“…Secondly, hypoxia stimulates purine nucleotide release from endothelial cells (Bodin and Burnstock, 1995), and we have previously shown that ATP and ADP are powerful osteolytic agents, acting through P2 receptors on bone cells (Morrison et al, 1998;Hoebertz et al, 2000Hoebertz et al, , 2001; this mechanism could account for some of the resorptive action of hypoxia in intact bone but it remains to be investigated whether nucleotide release from other cell types in bone might also be enhanced by low PO 2 . Thirdly, one of the major effects of hypoxia on cells is to stimulate the production of potent angiogenic factors such as VEGF, tumor necrosis factor-a, and fibroblast growth factors (Lewis et al, 1999); these factors are also stimulators of the formation and/or function of osteoclasts (Simmons and Raisz, 1991;Nakagawa et al, 1999Nakagawa et al, , 2000Suda et al, 2001). It is already well documented that hypoxia increases VEGF production by osteoblasts (Steinbrech et al, 1999(Steinbrech et al, , 2000aAkeno et al, 2001), and VEGF production by human peripheral blood-derived macrophages is also strongly upregulated by hypoxia (Lewis et al, 1999).…”