During loading, cells of the intervertebral disc (IVD) experience compressive and tensile deformation, as well as hydrostatic and osmotic pressures, among other physical effects. Mechanical signals are important regulators of cell biological responses in the IVD. (A) Dynamic compression applied to rat tail IVDs in vivo differentially regulates extracellular matrix (ECM) expression (aggrecan, collagen I, collagen II) in the anulus fibrosus (AF) and nucleus pulposus (NP) regions to the same magnitude of loading (adapted from Maclean et al71). (B) Applied stretch to AF cells in vitro results in a magnitude and duration dependent changes in inflammatory genes (iNOS, Cox2) and protease expression and regulation (MMP1, MMP3, TIMP1, adapted from Sowa et al109). (C) Daily applied hydrostatic pressure induces inflammatory signaling in NP cells in vitro in a magnitude and duration dependent manner. Adapted from Shah and Chahine 121. (D) Hyperosmotic loading of human NP cells induced decreased cell volume and cytoskeletal reorganization, as well as regulate genes include neurotrophins (BDNF), pro‐inflammatory cytokines (IL‐6), proteases (ADAMTS1), and multiple solute transporters and ion channels (adapted from Boyd et al135)