title: Xanthine oxidase mediates cytokine-induced, but not hormone-induced bone resorption.
abstract: Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) have been implicated as mediators of osteoclastic bone resorption. Xanthine oxidase (XO) a ubiquitous enzyme is widely known for its production of these ROS. We therefore evaluated the potential of XO as a source of ROS in cytokine-and hormone-induced bone resorption. XO activity in rat calvarial osteoblasts was found to be significantly elevated upon stimulation by the cytokines, TNFalpha and IL-1beta. These cytokines also caused a dose related increase in bone resorption of mouse calvariae, which was significantly inhibited by catalase (10 IU/ml). Allopurinol, the competitive inhibitor of XO, also caused a dose related (1-50 microM) inhibition of TNFalpha (20 ng/ml) and (0.01-10 microM) IL-1beta (50 IU/ml)-induced bone resorption, respectively. PTH- and 1,25-(OH)2 Vitamin D3-induced bone resorption could also be inhibited by catalase (100 IU/ml) but was unaffected by allopurinol, indicating that another mediator, other than XO, is required for hormone-induced bone resorption. These results demonstrate, that modulation of the redox balance in the bone microenvironment, which contains XO, can affect the bone resorbing process. Therefore, XO may play a pivotal role in cytokine-induced bone resorption and, if manipulated appropriately, could show a therapeutic benefit in inflammatory bone disorders such as RA.
authors.affiliation: Department of Medical Sciences, Bone and Joint Research Group, University of Bath, Bath, BA2 7AY, UK. mpsjmk@bath.ac.uk
authors.forename: Janos M
authors.initials: JM
authors.lastname: Kanczler
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Millar
authors.forename: Tulin
authors.initials: T
authors.lastname: Bodamyali
authors.forename: David R
authors.initials: DR
authors.lastname: Blake
authors.forename: Cliff R
authors.initials: CR
authors.lastname: Stevens
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006728:Hormones / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D010281:Parathyroid Hormone / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014969:Xanthine Oxidase / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D006728:Hormones; D007375:Interleukin-1; D010281:Parathyroid Hormone; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D002762:Cholecalciferol; D000493:Allopurinol; D006861:Hydrogen Peroxide; D002374:Catalase; D014969:Xanthine Oxidase