The role of transforming growth factor-beta in Marfan syndrome

Abstract

The starting point, in Marfan syndrome (MFS) appears to be the mutation of fi brillin-1 gene whose deconstructed protein product cannot bind transforming growth factor beta (TGF-b), leading to an increased TGF-b tissue level. The aim of this review is to review the already known features of the cellular signal transduction downstream to TGF-b and its impact on the tissue homeostasis of microfi brils, and elastic fi bers. We also investigate current data on the extracellular regulation of TGF-b level including mechanotransduction and the feedback cycles of integrin-dependent and independent activation of the latent TGF-b complex. Together these factors, by the destruction of the connective tissue fi bers, may play an important role in the development of the diverse cardiac and extracardiac manifestations of MFS and many of them could be a target of conservative treatment. We present currently investigated drugs for

Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics

“…Interestingly, CDH2 engagement did not have the same effects, suggesting that CDH11 might be a distinct target for preventing fibrosis and promoting tissue regeneration. By contrast, a number of diseases are attributed to a loss or impaired state of the ECM, for example, stress urinary incontinence or improper bladder function, which is related to irregular distribution of elastin fibers (Goepel and Thomssen, 2006) and reduced collagen type I and III (Li et al, 2012a), and Marfan's syndrome, which is caused by a mutation in the fibrillin gene leading to lack of elastin fibers and reduced tissue levels of TGF-β in the aorta, with subsequent increase in stiffness (Benke et al, 2013). However, loss of CDH11 had no effect on the mRNA expression of the fibrillin gene, as shown in Cdh11 −/− mouse dermal fibroblasts.…”

“…As a result, loss of collagen and/or elastin has been implicated in many diseases and is welldocumented in aging (Kohl et al, 2011;Wagenseil and Mecham, 2012). For example, fragmented or irregular distribution of collagen and elastin fibrils have been implicated in bladder incontinence as well as cardiovascular disorders such as hypertension, aneurysms and Marfan's syndrome (Goepel and Thomssen, 2006;Li, 2012a;Benke et al, 2013). By contrast, excessive and cumulative deposition of collagen disrupts organ architecture, leading to scar formation and loss of function.…”

Hungarian Marfan family with large FBN1 deletion calls attention to copy number variation detection in the current NGS era

“…Cardiovascular abnormalities can be lifethreatening and include dilatation of the ascending aorta, which can result in dissection, mitral valve prolapse with or without regurgitation as well as tricuspid valve prolapse (3)(4)(5)(6). MFS is caused by heterozygous pathogenic sequence variants in the FBN1 gene, which consists of 65 coding exons and encodes the protein fibrillin-1, a key component of elastic fibers (7,8).…”

Hereditary Connective Tissue Disorders: Nomenclature and Diagnostic Algorithm

“…Установление патогенетиче-ской роли трансформирующего фактора роста-β (TGF-β) позволило лучше понять происхождение из-вестных клинических проявлений синдрома Марфана и обозначить новые перспективы консервативного лечения данной патологии с применением фармако-логических средств, уменьшающих концентрацию TGF-β [6][7][8].…”