Fibrosis occurs when there is an imbalance in extracellular matrix (ECM) deposition and degradation. Excessive ECM deposition results in scarring and thickening of the affected tissue, and interferes with tissue and organ homeostasis – mimicking an exaggerated “wound healing” response. Many transforming growth factor-β (TGF-β) ligands are potent drivers of ECM deposition, and additionally, have a natural affinity for the ECM, creating a concentrated pool of pro-fibrotic factors at the site of injury. Consequently, TGF-β ligands are upregulated in many human fibrotic conditions and, as such, are attractive targets for fibrosis therapy. Here, we will discuss the contribution of TGF-β proteins in the pathogenesis of fibrosis, and promising anti-fibrotic approaches that target TGF-β ligands.
Significance
Myostatin, via activation of the Smad2/3 pathway, has long been recognized as the body’s major negative regulator of skeletal muscle mass. In this study, however, we demonstrate that other TGF-β proteins, particularly activin A and activin B, act in concert with myostatin to repress muscle growth. Preventing activin and myostatin signaling in the tibialis anterior muscles of mice resulted in massive hypertrophy (>150%), which was dependent upon both the complete inhibition of the Smad2/3 pathway and activation of the parallel bone morphogenetic protein (BMP)/Smad1/5 axis. Using this approach in models of muscular dystrophy and cancer cachexia increased muscle mass or prevented muscle wasting, respectively, highlighting the potential therapeutic advantages of complete inhibition of Smad2/3 ligand activity in skeletal muscle.
Mutations in BMP15 associated with POI reduce mature protein production, activity, or synergy with GDF9. The latter effect is perhaps most interesting given that interactions with GDF9 most likely underlie the physiology of BMP15 in the human ovary.
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