Search

The transforming growth factor-β (TGF-β) family of cytokines exerts pleiotropic functions during embryonic development, tissue homeostasis and repair as well as within the immune system. Single gene defects in individual component of this signaling machinery cause defined Mendelian diseases associated with aberrant activation of TGF-β signaling, ultimately leading to impaired development, immune responses or both. Gene defects that affect members of the TGF-β cytokine family result in more restricted phenotypes, while those affecting downstream components of the signaling machinery induce broader defects. These rare disorders, also known as TGF-β signalopathies, provide the unique opportunity to improve our understanding of the role and the relevance of the TGF-β signaling in the human immune system. Here, we summarize this elaborate signaling pathway, review the diverse clinical presentations and immunological phenotypes observed in these patients and discuss the phenotypic overlap between humans and mice genetically deficient for individual components of the TGF-β signaling cascade., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rodari, Cerf-Bensussan and Parlato.)

Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-β signaling remain elusive. Heterozygous loss-of-function mutations in TGF-β receptors 1 and 2 ( TGFBR1 and TGFBR2 ) cause LDS, but TGF-β signaling is activated in the aorta (referred to as the TGF-β paradox) by mechanisms yet to be elucidated. In this review, we present and discuss the current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders.

This review focusses on impact of a better knowledge of pathogenic mechanisms of Marfan and related disorders on their treatment strategies. It was long believed that a structural impairment formed the basis of Marfan syndrome as deficiency in the structural extracellular matrix component, fibrillin-1 is the cause of Marfan syndrome. However, the study of Marfan mouse models has revealed the strong involvement of the transforming growth factor-β signalling pathway in the pathogenesis of Marfan. Similarly, this pathway was demonstrated to be key in the pathogenesis of Loeys-Dietz and Shprintzen-Goldberg syndrome. The elucidation of the underlying pathogenic mechanisms has led to new treatment strategies, targeting the overactive TGF-β pathway. Various clinical trials are currently investigating the potential new treatment options. A meta-analysis will contribute to a better understanding of the various trial results., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular and skeletal abnormalities resembling Marfan syndrome, including a predisposition for pathologic fracture. LDS is caused by heterozygous mutations in the genes encoding transforming growth factor-β (TGF-β) type 1 and type 2 receptors. In this study, we characterized the skeletal phenotype of mice carrying a mutation in the TGF-β type 2 receptor associated with severe LDS in humans. Cortical bone in LDS mice showed significantly reduced tissue area, bone area, and cortical thickness with increased eccentricity. However, no significant differences in trabecular bone volume were observed. Dynamic histomorphometry performed in calcein-labeled mice showed decreased mineral apposition rates in cortical and trabecular bone with normal numbers of osteoblasts and osteoclasts. Mechanical testing of femurs by three-point bending revealed reduced femoral strength and fracture resistance. In vitro, osteoblasts from LDS mice demonstrated increased mineralization with enhanced expression of osteoblast differentiation markers compared with control cells. These changes were associated with impaired TGF-β1-induced Smad2 and Erk1/2 phosphorylation and upregulated TGF-β1 ligand mRNA expression, compatible with G357W as a loss-of-function mutation in the TGF-β type 2 receptor. Paradoxically, phosphorylated Smad2/3 in cortical osteocytes measured by immunohistochemistry was increased relative to controls, possibly suggesting the cross-activation of TGF-β-related receptors. The skeletal phenotype observed in the LDS mouse closely resembles the principal structural features of bone in humans with LDS and establishes this mouse as a valid in vivo model for further investigation of TGF-β receptor signaling in bone., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by skeletal abnormalities, craniofacial malformations, and a high predisposition for aortic aneurysm. In this issue of the JCI, Gallo et al. developed transgenic mouse strains harboring missense mutations in the genes encoding type I or II TGF-β receptors. These mice exhibited several LDS-associated phenotypes. Despite being functionally defective, the mutated receptors enhanced TGF-β signaling in vivo, inferred by detection of increased levels of phosphorylated Smad2. Aortic aneurysms in these LDS mice were ablated by treatment with the Ang II type 1 (AT1) receptor antagonist losartan. The results from this study will foster further interest into the potential therapeutic implications of AT1 receptor antagonists.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan syndrome. LDS is caused by heterozygous missense mutations in either TGF-β receptor gene (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-β signaling; however, aortic surgical samples from patients show evidence of paradoxically increased TGF-β signaling. We generated 2 knockin mouse strains with LDS mutations in either Tgfbr1 or Tgfbr2 and a transgenic mouse overexpressing mutant Tgfbr2. Knockin and transgenic mice, but not haploinsufficient animals, recapitulated the LDS phenotype. While heterozygous mutant cells had diminished signaling in response to exogenous TGF-β in vitro, they maintained normal levels of Smad2 phosphorylation under steady-state culture conditions, suggesting a chronic compensation. Analysis of TGF-β signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-β target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-β1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-β1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan. Together, these data suggest that increased TGF-β signaling contributes to postnatal aneurysm progression in LDS.

The extracellular matrix (ECM) is a complex entity with structural proteins (such as fibrillins, collagen, elastin), ground substance (proteoglycans), modifying enzymes (ADAMTS, PLOD, lysyloxidases (LOX)) and cytokines that regulate morphogenesis, growth, homeostasis and repair (transforming growth factor-beta [TGF-beta], bone morphogenic protein [BMP]). Over the last decade, the intimate relationship between structural proteins and these growth factors has emerged. The study of the extracellular matrix in human conditions and relevant mouse models is gradually unmasking the key role of these structural molecules in the regulation of the bio-availability of these growth factors. Major progress has been made in the study of the cardiovascular system (1) and the first clues in the skeletal system have emerged. (2) In this review, we will discuss the clinical, molecular, and pathogenic aspects of Marfan syndrome, Loeys-Dietz syndrome and related disorders with emphasis on the role of fibrillins and TGF-beta.

The transforming growth factor β (TGFβ) superfamily consists of multipotential secreting cytokines that mediate many key events in normal cellular growth and development, including differentiation, proliferation, motility, organization and death. TGFβs act as ligand for 3 classes of cell surface receptors, the transmembrane serine-threonine kinase receptors, TGFβ receptor type I (TGFβRI) and type 2 (TGFβRII), and TGFβRIII receptors which include an ubiquitous extracellular β-glycan and the membrane glycoprotein endoglin (CD105). Binding of TGFβs to their receptors initiates diverse cellular responses resulting in the phosphorilation of Smad proteins, which then translocate to the nucleus and regulate the transcription of target genes. Perturbation of TGFβ signaling has been implicated in various human disorders including cancer, fibrosis and auto-immune diseases. Recently, mutations in TGFβR1 and TGFβR2 genes have been found in association with a continuum of clinical features with widespread vascular involvement. The extreme of clinical severity is represented by the Loeys-Dietz syndrome (LDS), an autosomal dominant disorder characterized by hypertelorism, bifid uvula, and/or cleft palate, and aggressive arteriopathy causing arterial tortuosity as well as life-threatening complications such as vascular aneurysms and dissections. Elastin disarray, loss of elastic fibre architecture and increased collagen expression in the arterial wall are the pathologic hallmark of LDS. In the present review article we will provide details on the activation of TGFβ cascade, on the clinical features of LDS, as well as on the mechanisms of TGFβ signaling perturbation leading to this condition and the potential role of the antagonism of TGFβ activity in disease management.