Chung, G.J-H.; (2008) Towards defining a role for zoledronate as a disease-modifying treatment in osteoarthritis : an in vitro study of the effects of zoledronate on cartilage and chondrocyte proteoglycan metabolism. Doctoral thesis , University of London.

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Abstract

Osteoarthritis (OA) is a common group of disabling joint disorders for which there are limited pharmacological therapies to alter disease progression. Zoledronate, one of several bisphosphonates found to modulate joint changes in animal OA models, may have a disease-modifying role, and potential mechanisms of action include effects on cartilage and/or subchondral bone. In OA cartilage, loss of aggrecan, the main glycosaminoglycan-bearing proteoglycan, and degradation of type II collagen are major biochemical changes arising from imbalances in matrix synthesis and degradation. Zoledronate, in common with other bisphosphonates, is capable of inhibiting matrix metallo-proteinases, enzymes implicated in OA cartilage matrix catabolism, providing a biochemical basis for cartilage effects but it is not known whether direct effects occur at the cell/tissue level. Studies described in this thesis have explored the hypothesis that zoledronate modifies cartilage metabolism to reduce cartilage glycosaminoglycan loss in OA. Short-term treatment effects on proteoglycan synthesis and degradation were examined in vitro in models of cartilage and chondrocyte metabolism, with IL-1a used to stimulate "OA-like" tissue glycosaminoglycan release. Zoledronate 10M adversely affected cell viability, proliferation and proteoglycan synthesis in bovine articular chondrocytes and, thus, was the upper limit of the concentration range investigated. No enhancing effects were observed with zoledronate 10"10M to 10/1 on proteoglycan synthesis in bovine articular chondrocytes. No effects on glycosaminoglycan release were seen with zoledronate 10"10M to 10"5M in bovine articular cartilage or with zoledronate 10"8M to "10M in alginate bead constructs containing bovine articular chondrocytes and matrix. Thus, a direct effect on cartilage proteoglycan metabolism following short-term treatment does not appear to be a mechanism of action for zoledronate as a disease-modifying treatment in OA. However, preventative or delayed treatment effects remain unaddressed and other potential targets for zoledronate in the OA joint include cartilage type II collagen metabolism and subchondral bone metabolism.

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