Abstract
The basis of back pain and disc degeneration is little understood. The end point of disk degeneration is cellular decline, loss of water content, decrease of proteoglycans, decrease in Type II collagen with consequent increase in Type I collagen as well as anular fissures, loss of mechanical competence of the disk facet complex as well as bony changes. Little is known of the process from the healthy disk to more degenerated disc.
The current solution to what is thought to be the causes of the problem is surgery involving disc excision, fusion and/or replacement. These solutions may be the cause of more problems. Frequently these solutions are temporary. The question is whether there is a better or different way to treat this pain-generating disc degeneration. In intervening with disc degeneration by manipulating the cellular environment, timing may be everything. However we do not know at which time point the decline of disc tissue becomes irreversible, when any cellular, genetic or growth factor therapies to try to regenerate will be futile. The goal is to find this point and try to perform therapies that are appropriate at that time point. The strategies should include promoting and upgrading matrix synthesis within the disc, inhibiting the catabolic processes that may be a normal aging process, and to try to replace the loss number of cells to increase the matrix to avoid the imbalance between synthesis and catabolism that maybe causing the disk degeneration.
Disc tissue and chondrocytes cultured using a variety of techniques synthesize proteoglycans and collagen type II. These culture systems can be used to manipulate the biology using growth factors, gene therapy methods and environmental cues to increase proteoglycans or collagen II production. Human OP-1 has been shown to increase proteoglycan synthesis while collagen type II can be increased when cultures are exposed to recombinant human BMP. Unfortunately, growth factors have a short half life and must therefore be administered in multiple doses to prolong their effect.
The potential solution may be the use of viral vector or gene therapy. When a viral vector with an exogenous gene is introduced into cell cultures, the gene is incorporated into the target cell which can express the gene producing growth factors long term. Adenoviral vector systems using a therapeutic gene containing TGF beta 1 promotes both proteoglycan and collagen synthesis. This response is dose dependent. Similarly, anulus fibrosis cell cultures show increased collagen synthesis when exposed to viral vectors carrying BMPs and Sox-9 genes. Combined use of multiple growth factors genes such as TGF beta 1, BMP 2, and IGF has an additive effect on proteoglycan synthesis. The Sox-9 gene is essential for chondrogenesis. It has been shown to promote type II collagen synthesis in disc cell cultures. In animal studies adeno Sox-9 inoculation of the disc maintains normal disc anatomy while controls show disc degeneration and osteophyte formation.
To date, studies show that growth factors may slow the degenerative process but not reverse it. Disc chondrocytes are sparse in numbers and difficult to isolate and culture. Mesenchymal stem cells grown in an hypoxic environment will produce collagen and Sox-9 markers similar to nucleus pulposus cells. Cells harvested from the disc and grown in culture will survive and synthesis matrix when retransplanted into the disc environment. If suitable cells can be cultured and genetically manipulated to up regulate growth factor production, then introduction of these cells into a degenerating disc at an appropriate stage might favorably moderate the degenerative process hopefully obviating the need for surgery.
The abstracts were prepared by Assoc Prof Bruce McPhee. Correspondence should be addressed to him at the Division of Orthopaedics, The University of Queensland, Clinical Sciences Building, Royal Brisbane Hospital, Herston, Brisbane, 4029, Australia.
