Effect of interleukin-17 on nitric oxide production and osteoclastic bone resorption: Is there dependency on nuclear factor-kappa B and receptor activator of nuclear factor kappa B (RANK)/RANK ligand signaling?

Interleukin-17 (IL-17) is a proinflammatory cytokine produced exclusively b y activated memory T cells and has recently been found to stimulate osteocl astic resorption, Like other proinflammatory cytokines, IL-17 may affect os teoclastic bone resorption indirectly via osteoblasts, possibly by mechanis ms previously reported for chondrocytes that respond in very similarly to o steoblasts, As in chondrocytes, but only in combination with tumor necrosis factor-alpha (TNF-alpha), IL-17 induced nitric oxide (NO) production in os teoblastic cells and fetal mouse metatarsals by a nuclear factor-kappaB (NF -kappaB)-dependent mechanism. This effect was associated with elevated mRNA levels of the NF-kappaB isoforms RelA and p50, In fetal mouse metatarsals, IL-17 stimulated osteoclastic bone resorption only in combination with TNF -alpha, The pathway by which the cytokine combination exerts this effect wa s examined using inhibitors of NO synthesis and NF-kappaB activation. Altho ugh both inhibitors used abolished NO production, they did not prevent the stimulatory effect of the cytokine combination on osteoclastic resorption, In contrast, the inhibitors slightly increased osteoclastic resorption, sug gesting a suppressive rather than stimulatory effect of NO on cytokine-indu ced bone resorption, In addition, we showed that IL-17 + TNF-alpha stimulat ed osteoclastic resorption independent of NF-kappaB signaling. To further e xamine the pathway by which osteoclastic resorption was stimulated, we used osteoprotegerin, a specific inhibitor of the receptor activator of NF-kapp aB (RANK)/receptor activator of the NF-kappaB ligand (RANKL) pathway. Osteo protegerin partially inhibited IL-17 + TNF-alpha -stimulated osteoclastic r esorption only at the high concentration of 1000 ng/mL, whereas it complete ly blocked parathyroid hormone-related peptide-stimulated resorption at 300 ng/mL. In conclusion, IL-17 stimulated NO production by an NF-kappaB-depen dent pathway in osteoblastic cells and fetal mouse metatarsals only in comb ination with TNF-alpha, Neither NO production nor NF-kappaB signaling, and only partly the RANK/RANKL pathway, were involved in the stimulatory effect of the cytokine combination on osteoblastic bone resorption in these long bones, suggesting the existence of other pathways by which osteoclastic res orption can be stimulated. (Bone 28:378-386; 2001) (C) 2001 by Elsevier Sci ence Inc. All rights reserved.