RANKL-mediated Reactive Oxygen Species Pathway That Induces Long Lasting Ca2+ Oscillations Essential for Osteoclastogenesis

Abstract

RANKL (receptor activator of NF-B ligand) induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration ofBone is a dynamic tissue that is constantly being remodeled. The remodeling process is a delicate balance between the activities of osteoblasts and osteoclasts. Interference with this balance results in serious human pathologies that affect bone integrity. Tipping the balance in favor of osteoclasts leads to pathological bone resorption, which is observed in autoimmune arthritis, osteoporosis, and periodontitis (1, 2).Bone marrow-derived monocyte/macrophage precursor cells (BMM) 2 of a hematopoietic origin develop into osteoclasts through cell-to-cell signaling with mesenchymal cells, such as osteoblasts (3, 4). Cell-to-cell interaction between the osteoclast precursors and osteoblastic/stromal cells are also essential for the differentiation of osteoclast progenitor cells into mature osteoclasts (5, 6). RANKL (receptor activator of NF-B ligand) is expressed in osteoblastic/stromal cells and is vital for osteoclast differentiation (7-11). Stimulation of the RANK receptor by RANKL in the presence of the macrophage colonystimulating factor (M-CSF) causes osteoclast differentiation and activation in vitro (6,8,12). Moreover, the binding of RANKL to its receptor results in the recruitment of the TNF receptor-associated factor (TRAF) family of proteins, e.g. TRAF6, which are linked to the NF-B and JNK pathways (13-15). Of particular importance, a series of signals following RANK activation induce oscillations in the free intracellular concentration of Ca 2ϩ ([Ca 2ϩ ] i ), which trigger the late stage of osteoclast differentiation by activating the nuclear factor of activated T cells type c1 (NFATc1) (16). Unique aspects of these RANKL-stimulated Ca 2ϩ oscillations is that they are observed only 24 -48 h post-stimulation, indicating the need for induction of the pathway responsible for the Ca 2ϩ oscillations. The nature of this pathway and how it is induced are not known. Ca 2ϩ is a ubiquitous intracellular messenger that mediates a wide variety of cellular functions and is involved in the fundamental cellular processes of proliferation, differentiation, and programmed cell death (17). In the case of osteoclast differentiation, Ca 2ϩ plays an important role by sequentially activating calcineurin and NFATc1 (16). Members of the NFAT family are among the most strongly induced transcription factors following RANKL stimulation. During osteoclastogenesis, costimulatory signals mediated by the immunoreceptor tyrosine-based

Nanocrystalline silicon substituted hydroxyapatite effects on osteoclast differentiation and resorptive activity

“…54 Thus, following stimulation with RANKL, the pre-osteoclasts increase intracellular ROS by activation of NADPH oxidase (Nox) homologs or by increased mitochondria ROS production, which subsequently induced long lasting Ca 2+ oscillations. [54][55][56] In the present study both intracellular ROS and Ca 2+ content of osteoclast-like cells cultured on nano-HA disks and nano-SiHA disks were analyzed by Flow Cytometry and higher values of both parameters were obtained in cells cultured on nano-SiHA than on nano-HA ( Fig. 9B and 9C).…”

PC‐PLC is involved in osteoclastogenesis induced by TNF‐α through upregulating IP3R1 expression

“…However, the oscillations of calcium was not determined by their study. Long time lasting ROS production induced by RANKL is reported to mediate Ca 2+ oscillations and essential for osteoclast precursor differentiation [25], thus intracellular ROS level is probably involved in the promotion of TNF-a on calcium oscillation. Production of ROS associates to signals mediated by TNF-a [32,33].…”

“…It has been reported that long term ROS production induced by RANKL mediates the Ca 2+ oscillations and regulates osteoclast differentiation [25]. TNF-a targets molecules which regulate calcium signaling.…”

Studies on the Effects of Protamine-Reduced Peptide on Experimental Periodontitis Analyzed by Micro-Computerized Tomography

“…A previous investigator described that HPC attached to both the tooth surface and soft [33][34][35] ; however, NO is a reactive oxygen species (ROSs), which play a very important role in providing protection against bacterial infection; however, surplus ROSs cause cell damage 36,37) . From the point of view of bone remodeling or bone regeneration, ROSs act on the differentiation and activation of osteoclasts [38][39][40] . Since NO is supplied by arginine, the arginine level in gingival crevicular fluid from patients with chronic periodontitis is much higher than from a periodontally healthy group 41) .…”