Versican regulates Collagen fibrillation and Tenascin-C expression, suppressing podosome formation and pulmonary fibrosis

The activation and accumulation of lung fibroblasts, leading to aberrant deposition of extracellular matrix (ECM) components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis (IPF), a lethal and currently incurable disease. ECM deposition perpetuates fibroblast activation and stimulates ECM invasion via the formation of podosomes, an inherent property of IPF fibroblasts that is well amenable to pharmaceutical targeting. Proteoglycans (PGs), a significant component of the interstitial ECM, fine-tune the overall tissue architecture determined by fibrous proteins and regulate several ECM-controlled signalling pathways. In this report, increased expression of Versican (VCAN), a multifunctional PG, was detected in mouse and human pulmonary fibrosis, predominantly in monocytic cells and fibroblasts. Genetic downregulation of Vcan expression in mice modulated pulmonary ECM composition and organisation, promoted collagen expression and lung stiffness, exacerbating modelled pulmonary fibrosis and worsening respiratory functions. The decrease of Vcan levels in the ECM resulted in longer, thicker and tangled collagen fibrils, altered PG distribution, and increased levels of Tenascin-C (TNC), an ECM glycoprotein, shown here as a potent podosome inducer promoting ECM invasion. Thus, Vcan expression from fibroblasts is established as an autologous fibrotic brake, and TNC is suggested as a promising therapeutic target in IPF.