Objective: To examine the potential of insulin, in a sustained delivery system, as a treatment for arthritis.
Design: The effect of insulin on matrix synthesis, matrix breakdown, and nitric oxide production in primary cartilage explants was examined. The activity of insulin on diseased cartilage from Dunkin Hartley guinea pigs, diabetic mice, and osteoarthritic patients was measured. The specificity of insulin stimulation was compared to that of IGF-I using osteoblasts and fibroblasts. Finally, the stability of insulin in a biologically relevant system was tested, and a slow-release formulation of insulin was developed and characterized.
Results: In articular cartilage explants, insulin stimulated proteoglycan (PG) synthesis, inhibited PG release and nitric oxide production, and overcame the detrimental effects of interleukin 1 (IL-1). The mechanism whereby insulin decreased matrix breakdown was through inhibition of aggrecanase activity. Insulin was active on cartilage at concentrations at which insulin does not cross-react with insulin-like growth factor I (IGF-I) receptors nor stimulate proliferation of other cells types. The response of cartilage to insulin did not diminish with age or disease. Insulin stimulated matrix synthesis in osteoarthritic cartilage and local treatment with insulin overcame endogenous suppression of matrix synthesis in diabetic cartilage. Poly-lactic-coglycolic acid (PLGA) was found to be an effective carrier for delivery of insulin, and PLGA-Insulin was active on articular cartilage in vitro and in vivo.
Conclusions: As the incidence of arthritis increases with the aging population, an effective therapy to induce repair of cartilage is needed. Based on its biological activities, insulin appears to be an attractive protein therapeutic candidate. Maximum insulin effectiveness may require a sustained delivery system.
Osteoarthritis and Cartilage 10(9): 692-706