Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis

Smaldone, Silvia; Bigarella, Carolina L.; Solar, Maria del; Ghaffari, Saghi; Ramirez, Francesco

doi:10.1016/j.matbio.2015.11.006

Cited by 11 publications

(10 citation statements)

References 29 publications

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“…2B). With regard to enhanced bone resorption, dysregulated marrow hematopoiesis in Fbn1 Pr1x −/− mice might also contribute to increasing the number of osteoclasts [46]. A decreased amount of proteolytic fragments of fibrillin-1 that normally restrict osteoclast differentiation through RANKL sequestration and NFATc inhibition might potentially be another stimulator of bone catabolism in Fbn1 Pr1x −/− mice [47].…”

Section: Mfs; Molecular Pathophysiologymentioning

confidence: 99%

Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFβ signaling and cell stemness

et al. 2018

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Mutations in fibrillin-1 cause Marfan syndrome (MFS), the most common heritable disorder of connective tissue. Fibrillin-1 assemblies (microfibrils and elastic fibers) represent a unique dual-function component of the architectural matrix. The first role is structural for they endow tissues with tensile strength and elasticity, transmit forces across them and demarcate functionally discrete areas within them. The second role is instructive in that these macroaggregates modulate a large variety of sub-cellular processes by interacting with mechanosensors, and integrin and syndecan receptors, and by modulating the bioavailability of local TGFβ signals. The multifunctional, tissue-specific nature of fibrillin-1 assemblies is reflected in the variety of clinical manifestations and disease mechanisms associated with the MFS phenotype. Characterization of mice with ubiquitous or cell type-restricted fibrillin-1 deficiency has unraveled some pathophysiological mechanisms associated with the MFS phenotype, such as altered mechanotransduction in the heart, dysregulated TGFβ signaling in the ascending aorta and perturbed stem cell fate in the bone marrow. In each case, potential druggable targets have also been identified. However, the finding that distinct disease mechanisms underlie different organ abnormalities strongly argues for developing multi-drug strategies to mitigate or even prevent both life-threatening and morbid manifestations in pediatric and adult MFS patients.

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Section: Mfs; Molecular Pathophysiologymentioning

confidence: 99%

Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFβ signaling and cell stemness

et al. 2018

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“…Both β3 integrins belong to the subgroup of RGD binding integrins, i.e., integrins recognizing ligands containing an RGD tripeptide sequence. These integrins are among the most promiscuous and bind to a large number of ligands, including extracellular matrix and soluble vascular ligands [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Important ligands for the β3 integrins are given in Table 1 .…”

Section: The Promiscuity Of β3 Integrin Ligand Bindingmentioning

confidence: 99%

The Possible Importance of β3 Integrins for Leukemogenesis and Chemoresistance in Acute Myeloid Leukemia

Johansen

Brenner

Bartaula-Brevik

et al. 2018

IJMS

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Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy where the immature leukemia cells communicate with neighboring cells through constitutive cytokine release and through their cell surface adhesion molecules. The primary AML cells express various integrins. These heterodimeric molecules containing an α and a β chain are cell surface molecules that bind extracellular matrix molecules, cell surface molecules and soluble mediators. The β3 integrin (ITGB3) chain can form heterodimers only with the two α chains αIIb and αV. These integrins are among the most promiscuous and bind to a large number of ligands, including extracellular matrix molecules, cell surface molecules and soluble mediators. Recent studies suggest that the two β3 integrins are important for leukemogenesis and chemosensitivity in human AML. Firstly, αIIb and β3 are both important for adhesion of AML cells to vitronectin and fibronectin. Secondly, β3 is important for the development of murine AML and also for the homing and maintenance of the proliferation for xenografted primary human AML cells, and for maintaining a stem cell transcriptional program. These last effects seem to be mediated through Syk kinase. The β3 expression seems to be regulated by HomeboxA9 (HoxA9) and HoxA10, and the increased β3 expression then activates spleen tyrosine kinase (Syk) and thereby contributes to cytokine hypersensitivity and activation of β2 integrins. Finally, high integrin αV/β3 expression is associated with an adverse prognosis in AML and decreased sensitivity to the kinase inhibitor sorafenib; this integrin can also be essential for osteopontin-induced sorafenib resistance in AML. In the present article, we review the experimental and clinical evidence for a role of β3 integrins for leukemogenesis and chemosensitivity in AML.

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“…It was recently shown that fibrillin-1 microfibrils have an important role in bone marrow ECM. Specifically, immunofluorescence was used to localize fibrillin-1 to stem cell niches, and Prx1-Cremediated loss of fibrillin-1 ( Fbn1 Prx −/− ) modified skeletal stem cell fate, erythroid expansion, and HSC maintenance [19,20]. The presence ofMAGP1’smajor binding partner - fibrillin-1 - within the bone marrow provides an ideal docking station for MAGP1 protein in Mfap2 Prx −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Contribution of metabolic disease to bone fragility in MAGP1-deficient mice

et al. 2018

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Microfibril-associated glycoprotein-1 (MAGP1) is an extracellular matrix protein that interacts with fibrillin and is involved in regulating the bioavailability of signaling molecules such as TGFβ. Mice with germline MAGP1 deficiency (Mfap2) develop increased adiposity, hyperglycemia, insulin resistance, bone marrow adipose tissue expansion, reduced cancellous bone mass, cortical bone thinning and bone fragility. The goal of this study was to assess whether the Mfap2 bone phenotypes were due to loss of MAGP1 locally or secondary to a change in whole body physiology (metabolic dysfunction). To do this, mice with conditional deletion of MAGP1 in the limb skeleton were generated by crossing MAGP1-flox mice (Mfap2) with Prx1-Cre mice. Mfap2 mice did not show any changes in peripheral adiposity, hyperglycemia or insulin sensitivity, but did have increased bone length and cancellous bone loss that was comparable to the germline Mfap2 knockout. Unlike the germline knockout, marrow adiposity, cortical bone thickness and bone strength in Mfap2 mice were normal. These findings implicate systemic metabolic dysfunction in the development of bone fragility in germline Mfap2 mice. An unexpected finding of this study was the detection of MAGP1 protein in the Mfap2 hematopoietic bone marrow, despite the absence of MAGP1 protein in osseous bone matrix and absent Mfap2 transcript expression at both sites. This suggests MAGP1 from a secondary site may accumulate in the bone marrow, but not be incorporated into the bone matrix, during times of regional MAGP1 depletion.

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Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis

Cited by 11 publications

References 29 publications

Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFβ signaling and cell stemness

Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFβ signaling and cell stemness

The Possible Importance of β3 Integrins for Leukemogenesis and Chemoresistance in Acute Myeloid Leukemia

Contribution of metabolic disease to bone fragility in MAGP1-deficient mice

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