Pharmacological Study on Neuronal Regulation of Osteoclast Formation

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In the present study, to prove the physiological role of sympathetic nerves in bone metabolism in vivo, we examined by RT-PCR analysis the effects of a restraint stress (30 min) and intracerebroventricular (i.c.v.) injection of IPS (50 ng/mouse) on COX-2 and IL-6 mRNAs expression in mouse calvaria. LPS (i.c.v.) is well known to increase the outflow of the peripheral sympathetic nervous system. The expression of COX-2 and IL-6 mRNAs were increased by the treatment with the neurotoxin 6-hydroxydopamine (6-OHDA, 100 mg/kg/day, i.p., for 3 days) or β-blocker, propranolol (25 mg/kg, i.p.). Similarly, a restraint stress induced the expression of IL-6 mRNA in mouse calvaria. The induction was not influenced by 6-OHDA, but inhibited by propranolol. In addition, the treatment of calvaria with isoprenaline (Isp ; 100 μM) increased PGE2 and IL-6 synthesis in the organ culture system. These findings show that gene expressions increased by a restraint stress and i.c.v. injection of LPS was mediated … More by the activation of sympathetic nerve fibers and β-adrenoceptor in mouse calvaria and suggests that in vivo activation of the sympathetic nervous system modulates bone metabolism. Secondly, to elucidate the mode of action of Isp on osteoclast formation and to characterize the effect of the calcitonin gene-related peptide (CGRP) on osteoclast formation induced by Isp in a mouse bone marrow culture system. Treatment of mouse bone marrow cells with Isp generated tartrate-resistant acid phosphatase-positive multinuclear cells capable of excavating resorptive pits on dentine slices, and caused an increase in receptor activator of NF-κB ligand (RANKL) and a decrease in osteoprotegerin (OPG) production by the marrow cells. The osteoclast formation was significantly inhibited by OPG, suggesting the involvement of the RANKL-RANK system. CGRP inhibited the osteoclast formation caused by Isp or soluble RANKL but had no influence on RANKL or OPG production by the bone marrow cells treated with Isp, suggesting that CGRP inhibited the osteoclast formation by interfering with the action of RANKL produced by the Isp-treated bone marrow cells without affecting RANKL or OPG production. Since the mRNA encoding the calcitonin receptor-like receptor has been reported to express in mature osteoclast precursors, pre-osteoclasts, and mature osteoclast. This in vitro data suggest the physiological interaction of sympathetic and sensory nerves in osteoclastogenesis in vivo. Less