Year of Publication

2015

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Agriculture, Food and Environment

Department

Veterinary Science

First Advisor

Dr. James MacLeod

Abstract

Intra-articular glucocorticoid injections are commonly used to treat synovitis and osteoarthritis in horses. These agents are highly effective at relieving pain, swelling, and other symptoms of joint inflammation. The drugs also have therapeutic benefits by down regulating the expression of cytokines and protease enzymes that participate in the degradation of articular cartilage. However, detrimental effects on chondrocyte function and cell viability that is independent of osteoarthritis pathogenesis have been described and linked to glucocorticoid use. These side effects are both drug- and dose-dependent. This study tested the hypothesis that manufacture recommended dosage levels of methylprednisolone, betamethasone, and triamcinolone that are widely used in equine clinical practice are cytotoxic to articular chondrocytes. Drug-induced chondrocyte cytotoxicity was evaluated in monolayer cultures, cartilage explants, and equine fetlock joints. Total RNA was isolated from control and IL-1β stimulated primary chondrocytes and synoviocytes in culture. Changes in steady state mRNA for targeted gene transcripts related to inflammation and normal cell function were measured using reverse transcription and quantitative PCR. Inducible nitric oxide synthase activity was evaluated using nitrite production. Drug-induced chondrocyte cytotoxicity occurred at drug dosage levels frequently used in equine clinical practice. Both drug- and dose-dependent effects on chondrocyte and synoviocyte gene expression were observed. Maximum anti-inflammatory activities for the glucocorticoids were observed at in vitro concentrations below manufacturer-recommended levels. Results from this study suggest that lower glucocorticoid dose ranges for intra-articular therapy in horses should be validated to maximize the ratio of their therapeutically beneficial anti-inflammatory efficacy against detrimental effects on cell function and viability.

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