Increased expression of type I collagen induced by microfibril‐associated glycoprotein 2: Novel mechanistic insights into the molecular basis of dermal fibrosis in scleroderma

Lemaire, Raphaël; Korn, Joseph H.; Shipley, J. Michael; Lafyatis, Robert

doi:10.1002/art.21059

Cited by 28 publications

(24 citation statements)

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“…As stated previously, MAGPs covalently bind fibrillins on the microfibril. Disease-causing mutations in fibrillin-1 in mice are associated with increases in MAGP2 expression in vivo, suggesting a regulatory link between these microfibrillar proteins (24,53,54). Increased gene expression and/or mutations in MAGPs or fibrillins may result in unbound MAGPs in the ECM with unknown effects on growth factor signaling and matrix metalloproteinases expression.…”

Section: Discussionmentioning

confidence: 99%

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Combs¹,

Knutsen²,

Broekelmann³

et al. 2013

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Combs¹,

Knutsen²,

Broekelmann³

et al. 2013

Journal of Biological Chemistry

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“…Thus, while the relation between fibrillin-1 abnormality and TGF-␤ in the Tsk lungs is unclear, it is possible that TGF-␤ activity is altered, leading to the observed excessive collagen production (42). Perhaps more importantly, MAGP-2 has a direct association with both fibrillin and collagen (18,19). In response to MAGP-2 stimulation, fibroblast cells in culture increase collagen levels in the ECM without affecting the intracellular mRNA of procollagen.…”

Section: Possible Mechanisms Of Progressionmentioning

confidence: 99%

“…Collagen secreted into the ECM is thermally unstable (51) and in the normal lung only ‫ف‬ 40% of the secreted molecules are incorporated into existing fibrils (52). However, MAGP-2 is able to stabilize type I collagen (19). An excess of stable collagen in the ECM not only increases collagen levels (42) but may disturb the remodeling process, leading to abnormal collagen assembly.…”

Section: Possible Mechanisms Of Progressionmentioning

confidence: 99%

“…The Pa mouse has been reported to develop emphysema only around 10 mo of age, and it is related to a reduced serum ␣ 1 -antitrypsin concentration (17) and is considered as the control of Tsk mice (4,5,18). To investigate the relation between fibrillin-1 and collagen assembly, we also examined the expression of a particular class of molecules, the microfibril-associated glycoproteins (MAGP) that have a direct association with both fibrillin and collagen (18,19). Our results suggest a novel link among MAGP, collagen, and the nonlinear mechanical properties of the lung that we support using a network model of the parenchyma.…”

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confidence: 99%

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Early Emphysema in the Tight Skin and Pallid Mice

Ito

Bartolák‐Suki

Shipley

et al. 2006

Am J Respir Cell Mol Biol

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The nature of the development of emphysema in the tight skin (Tsk) and the pallid (Pa) mice are not well understood. We assessed the mechanical and nonlinear properties of the respiratory system, the alveolar structure, and the levels of microfibril-associated glycoproteins (MAGP) 1 and 2 in Tsk mice with developmental emphysema; in Pa mice, which are thought to develop adult onset emphysema; and their background, the C57BL/6 mice, at an age of 7 wk. Minor differences between collagen-related elastic properties of the lungs of the Pa and C57BL/6 mice were seen at this early age. The lungs of the Tsk mice were significantly softer yet more nonlinear than those of the Pa and C57BL/6 mice. The MAGP-1 levels were similar in all three groups. However, the level of MAGP-2, which is associated with both fibrillin-1 and collagen, was higher in the Tsk than in the Pa mice, which also had more MAGP-2 than the C57BL/6. Both the mean and the variance of alveolar diameters were larger in the Tsk than in the other two groups, while the variance in the Pa was larger than in the C57BL/6 mice, implying early development of heterogeneity. Using a network model of the parenchyma, we linked the pathophysiologic changes in the Tsk mice to mechanical forces and failure of the alveolar walls. Our findings suggest the possibility that MAGP-2-related abnormal collagen assembly, combined with mechanical forces, is involved in the progression of emphysema in the Tsk mice.

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“…However, it may have a specialized function in matrix homeostasis. We have recently shown that fibrosis in skin of scleroderma patients and Tsk mice is associated with increased MAGP-2 levels (13) and that MAGP-2 stimulates expression of type I procollagen (25). Other evidence suggests that MAGP-2 may also modulate microfibril function in elastogenesis, as MAGP-2 is associated with elastin-associated microfibrils in developing nuchal ligaments (26); MAGP-2 mRNA expression peaks at the period of onset of elastogenesis in this tissue (27), and increased matrix-associated MAGP-2 in the hypodermis of Tsk mice is associated with increased elastic fiber assembly.…”

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confidence: 99%

Microfibril-associated MAGP-2 Stimulates Elastic Fiber Assembly

Lemaire

Bayle

Mecham

et al. 2007

Journal of Biological Chemistry

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Elastic fibers are complex structures composed of a tropoelastin inner core and microfibril outer mantle guiding tropoelastin deposition. Microfibrillar proteins mainly include fibrillins and microfibril-associated glycoproteins (MAGPs). MAGP-2 exhibits developmental expression peaking at elastic fiber onset, suggesting that MAGP-2 mediates elastic fiber assembly. To determine whether MAGP-2 regulates elastic fiber assembly, we used an in vitro model featuring doxycycline-regulated cells conditionally overexpressing exogenous MAGP-2 and constitutively expressing enhanced green fluorescent protein-tagged tropoelastin. Analysis by immunofluorescent staining showed that MAGP-2 overexpression dramatically increased elastic fibers levels, independently of extracellular levels of soluble tropoelastin, indicating that MAGP-2 stimulates elastic fiber assembly. This was associated with increased levels of matrix-associated MAGP-2. Electron microscopy showed that MAGP-2 specifically associates with microfibrils and that elastin globules primarily colocalize with MAGP-2-associated microfibrils, suggesting that microfibril-associated MAGP-2 facilitates elastic fiber assembly. MAGP-2 overexpression did not change levels of matrix-associated fibrillin-1, MAGP-1, fibulin-2, fibulin-5, or emilin-1, suggesting that microfibrils and other elastic fiberassociated proteins known to regulate elastogenesis do not mediate MAGP-2-induced elastic fiber assembly. Moreover, mutation analysis showed that MAGP-2 does not stimulate elastic fiber assembly through its RGD motif, suggesting that integrin receptor binding does not mediate MAGP-2-induced elastic fiber assembly. Because MAGP-2 interacts with Jagged-1 that controls cell-matrix interaction and cell motility, two key factors in elastic fiber macroassembly, microfibril-associated MAGP-2 may stimulate elastic fiber macroassembly by targeting the release of elastin globules from the cell membrane onto developing elastic fibers.

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Increased expression of type I collagen induced by microfibril‐associated glycoprotein 2: Novel mechanistic insights into the molecular basis of dermal fibrosis in scleroderma

Cited by 28 publications

References 50 publications

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Early Emphysema in the Tight Skin and Pallid Mice

Microfibril-associated MAGP-2 Stimulates Elastic Fiber Assembly

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