBP-2 with fibulin-5 and fibrillin-1 and partial co-distribution with heparan sulfate proteoglycans, perlecan and syndecan-4. Also addition of exogenous LTBP-2 to ear cartilage chondrocyte cultures blocked elastinogenesis in a concentration-dependent manner. Overall the results indicate that LTBP-2 may have a negative regulatory role during elastic fiber assembly, perhaps in displacing elastin microassemblies from complexes with fibulin-5 and/or cell surface heparan sulfate proteoglycans.

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Latent Transforming Growth Factor-β Binding Protein 2 Negatively Regulates Coalescence of Oxytalan Fibers Induced by Stretching Stress

Cited by 6 publications

References 24 publications

Latent TGF-β-binding proteins

Latent TGF-β-binding proteins

Stretching Induces the Rearrangement of the Periodontal Ligament Cells without Altering the Orientation of Oxytalan Fibers Relative to the Cell Axis <i>in Vitro</i>

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

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Latent Transforming Growth Factor-β Binding Protein 2 Negatively Regulates Coalescence of Oxytalan Fibers Induced by Stretching Stress

Cited by 6 publications

References 24 publications

Latent TGF-β-binding proteins

Latent TGF-β-binding proteins

Stretching Induces the Rearrangement of the Periodontal Ligament Cells without Altering the Orientation of Oxytalan Fibers Relative to the Cell Axis &lt;i&gt;in Vitro&lt;/i&gt;

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

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Stretching Induces the Rearrangement of the Periodontal Ligament Cells without Altering the Orientation of Oxytalan Fibers Relative to the Cell Axis <i>in Vitro</i>