The role of the reactive oxygen species-generating enzyme, xanthine oxidoreductase, in cytokine- and hormone-induced bone resorption

Abstract

Bone resorption underlies the pathology of many disabling diseases, ranging from the inflammatory condition, rheumatoid arthritis to the hormonally controlled, metabolic disorder, osteoporosis. It is known that various agents, including cytokines, prostaglandins, parathyroid hormone (PTH), l a ,25 dihydroxy vitamin D3 and free radicals influence the bone resorptive process. Pro-inflammatory cytokines such as TN Fa and IL -lp have been ascribed a pivotal role in rheumatoid arthritis (RA).
Bone resorptive mechanisms employ complex cellular signalling pathways between osteoblasts and osteoclasts that involve reactive oxygen (ROS) and nitrogen species (RNS). Recent studies have demonstrated that one of these species, hydrogen peroxide (H2O2) can increase osteoclast differentiation and bone resorption. One possible source of these ROS is xanthine oxidase. This thesis explores the role of XO derived ROS directly and as mediators of cytokine- and hormone-induced bone resorption in vitro.
The results of this thesis demonstrated that calvarial osteoblasts contain XO, which can be upregulated by TN Fa and I L - ip . Consequently, induction of XO by these cytokines led to the generation of hydrogen peroxide. TN Fa and IL -lp caused a dose-related increase in resorption of mouse calvariae in culture, which was inhibited by lOU/ml catalase. The competitive inhibitor of XO, allopurinol, also caused a dose related (0.05-50p,M) inhibition of TNF-a (O.l-lOpM) and IL-lp-induced resorption respectively. Additionally, IFN-y inhibition of bone resorption could be reversed by the addition of superoxide dismutase to the cultures. PTH- and l a , 25(OH) 2 D3-induced bone resorption could be inhibited by catalase (lOU/ml) but was unaffected by allopurinol, implying that a different mediator, other than XO, is required for hormone-induced bone resorption.
In conclusion, this thesis demonstrates that modulation of the redox balance in the bone microenvironment can have profound effects on the bone resorbing process. Our results show that XO may play a pivotal role in affecting this redox balance and if manipulated appropriately, could be used to have a therapeutic benefit in inflammatory bone disorders such as RA

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ORCID for Janos Kanczler: orcid.org/0000-0001-7249-0414

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