Osteoarthritis is an insidious disease that results in a heavy toll of human suffering, debilitation, and economic loss. Treatment of osteoarthritic joints with injections of hyaluronic acid has proven to provide short term improvement of clinical signs possibly because of its lubricating properties and/or stabilizing influence on cells of the immune system. Members of the transforming growth factor beta family of proteins have been shown to stimulate proteoglycan synthesis, prevent proteoglycan catabolism, and regulate certain aspects of the immune system. A composite of hyaluronic acid and transforming growth factor beta could be a useful agent in the treatment of osteoarthritis to limit articular cartilage degeneration and potentially facilitate its repair. Objectives: The proposed study will evaluate the efficacy of a composite of hyaluronic acid and TGF-B can: (1) stimulate dormant chondrocytes capable of matrix synthesis to regenerate atrophic articular cartilage to regenerate the cartilage lost in a knee destabilization model, (3) prevent the potential fibrogenic side effect observed with TGF-B in soft tissues, and (4) reduce the production eicosanoid inflammatory mediators in atrophic and osteoarthritic joints. Joint Immobilization Study: Atrophic articular cartilage containing chondrocytes with minimal synthetic activity will be produced by joint immobilization. The left knees of 4 groups of 4 dogs will be immobilized by casts for 56 days. A fifth group of 4 dogs will serve as untreated controls. On day 56, the cast will be replaced with casts containing injection portals. Each group will be treated by intraarticular injections of hyaluronic acid (HA),HA+20 microgram TGF-B,HA+50 micrograms TGF-, or nothing (cast control). Injections will be given at 4-day intervals for 28 days. After euthanasia of all dogs on day 88, articular cartilage will be analyzed for proteoglycan content and rate of synthesis by resident chondrocytes. PGE2, as an indicator of inflammatory mediators, will be quantified. The results wil determine the ability of the HA/TGF-B composite to stimulate the synthesis of proteoglycans, and potentially decrease catabolism, by chondrocytes capable of responding to stimuli in vivo. Joint Destabilization Study: Osteoarthritic articular cartilage, containing chondrocytes actively secreting proteoglycans and active matrix degradation by proteases, will be created by transection of the cranial cruciate ligament of the knee joint. The cranial cruciate ligament of the left knee of 5 groups of 4 dogs will be transected. After 84 days of ad libitum exercise, the operated leg will be casted containing an portal for intraarticular injection and treated with HA, HA+20 micrograms TGF-B, or HA+50 micrograms TGF-B, or nothing (casted and non-cast controls). After injections at 4 day intervals for 28 days, the articular cartilage will be analyzed for proteoglycan content and rate of synthesis as well as PGE2 level. The results will establish the capacity of HA/TGF-B to sustain proteoglycan syntheses to facilitate repair of osteoarthritic articular cartilage.
| Comer, J S; Kincaid, S A; Baird, A N et al. (1996) Immunolocalization of stromelysin, tumor necrosis factor (TNF) alpha, and TNF receptors in atrophied canine articular cartilage treated with hyaluronic acid and transforming growth factor beta. Am J Vet Res 57:1488-96 |
