Cytokines and bone : On the role of IL-1 and IL-6 in bone metabolism

Abstract: Cytokines such as interleukin-1 (IL-l) and interleukin-6 (IL-6) have been implicated in the pathogenesis of postmenopausal osteoporosis. The regulation of cytokine release is unclear, and the mechanism of cytokine induced bone resorption remains to be elucidated. In the present thesis, the interplay between calcium homeostasis and cytokine release from isolated human mononuclear blood cells (MBC) was studied. Furthermore, the second messenger events involved in bone resorption induced by IL-1 were investigated.Oral intake of 1 g calcium in healthy volunteers stimulated the release of IL-6 from isolated MBC, ex vivo. In vitro, ionised calcium (Ca2+) induced a time and dose related increase in cytokine secretion from isolated MBC, with an EC50 at the physiological Ca2+ concentration 1.2 mM. Mg2+ or neomycin, known calcium receptor (CaR) agonists, did not stimulate cytokine secretion in MBC. Extracellular Ca2+ did not increase intracellular Ca2+ in MBC, and the calcium channel blocker nifedipine did not abolish Ca2+ induced cytokine release from MBC. These data indicate that CaR or voltage sensitive Ca2+ channels of L-type are not mediating the Ca2+ induced cytokine release from MBC.IL-1 potently induced bone resorption in isolated neonatal mouse calvariae. This could partly be inhibited by indomethacin, indicating a role for prostaglandins in mediating IL-1 induced bone resorption. IL-1 induced cyclic AMP (CAMP) formation in isolated human osteoblasts was independent of prostaglandin release. Cyclic AMP, however, does not appear to be responsible for the non-prostaglandin mediated part of IL-l-induced bone resorption. Neither of the protein kinase A antagonists Rp-cAMPS and affected IL-1 induced bone resorption. Bone resorption stimulated by PGE2, however, was inhibited by Rp-cAMPS and H8.The findings demonstrate that IL-1 is a potent stimulator of bone resorption, through yet unclarified second messenger events. There is a relationship between cytokine release and plasma Ca2+ which might be of importance when discussing the role of cytokines in postmenopausal osteoporosis, as well as in the pathogenesis of malignant hypercalcemia.