SPINAL MATRIX METABOLISM UNDER ALTERING STRESS STATES

University Of Tennessee Health Sci Ctr, Memphis TN

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): While the etiology of disc degeneration is poorly understood, its progression appears to be a function of altered load transmission between the nucleus pulposus and annulus fibrosus. In the healthy disc, pressure under compressive loading develops in the nucleus through the annulus acting in tension. If the nucleus degenerates, it loses its water-imbibing ability and no longer functions to radially transmit load to the annulus. This change in loading is postulated to initiate a pathologic remodeling process that with time results in disc narrowing and may lead to nerve root impingement in the foramen. Data from simple cell-loading devices suggest that disc degeneration is driven by a mechanobiological interplay in which the intervertebral disc cells and accelerate their turnover rate of extracellular matrix components. Studies of intervertebral disc cells have shown up- or down-regulation of proteoglycan (PG) synthesis in response to various magnitudes of hydrostatic load. Although these data are relevant for the nucleus, the key to understanding the progression of disc degeneration is to study the metabolic effects of reversal of the stress states in the annulus from tension to compression. Disc degeneration in the workplace, furthermore, is known to occur with combined lifting and twisting suggesting that shear loading in the annulus is particularly relevant to aberrant biomechanical signaling. Our aims will be (1) To test the hypothesis that reversal of stress state in the annulus results in pathologic regulation of intervertebral disc matrix metabolism. Using a modified stretch apparatus to apply a full spectrum of stress from tension to compression, we expect to find an upregulation of prostaglandin E2 synthesis, correlated with expression of the inflammatory cytokines TNFalpha and IL-1 beta and induction of metalloproteinases (MMP) MMP-1, MMP-13 synthesis in annular fibroblast cells at critical thresholds of tension and compression. We also predict that excessive load will lead to down-regulation of PG and Collagen synthesis. A corollary of this hypothesis, suggested by in vivo findings, is that reversal of stress states leads to conversion of Collagen type II (CII) to type I (CI) gene expression in the inner annulus. (2) To test the hypothesis that the addition of shear to high compressive loads results in a lower threshold for up-regulation of the inflammatory pathways and metalloproteinase expression. We will use a novel cell pressurizing device with shearing capacity to examine the effects of simultaneously applying these two stresses. The proposed study will investigate these gene expressions and metabolic agents under the specified loading conditions.