IL-6, Leukemia Inhibitory Factor, and Oncostatin M Stimulate Bone Resorption and Regulate the Expression of Receptor Activator of NF-κB Ligand, Osteoprotegerin, and Receptor Activator of NF-κB in Mouse Calvariae

Abstract

IL-6, leukemia inhibitory factor (LIF), and oncostatin M (OSM) are IL-6-type cytokines that stimulate osteoclast formation and function. In the present study, the resorptive effects of these agents and their regulation of receptor activator of NF-κB ligand (RANKL), RANK, and osteoprotegerin (OPG) were studied in neonatal mouse calvaria. When tested separately, neither human (h) IL-6 nor the human soluble IL-6R (shIL-6R) stimulated bone resorption, but when hIL-6 and the shIL-6R were combined, significant stimulation of both mineral and matrix release from bone explants was noted. Semiquantitative RT-PCR showed that hIL-6 plus shIL-6R enhanced the expression of RANKL and OPG in calvarial bones, but decreased RANK expression. Human LIF, hOSM, and mouse OSM (mOSM) also stimulated 45Ca release and enhanced the mRNA expression of RANKL and OPG in mouse calvaria, but had no effect on the expression of RANK. In agreement with the RT-PCR analyses, ELISA measurements showed that both hIL-6 plus shIL-6R and mOSM increased RANKL and OPG proteins. 1,25-Dihydroxyvitamin D3 (D3) also increased the RANKL protein level, but decreased the protein level of OPG. OPG inhibited 45Ca release stimulated by RANKL, hIL-6 plus shIL-6R, hLIF, hOSM, mOSM, and D3. An Ab neutralizing mouse gp130 inhibited 45Ca release induced by hIL-6 plus shIL-6R. These experiments demonstrated stimulation of calvarial bone resorption and regulation of mRNA and protein expression of RANKL and OPG by D3 and IL-6 family cytokines as well as regulation of RANK expression in preosteoclasts/osteoclasts of mouse calvaria by D3 and hIL-6 plus shIL-6R.

Bradykinin potentiates cytokine‐induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression

“…In contrast, 1,25-dihydroxyvitamin D 3 caused a significant enhancement of RANK mRNA, in agreement with previous findings (37).…”

Targeting Interleukin-6 in Rheumatoid Arthritis

“…IL-6 promotes synovitis by inducing neovascularisation via vascular endothelial growth factor (VEGF)-stimulated pannus proliferation, resulting in infiltration of inflammatory cells and synovial hyperplasia [17]. In terms of joint erosion, IL-6 causes bone resorption by inducing osteoclast formation via the induction of RANKL in synovial cells [18,19], and cartilage degeneration by producing matrix metalloproteinases (MMPs) in synovial cells and chondrocytes [20,21].…”

“…Osteoclastogenesis occurs from the interaction between receptor activator of NF-B (RANK) and its ligand (RANKL) [61,62]. In neonatal mouse calvaria experiment, IL-6 in the presence of sIL-6R, enhanced the expression of RANKL and osteoprotegerin (OPG) thus inducing bone resorption [19]. However the RANK expression was also found decreased, suggesting that sIL-6R transsignalling influences osteoclastogenesis through osteoblast and osteoclast interaction.…”

Effects of inflammatory and anti‐inflammatory cytokines on the bone

“…The apparent paradoxical effect can be explained by the fact that IL-6 per se is inhibitory to osteoclasts; however, the complex of IL-6 and its soluble receptor IL-6R is indeed stimulatory to osteoclastogenesis by activating trans-signalling through the IL-6R-associated adaptor protein gp130 [32,33]. Interestingly, also other cytokines engaging gp130-containing receptors (like IL-11 and OSM) have stimulatory function on osteoclasts [34,35]. Interference with the binding of pro-osteoclastogenic cytokines to gp130 may at least in part explain the observation that neutralization IL-6R (by the neutralizing antibody tocilizumab) effectively blocks osteoclast formation and retards structural damage in patients with RA.…”