AUTOCRINE AND PARACRINE OF HOMEOSTASIS OF THE INTERVERTEBRAL DISC

Rush University Medical Center, Chicago IL

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Abstract

We have documented age-related and degeneration-related changes in the metabolism of collagens,[unreadable] proteoglycans, and matrix-degrading enzymes in the human intervertebral disc. Our studies (i) confirmed the[unreadable] pivotal roles that cytokines and growth factors play in intervertebral disc degeneration and repair, (ii)[unreadable] demonstrated that certain growth factors inhibit the autocrine production of cytokines and that cytokine[unreadable] inhibitors can change basal levels of synthesis of matrix molecules and metalloproteinases, and (iii) found[unreadable] that biglycan was expressed in greater amounts than other small proteoglycans during late stages of disc[unreadable] degeneration and in the discs of old donors and plays an important regulatory role in matrix homeostasis.[unreadable] Our data suggest that an intricate balance of growth factors, cytokines and regulatory molecules is important[unreadable] for the maintenance of tissue homeostasis. Over the next five years, we propose to investigate the[unreadable] mechanisms of action and the interplay between growth factors, cytokines and various regulatory molecules[unreadable] in order to determine their respective roles in tissue homeostasis and their potential use in promoting tissue[unreadable] repair. Hypothesis 1: The effects of growth factors on the intervertebral disc are regulated by the production[unreadable] of cytokines by intervertebral disc cells and by the presence of inhibitory factors; growth factors have a[unreadable] negative feed back on the production of these cytokines. Hypothesis 2: The regulatory mechanisms of[unreadable] matrix homeostasis by cytokines and growth factors vary at different stages of disc degeneration because of[unreadable] changes in the cellular microenvironment in situ within the disc. The response to cytokines and growth[unreadable] factors and the production and activation of matrix-degrading enzymes will be different at advanced stages[unreadable] of disc degeneration. Hypothesis 3: The inhibition of cytokine action by cytokine blockers and the inhibition[unreadable] of cytokine production by growth factors can delay or reverse the degenerative status of intervertebral disc[unreadable] cells in the cellular microenvironment that can be observed in the early and middle stages of disc[unreadable] degeneration. Low back pain is responsible for enormous human suffering, high health care costs and[unreadable] significant socioeconomic losses. Although the etiology of back pain is often unknown, the intervertebral[unreadable] disc is a significant source of back problems. The results from this study will advance the field of biological[unreadable] treatment and tissue engineering for intervertebral disc degeneration.