Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome

Abstract

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.

New insights into elastic fiber assembly

“…Furthermore, in vivo assembly of fibrillin may require cell-surface receptors in a similar manner to fibronectin (Wu et al, 1995). Fibrillins also have a major role in binding and sequestering growth factors, such as TGF-b, into the ECM (Neptune et al, 2003).…”

Tissue elasticity and the ageing elastic fibre

“…LTBPs appear to fulfil dual roles as both structural components of the ECM (Dallas et al 1995) and as TGFβ trafficking molecules (Miyazono et al 1991). Furthermore, the association of LTBPs with fibrillin microfibrils (Raghunath et al 1998;Unsold et al 2001) and the perturbations of normal TGFβ signalling in FBN1-mutant mice led to the hypothesis that fibrillin microfibrils play a major role in maintaining tissue homeostasis via LTBP-mediated sequestration of TGFβ (Denton and Abraham 2001;Neptune et al 2003). Fibulins are small ECM glycoproteins which appear to play important roles during development and wound healing (for a review see Chu and Tsuda 2004).…”

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

“…Alveolar formation in mouse begins with eruption of secondary crests accompanied by coordinated expression of contractile proteins by interstitial cells (Adler et al, 1989;Jostarndt-Fogen et al, 1998;Yamada et al, 2005) and increased production of elastic matrix (Mariani et al, 2002;RothKleiner and Post, 2005;Foster et al, 2006). Many available mouse genetic models showing severe lung defects in the first postnatal week (Bostrom et al, 1996;Weinstein et al, 1998;Neptune et al, 2003) highlight the importance of the specialized constituents of the lung elastic matrix or the numbers and behavior of interstitial myofibroblasts in secondary septation (reviewed in Bourbon et al, 2005). We, therefore, evaluated these features in mutant lungs by immunostaining for the elastic matrix proteins elastin and fibrillin-1 and for the contractile cell marker SMA (Fig.…”

“…In those mice, alveolarization is delayed, but they finally form normal lungs (Sonja Mund and J.C.S., unpublished results). The alterations in cellular number and phenotype seen in older mutant lungs could in principle be a secondary consequence of the ECM alterations present at P1 (e.g., McGowan and Torday, 1997;Neptune et al, 2003;Thannickal et al, 2003); or could reflect an independent requirement for ephrinB2 function.…”