Articular cartilage is subjected to a wide range of static and dynamic mechanical loads in human synovial joints. Studies in vivo have shown that joint loading can induce a range of metabolic responses in cartilage. During the past two decades, a large body of evidence has emerged documenting the effects of various mechanical loading modalities on chondrocyte biosynthesis and gene expression. While specific components of certain mechanotransduction pathways have been identified, the exact mechanisms by which mechanical forces influence the biological activity of chondrocyte are not yet fully understood. A more comprehensive understanding of chondrocyte mechanobiology is critically important for a clear understanding of the etiopathology and treatment of osteoarthritis as well as for the long-term survival of tissue engineered implants for cartilage repair. Since mechanotransduction mechanisms are difficult to quantify in vivo, model systems such as cartilage explant organ culture and three dimensional chondrocyte/ gel culture systems have been used. We hypothesize that specific components of mechanical matrix proteins which, together, regulate cartilage's functional biomechanical properties and normal homeostasis.
The Specific Aims of this research are (1) to quantify the effects of ram-and-hold compression, dynamic compression and tissue shear on patterns of gene expression in bovine calf and adult human cartilage explants with time after loading via real time PCR and, using gene clustering algorithms, to identify groups of genes whose transcription may be co-regulated by specific components of load: (2) to quantify the effects of these loading protocols on protein synthesis via immunohistochemistry and mass spectroscopy: (3) to identify mechanically-induced changes in gene expression and protein production in chondrocyte-seeded self-assembling peptide and alginate gel culture systems where, in parallel studies, the physical properties of the developing pericellular matrix will be characterized after removal of cells from alginate using recently developed atomic force microscopy methodologies; and (4) Determine the molecular-level shear and compressive deformation properties of matrix aggrecan isolated from native tissue and from the 3D-gel systems after extended application of static and dynamic compression and shear to these systems. ? ? ?
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