Extracellular Regulation of Bone Morphogenetic Protein Activity by the Microfibril Component Fibrillin-1

Wohl, Alexander P.; Troilo, Helen; Collins, Richard F.; Baldock, Clair; Sengle, Gerhard

doi:10.1074/jbc.m115.704734

Cited by 66 publications

(91 citation statements)

References 46 publications

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“…Heparin also reduced BMP-2 interaction with its antagonist noggin by modulating its distribution on the cell surface with prolonged half-life[55]. Extracellular regulation of BMP activity by other ECM proteins was also studied that BMP-7 underwent conformational change from bioactive open V-shape to latent closed ring shape upon binding to fibrillin-1[56]. …”

Section: Discussionmentioning

confidence: 99%

Design of hydrogels to stabilize and enhance bone morphogenetic protein activity by heparin mimetics

et al. 2018

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Although bone morphogenetic protein-2 (BMP-2) is believed to be the most potent cytokine for bone regeneration, its clinical applications require supraphysiological BMP dosage due to its intrinsic instability and fast enzymatic degradation, leading to worrisome side effects. This study demonstrates a novel hydrogel platform that mimics a natural protector of BMPs, heparin, to sequester and stabilize BMP-2 for increased osteoinductive signaling. This study will achieve the stabilization of BMPs with prolonged bioactivity by a synthetic heparin mimic that has not been examined previously. Moreover, the heparin mimetic hydrogel surface can augment endogenous BMP activity by sequestering and localizing the cell-produced BMPs. The additional knowledge gained from this study may suggest basis for future development of material-based therapeutics for tissue engineering.

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Section: Discussionmentioning

confidence: 99%

Design of hydrogels to stabilize and enhance bone morphogenetic protein activity by heparin mimetics

et al. 2018

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“…Some fibrillin‐1 mutations may also disrupt BMP prodomain interactions with fibrillin‐1 (Wohl et al . ), altering BMP signals which regulate musculoskeletal growth.…”

Section: ‘Tall’ Fibrillinopathiesmentioning

confidence: 99%

“…However, latent TGF-b also binds other matrix components such as fibronectin (Horiguchi et al 2012), whilst LTBP-1 also independently multimerizes in a heparin-/HS-dependent manner . In contrast, fibrillin-1 can directly bind prodomains of BMPs 2, 4, 5, 7 and 10, inducing a conformational change that blocks BMP interactions with its receptors (Gregory et al 2005;Sengle et al 2011;Wohl et al 2016).…”

Section: Microfibril-associated Moleculesmentioning

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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“…The complex has been reported to resemble the overall shape displayed by proBMP9 (Wohl et al, 2016). Interestingly, the authors observed that proregion-mediated binding to fibrillin induced a conformational switch that could be observed by electron microscopy.…”

Section: The Functionally Versatile Bmp Proregionsmentioning

confidence: 81%

Cystine knot growth factors and their functionally versatile proregions

Schwarz

2017

Biological Chemistry

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Abstract:The cystine knot disulfide pattern has been found to be widespread in nature, since it has been detected in proteins from plants, marine snails, spiders and mammals. Cystine knot proteins are secreted proteins. Their functions range from defense mechanisms as toxins, e.g. ion channel or enzyme inhibitors, to hormones, blood factors and growth factors. Cystine knot proteins can be divided into two superordinate groups. (i) The cystine knot peptides, also referred to -with other non-cystine knot proteins -as knottins, with linear and cyclic polypeptide chains. (ii) The cystine knot growth factor family, which is in the focus of this article. The disulfide ring structure of the cystine knot peptides is made up by the half-cystines 1-4 and 2-5, and the threading disulfide bond is formed by the half-cystines, 3-6. In the growth factor group, the disulfides of half-cystines 1 and 4 pass the ring structure formed by the half-cystines 2-5 and 3-6. In this review, special emphasis will be devoted to the growth factor cystine knot proteins and their proregions. The latter have shifted into the focus of scientific interest as their important biological roles are just to be unravelled.

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Extracellular Regulation of Bone Morphogenetic Protein Activity by the Microfibril Component Fibrillin-1

Cited by 66 publications

References 46 publications

Design of hydrogels to stabilize and enhance bone morphogenetic protein activity by heparin mimetics

Design of hydrogels to stabilize and enhance bone morphogenetic protein activity by heparin mimetics

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

Cystine knot growth factors and their functionally versatile proregions

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