Extracellular mechanotransduction mechanisms. (A) Collagen fiber remodeling based on a cell regulated paradigm (top) and an extracellular regulated paradigm (bottom). Note: These mechanisms are not mutually exclusive. (B) Latent TGFB, bound by latent TGFB binding protein (LTBP), is initially sequestered in matrix by fibrillin-1 microfibrils and bound by other matrix components (e.g., fibronectin). Free TGFB capable of interacting with cell surface receptors can be activated following: (1) enzymatic cleavage; (2) integrin-mediated cellular traction; and (3) residual matrix strain. Note: The proposed mechanism for residual matrix strain is decreased protein–protein interactions between fibrillin-1 microfibrils and the latent TGFB complex. (C) Fibronectin is initially secreted with both exposed and cryptic integrin binding sites. Cellular integrin-mediated forces unfold fibronectin such that cryptic integrin binding sites become exposed.