Mechanotransduction and cell biomechanics of the intervertebral disc

Abstract

Mechanical loading of the intervertebral disc (IVD) initiates cell-mediated remodeling events that contribute to disc degeneration. Cells of the IVD, nucleus pulposus (NP) and anulus fibrosus (AF), will exhibit various responses to different mechanical stimuli which appear to be highly dependent on loading type, magnitude, duration, and anatomic zone of cell origin. Cells of the NP, the innermost region of the disc, exhibit an anabolic response to low-moderate magnitudes of static compression, osmotic pressure, or hydrostatic pressure, while higher magnitudes promote a catabolic response marked by increased protease expression and activity. Cells of the outer AF are responsive to physical forces in a manner that depends on frequency and magnitude, as are cells of the NP, though they experience different forces, deformations, pressure, and osmotic pressure in vivo. Much remains to be understood of the mechanotransduction pathways that regulate IVD cell responses to loading, including responses to specific stimuli and also differences among cell types. There is evidence that cytoskeletal remodeling and receptor-mediated signaling are important mechanotransduction events that can regulate downstream effects like gene expression and posttranslational biosynthesis, all of which may influence phenotype and bioactivity. These and other mechanotransduction events will be regulated by known and to-be-discovered cell-matrix and cell-cell interactions, and depend on composition of extracellular matrix ligands for cell interaction, matrix stiffness, and the phenotype of the cells themselves. Here, we present a review of the current knowledge of the role of mechanical stimuli and the impact upon the cellular response to loading and changes that occur with aging and degeneration of the IVD.

Homeostasis of the intervertebral disc requires regulation of STAT3 signaling by the adhesion G-protein coupled receptor ADGRG6

“…In addition, we observed gene expression changes in several genes associated with ion transport in the IVD of Col2Cre;Adgrg6 f/f mutant mice at P20, including reduced expression of Fxyd2, Capn3, Panx3, and Atp13a4, as well as increased expression of Serpine1, Chrna4, and Slc4a1 ( Figure 4F). High osmotic pressure is a characteristic of the IVD (Fearing et al, 2018) and ion channel activity plays a critical role in the regulation of osmotic changes (Erickson et al, 2001;Matta et al, 2015). In agreement, recent analysis of the SM/J isotype mouse model of disc degeneration mice is associated with gene expression changes in ion transport systems (Zhang et al, 2018).…”

Interaction between Mesenchymal Stem Cells and Intervertebral Disc Microenvironment: From Cell Therapy to Tissue Engineering

“…Mechanical stimuli (flexion, torsion, shear, and compression) regulate IVD cell activity and metabolism within a physiological range (0.1-2.5 MPa) [46,47] Disruption of IVD structure alters loading transmission across the IVD and the vertebral segments, resulting in tissue damage and cellular overstress [48] Inflammation Proinflammatory cytokines and chemokines may have a role in IVD development and recruitment of local progenitor cells [49,50] The excess of proinflammatory cytokines increases cell apoptosis, senescence, autophagy, matrix breakdown, and discogenic LBP [51] CEP = cartilaginous end plate; AF = annulus fibrosus; NP = nucleus pulposus; IVD = intervertebral disc; IDD = intervertebral disc degeneration; GAG = glycosaminoglycan; LBP = low back pain. 4 Stem Cells International enhanced radicular pain [88].…”

“…In most investigations, static compressive loading has been associated with increased cell death and matrix catabolism due to diminished expression of collagen and aggrecan while metalloproteases were produced in higher amounts. Conversely, dynamic compressive loading has been described to often elicit an anabolic response and to enhance transportation of nutrients and especially high molecular weight molecules, such as growth factors (IGF-1, TGF-β, FGF, and PDGF), within the NP [48]. The type, degree, and duration of metabolic responses of IVD cells to loading strictly depend upon experimental design, cell source, age of donor, and culturing conditions and have been reviewed elsewhere [46,48].…”

TRPV4 Inhibition and CRISPR-Cas9 Knockout Reduce Inflammation Induced by Hyperphysiological Stretching in Human Annulus Fibrosus Cells

“…Musculoskeletal disorders are often associated with abnormal mechanical stress applied to load-bearing tissues [2,3]. In the intervertebral disc (IVD), compressive forces from the body weight and spinal motions generate hydrostatic and osmotic pressures in the central gelatinous nucleus pulposus, which in turn increase tensile stresses in the ring-shaped annulus fibrosus (AF) [4]. While physiological mechanostimulation is favorable and even necessary to maintain IVD homeostasis, hyperphysiological mechanical loading is a well known contributor to IVD degeneration [5].…”