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.

The focal increase in cartilage thickness is one of the earliest measurable changes in OA and preceeds subchondral bone remodeling. The measurement of cartilage thickness variations with MRI can be used to follow the course of OA and to evaluate the potential beneficial effect of novel therapies.

Microfracture is a common cartilage repair procedure. Strategies to improve healing post-microfracture include the use of growth factors to enhance hyaline cartilage production. This study investigates the effect of intra-articular recombinant human fibroblastic growth factor 18 (rhFHF18) on the healing of a chondral defect treated with microfracture in an ovine model. Chondral defects (8 mm diameter) were created in the medial femoral condyle of 80 sheep (n ¼ 16/treatment group). Defects were treated with microfracture alone or microfracture þ intra-articular rhFGF-18 (administered either as one or two cycles of 3Â weekly injections). Outcome measures included mechanical testing, macroscopic International Cartilage Repair Society repair score, modified O'Driscoll histology score, qualitative histology, and immunohistochemistry for types I, II, and VI collagen. In treated animals, there was a statistically significant improvement in ICRS tissue repair score and tissue infill score, in the modified O'Driscoll score between control and 1 cycle of rhFGF-18 at 6 m, and in the cartilage repair score and structural characteristic score between the control and both rhFGF-18 groups at 6 m. There was no evidence of degeneration of adjacent cartilage in the rhFGF-18 treated cartilage. The increase in hyaline cartilage-like tissue formed in the microfracture þ rhFGF-18 treated groups indicates that rhFGF-18 potentiates the formation of hyaline cartilage repair following microfracture. ß

Alzheimer's disease (AD) is characterized by the accumulation of protein filaments, namely extracellular amyloid-beta (Abeta) fibrils and intracellular neurofibrillary tangles, which are composed of aggregated hyperphosphorylated tau. Tau hyperphosphorylation is the product of deregulated Ser/Thr kinases such as cdk5 and GSK3beta. In addition, tau hyperphosphorylation also occurs at Tyr residues. To find a link between Abeta and tau phosphorylation, we investigated the effects of short-term Abeta treatments on SHSY-5Y cells. We analyzed phosphorylated tau variants in lipid rafts and the possible role of Tyr18 and Ser396/404 tau phosphorylation in Abeta-induced signaling cascades. After 2 min of Abeta treatment, phospho-Tyr18-tau and its association with rafts increased. Phospho-Ser 396/404-tau became detectable in rafts after 10 min treatment, which temporally correlated with the detection of cdk5 and p35 activator in lipid rafts. To determine the role of cdk5 in tau phosphorylation at Ser396/404 in lipid rafts, we pre-incubated cells with cdk5 inhibitor roscovitine, and observed that the Abeta-induced tau phosphorylation at Ser 396/404 in rafts was abolished as well as cdk5/p35 association with rafts. These data suggest a role for cdk5 in the Abeta-promoted early events involving tau hyperphosphorylation, and their possible implications for AD pathogenesis.