Fibroproliferative disorders and their mechanobiology

Benign and malignant fibroproliferative disorders (FPDs) include idiopathic pulmonary fibrosis, hepatic cirrhosis, myelofibrosis, systemic sclerosis, Dupuytren's contracture, hypertrophic scars, and keloids. They are characterized by excessive connective tissue accumulation and slow but continuous tissue contraction that lead to progressive deterioration in the normal structure and function of affected organs. In recent years, research in diverse fields has increasingly highlighted the potential role of mechanobiology in the molecular mechanisms of fibroproliferation. Mechanobiology, the heart of which is mechanotransduction, is the process whereby cells sense mechanical forces and transduce them, thereby changing the intracellular biochemistry and gene expression. Understanding mechanosignaling may provide new insights into the convergent roles played by interrelated molecules and overlapping signaling pathways during the inflammatory, proliferative, and fibrotic cellular activities that are the hallmarks of fibroproliferation. The main cellular players in FPDs are fibroblasts and myofibroblasts. Consequently, this article discusses integrins and the roles they play in cellular-extracellular matrix interactions. Also described are the signaling pathways that are known to participate in mechanosignaling: these include the transforming growth factor-β/Smad, mitogen-activated protein kinase, RhoA/ROCK, Wnt/β-catenin, and tumor necrosis factor-α/nuclear factor kappa-light-chain-enhancer of activated B cells pathways. Also outlined is the progress in our understanding of the cellular-extracellular matrix interactions that are associated with fibroproliferative mechanosignaling through matricellular proteins. The tensegrity and tensional homeostasis models are also discussed. A better understanding of the mechanosignaling pathways in the FPD microenvironment will almost certainly lead to the development of novel interventions that can prevent, reduce, or even reverse FPD formation and/or progression.