In vitro inhibition of compression-induced catabolic gene expression in meniscal explants following treatment with IL-1 receptor antagonist.

BACKGROUND: Damage to the knee meniscus may result in tears that are difficult or unable to heal, and are often treated by partial removal of the damaged tissue. In vitro, 20% dynamic compressive strains on meniscal tissue explants have resulted in an increase in the release of sulfated glycosaminoglycans (GAG) and nitric oxide (NO) from the tissue explants and increased expression of matrix metalloproteinases (MMP) and interleukin-1α (IL-1α). The objective of this study was to explore the efficacy of IL-1 blockade on the expression of a wide range of genes, as well as NO and GAG release, following dynamic compression of porcine meniscal explants. METHODS: Explants were dynamically compressed for 2 h at 1 Hz to 0, 10, or 20% strain with and without a pre-treatment of 500 ng/ml interleukin-1 receptor antagonist (IL-1RA). Relative changes in gene expression of IL-1α, MMP-1, -3, -13, A Disintegrin and Metalloproteinase with ThromboSpondin 4 (ADAMTS-4), ADAMTS-5, iNOS, aggrecan, and COX-2, as well as changes in NO and GAG release, were measured with standard biochemical assays. RESULTS: Expression of IL-1α, MMP-3, MMP-13, and ADAMTS-4 in superficial explants was significantly downregulated at 20% dynamic strain compared to 10% strain following treatment with IL-1RA. GAG and NO release were not significantly influenced by IL-1RA treatment. CONCLUSIONS: Treatment of meniscal explants with IL-1RA inhibited the expression of many catabolic genes following a single bout of high dynamic strain. IL-1RA may therefore be a potential therapy option during the acute phase of meniscal tear or meniscectomy treatment.

Role of cell location and morphology in the mechanical environment around meniscal cells.

Fibrochondrocytes within meniscal tissue have been shown to alter their biochemical activity in response to changes in their mechanical environment. Meniscal tissue is known to contain both spherical (chondrocytic-like) and elliptical (fibroblastic-like) cells. We hypothesize that a cell's mechanical environment is governed by local material properties of the tissue around the cell, the cell morphology and the cell's position within the tissue. A two-dimensional, non-linear, fiber (collagen) reinforced, multi-scale, finite element model was utilized to quantify changes in the stress, strain, fluid velocity and fluid flow induced shear stress (FFISS) within and around fibrochondrocytes. Cells differing in morphology and size were modeled at different locations within an explant 6mm in diameter and 5mm thick, under 5% unconfined compression. Cellular stresses were an order of magnitude less than surrounding extracellular matrix stresses but cellular strains were higher. Cell size affected both the stress and strain levels within the cell, with smaller cells being exposed to smaller principal stresses and strains than larger cells of the same shape. The pericellular matrix of an elliptical cell was less effective at shielding the cell from large principal strains and stresses. FFISS were largest around small circular cells ( approximately 0.13Pa), and were dramatically affected by the position of the cell relative to the axis of the explant, with cells closer to the periphery experiencing greater FFISS than cells near the central axis of the explant. These results will allow biosynthetic activity of fibrochondrocytes to be correlated with position and morphology in the future.