Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Abstract

Most single-gene diseases, including muscular dystrophy, display a nonuniform phenotype. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. We employed an unbiased mapping approach to search for genes that modify muscular dystrophy in mice. In a genome-wide scan, we identified a single strong locus on chromosome 7 that influenced two pathological features of muscular dystrophy, muscle membrane permeability and muscle fibrosis. Within this genomic interval, an insertion/deletion polymorphism of 36 bp in the coding region of the latent TGF-β-binding protein 4 gene (Ltbp4) was found. Ltbp4 encodes a latent TGF-β-binding protein that sequesters TGF-β and regulates its availability for binding to the TGF-β receptor. Insertion of 12 amino acids into the proline-rich region of LTBP4 reduced proteolytic cleavage and was associated with reduced TGF-β signaling, decreased fibrosis, and improved muscle pathology in a mouse model of muscular dystrophy. In contrast, a 12-amino-acid deletion in LTBP4 was associated with increased proteolysis, SMAD signaling, and fibrosis. These data identify Ltbp4 as a target gene to regulate TGF-β signaling and modify outcomes in muscular dystrophy.

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

“…In both skeletal and cardiac muscle, manipulation of TGF-β via a neutralizing antibody or treatment with losartan leads to improvement in muscle function and histology and, coincidently, a decrease in periostin in the muscle (7,30). These results are consistent with the hypothesis that TGF-β secretion and its enhanced activity contribute to the demise of skeletal muscle in MD (9). However, one interesting possibility is that periostin functions as a key downstream effector of TGF-β that promotes its deleterious effects in MD (31).…”

“…One such inflammatory mediator, transforming growth factor (TGF)-β, is thought to worsen MD and lead to increased fibrosis in human dystrophic muscle (3,4) and animal models of dystrophy (5); for example, administration of decorin (a TGF-β antagonist) reduces collagen expression in the diaphragm of dystrophin-deficient mdx mice (6), and losartan (an angiotensin II type 1 receptor blocker thought to reduce TGF-β activity) normalizes muscle architecture and improves function in animal models of myopathy (7,8). Recently, genetic alterations in the TGF-β pathway, such as changes in latent TGF-β binding protein 4, also have supported the theory of a strong interplay between TGF-β-induced fibrosis and MD severity (9). In vitro, TGF-β can directly influence satellite cell proliferation, myocyte differentiation, and myofiber fusion (10).…”

Inhibiting myostatin reverses muscle fibrosis through apoptosis

“…These include factors and drugs which inhibit TGF-b extracellularly such as TGF-b neutralizing antibodies, the ECM proteoglycan decorin, and latent TGF-b-binding protein 4 (Andreetta et al, 2006;Heydemann et al, 2009;Li et al, 2007). It also includes factors and drugs which may modulate or cross-talk with TGF-b signaling including, in addition to myostatin, IGF-1 and angiotensin II receptor blockers Bedair et al, 2008).…”

Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

“…In a screen for genetic modifiers in another mouse model of muscular dystrophy, Heydemann et al identified a 36bp insertion/ deletion polymorphism in exon 12 of Ltbp4 (Heydemann et al 2009) that maps to the proline-rich, protease-sensitive region of LTBP4. The deletion (Ltbp4 D36 ) occurs in the more severely affected strain.…”