Fibrillin microfibrils in bone physiology

Smaldone, Silvia; Ramirez, Francesco

doi:10.1016/j.matbio.2015.09.004

Cited by 35 publications

(30 citation statements)

References 46 publications

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“…We favor the latter possibility based on recent evidence indicating that the initial consequence of fibrillin-1 deficiency in the aorta of MFS mice is to impair rather than stimulate TGFβ activity [24]. In this respect, differential modulation of TGFβ activity in HSC and erythroid niches is in line with prior evidence that fibrillin microfibrils provide contextual specificity to TGFβ and BMP signals during bone patterning and remodeling [17]. We further argue that osteopenia-dependent expansion of hematopoietic tissue, as evidenced by increased marrow cellularity in fibrillin-1-deficient bones, may also contribute to HSC depletion independently of TGFβ dysregulation.…”

Section: Discussionsupporting

confidence: 56%

“…A case in point is the skeleton where fibrillin-1 and the structurally related fibrillin-2 protein have been shown to differentially modulate TGFβ and BMP signals during bone patterning and remodeling [17]. We have recently reported that fibrillin-1 influences MSC fate determination by controlling TGFβ bioavailability within adult marrow niches [18].…”

Section: Introductionmentioning

confidence: 99%

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Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis

et al. 2016

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We have recently demonstrated that fibrillin-1 assemblies regulate the fate of skeletal stem cells (aka, mesenchymal stem cells [MSCs]) by modulating TGFβ activity within the microenvironment of adult bone marrow niches. Since MSCs can also influence hematopoietic stem cell (HSC) activities, here we investigated adult hematopoiesis in mice with Cre-mediated inactivation of the fibrillin-1 (Fbn1) gene in the mesenchyme of the forming limbs (Fbn1Prx1−/− mice). Analyses of 3-month-old Fbn1Prx1−/− mice revealed a statistically significant increase of circulating red blood cells, which a differentiation assay correlated with augmented erythropoiesis. This finding, together with evidence of fibrillin-1 deposition in erythroblastic niches, supported the notion that this extracellular matrix protein normally restricts differentiation of erythroid progenitors. Whereas flow cytometry measurements identified a decreased HSC frequency in mutant relative to wild type mice, no appreciable differences were noted with regard to the relative abundance and differentiation potential of myeloid progenitor cells. Together these findings implied that fibrillin-1 normally promotes HSC expansion but does not influence cell lineage commitment. Since local TGFβ hyperactivity has been associated with abnormal osteogenesis in Fbn1Prx1−/− mice, 1-month-old mutant and wild type animals were systemically treated for 8 weeks with either a pan-TGF-β-neutralizing antibody or an antibody of the same IgG1 isotype. The distinct outcomes of these pharmacological interventions strongly suggest that fibrillin-1 differentially modulates TGFβ activity in HSC vs. erythroid niches.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis

et al. 2016

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“…Murine models of MFS have focussed more on fibrillin-1 mutation-induced TGF-b perturbations than on structural microfibril defects as disease 'drivers' (Sengle & Sakai 2015;Smaldone & Ramirez 2016). The hypomorphic mgD mouse had pathologically elevated TGF-b activity in the lung (Neptune et al 2003), which correlated with initial predictions that perturbations in large latent TGF-b complexes interacting directly with fibrillin-1 (see LTBPs) would manifest as enhanced TGF-b signalling in affected tissues.…”

Section: 'Tall' Fibrillinopathiesmentioning

confidence: 85%

“…Murine models of MFS have focussed more on fibrillin‐1 mutation‐induced TGF‐β perturbations than on structural microfibril defects as disease ‘drivers’ (Sengle & Sakai ; Smaldone & Ramirez ). The hypomorphic mgΔ mouse had pathologically elevated TGF‐β activity in the lung (Neptune et al .…”

Section: ‘Tall’ Fibrillinopathiesmentioning

confidence: 99%

Fell‐Muir Lecture: Fibrillin microfibrils: structural tensometers of elastic tissues?

2017

Int J Experimental Path

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SummaryFibrillin microfibrils are indispensable structural elements of connective tissues in multicellular organisms from early metazoans to humans. They have an extensible periodic beaded organization, and support dynamic tissues such as ciliary zonules that suspend the lens. In tissues that express elastin, including blood vessels, skin and lungs, microfibrils support elastin deposition and shape the functional architecture of elastic fibres. The vital contribution of microfibrils to tissue form and function is underscored by the heritable fibrillinopathies, especially Marfan syndrome with severe elastic, ocular and skeletal tissue defects. Research since the early 1990s has advanced our knowledge of biology of microfibrils, yet understanding of their mechanical and homeostatic contributions to tissues remains far from complete. This review is a personal reflection on key insights, and puts forward the conceptual hypothesis that microfibrils are structural ‘tensometers’ that direct cells to monitor and respond to altered tissue mechanics.

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“…Furthermore, we were able to detect elevated TGFβ signaling in Mfap2 -/- adipose tissue but not in any of the fibrillin-1 mutant mice. MFS-associated skeletal anomalies have been documented in mouse models of fibrillin-1 disruption [24]. Despite lacking a metabolic phenotype, all three fibrillin-1 mutant lines recapitulated the Marfanoid features of long bone overgrowth and reduced bone mass.…”

Section: Introductionmentioning

confidence: 99%

Characterization of metabolic health in mouse models of fibrillin-1 perturbation

et al. 2016

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Mutations in the microfibrillar protein fibrillin-1 or the absence of its binding partner microfibrilassociated glycoprotein (MAGP1) lead to increased TGFβ signaling due to an inability to sequester latent or active forms of TGFβ, respectively. Mouse models of excess TGFβ signaling display increased adiposity and predisposition to type-2 diabetes. It is therefore interesting that individuals with Marfan syndrome, a disease in which fibrillin-1 mutation leads to aberrant TGFβ signaling, typically present with extreme fat hypoplasia. The goal of this project was to characterize multiple fibrillin-1 mutant mouse strains to understand how fibrillin-1 contributes to metabolic health. The results of this study demonstrate that fibrillin-1 contributes little to lipid storage and metabolic homeostasis, which is in contrast to the obesity and metabolic changes associated with MAGP1 deficiency. MAGP1 but not fibrillin-1 mutant mice had elevated TGFβ signaling in their adipose tissue, which is consistent with the difference in obesity phenotypes. However, fibrillin-1 mutant strains and MAGP1-deficient mice all exhibit increased bone length and reduced bone mineralization which are characteristic of Marfan syndrome. Our findings suggest Marfan-associated adipocyte hypoplasia is likely not due to microfibril-associated changes in adipose tissue, and provide evidence that MAGP1 may function independently of fibrillin in some tissues.

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Fibrillin microfibrils in bone physiology

Cited by 35 publications

References 46 publications

Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis

Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis

Fell‐Muir Lecture: Fibrillin microfibrils: structural tensometers of elastic tissues?

Characterization of metabolic health in mouse models of fibrillin-1 perturbation

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