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A slow release formulation of insulin as a treatment for osteoarthritis
L Cai1, F W Okumu, J L Cleland
1Department of Molecular Oncology, Genentech Inc. South San Francisco, CA 94080-4990, USA.
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.
Insights
Insulin shows promise for treating arthritis by stimulating cartilage repair and reducing inflammation. A sustained delivery system using PLGA enhances insulin
Area of Science:
- Biochemistry
- Orthopedics
- Pharmacology
Background:
- Arthritis incidence is rising with an aging population.
- Current therapies often fail to induce cartilage repair.
- Novel therapeutic strategies are needed for effective arthritis treatment.
Purpose of the Study:
- To investigate insulin's potential as a therapeutic agent for arthritis.
- To evaluate insulin's effects on cartilage matrix synthesis and degradation.
- To develop and characterize a sustained delivery system for insulin.
Main Methods:
- Assessed insulin's impact on proteoglycan synthesis, nitric oxide production, and matrix breakdown in cartilage explants.
- Tested insulin activity on cartilage from aged, diabetic, and osteoarthritic models.
- Compared insulin's specificity to IGF-I and developed a PLGA-based slow-release formulation.
Main Results:
- Insulin stimulated proteoglycan synthesis and inhibited matrix breakdown and nitric oxide production in cartilage.
- Insulin's beneficial effects were observed in aged, diabetic, and osteoarthritic cartilage.
- A poly-lactic-coglycolic acid (PLGA)-insulin formulation demonstrated in vitro and in vivo activity.
Conclusions:
- Insulin exhibits potent cartilage-protective and restorative properties.
- Insulin is a promising candidate for protein-based arthritis therapy.
- Sustained delivery systems are crucial for maximizing insulin's therapeutic efficacy in arthritis.