Molecular regulatory mechanisms of osteoclastogenesis through cytoprotective enzymes

Abstract

It has been reported that reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, take part in osteoclast differentiation as intra-cellular signaling molecules. The current assumed signaling cascade from RANK to ROS production is RANK, TRAF6, Rac1, and then Nox. The target molecules of ROS in RANKL signaling remain unclear; however, several reports support the theory that NF-κB signaling could be the crucial downstream signaling molecule of RANKL-mediated ROS signaling. Furthermore, ROS exert cytotoxic effects such as peroxidation of lipids and phospholipids and oxidative damage to proteins and DNA. Therefore, cells have several protective mechanisms against oxidative stressors that mainly induce cytoprotective enzymes and ROS scavenging. Three well-known mechanisms regulate cytoprotective enzymes including Nrf2-, FOXO-, and sirtuin-dependent mechanisms. Several reports have indicated a crosslink between FOXO- and sirtuin-dependent regulatory mechanisms. The agonists against the regulatory mechanisms are reported to induce these cytoprotective enzymes successfully. Some of them inhibit osteoclast differentiation and bone destruction via attenuation of intracellular ROS signaling. In this review article, we discuss the above topics and summarize the current information available on the relationship between cytoprotective enzymes and osteoclastogenesis.

Autocrine and paracrine STIP1 signaling promote osteolytic bone metastasis in renal cell carcinoma

“…Although a direct binding assay was not performed to confirm the interaction between STIP1 and PrPc in the osteoclast precursor cells, the results from several functional studies were supportive to our conclusion, i.e., 1) a dose-dependent induction of PrPc expression by hrSTIP1; 2) the anti-PrPc antibody impeded the hrSTIP1-induced osteoclast differentiation; and 3) the combination of anti-STIP1 and anti-PrPc antibodies inhibited the CTSK expression significantly. In vivo , several cancer-associated conditions, including hypoxia and oxidative or endoplasmic reticulum stresses can activate PrPc transcription [37, 38], which also been shown to increase osteoclast activity [39, 40]. Thus, the STIP1-PrPc signaling in osteolysis might be augmented and an in vivo verification in the bone metastasis RCC animal model or patient specimens would be needed.…”

Pathways that Regulate ROS Scavenging Enzymes, and Their Role in Defense Against Tissue Destruction in Periodontitis

“…NRF2 (Thimmulappa et al, 2002), Sirtuin (Chen et al, 2011), and FOXO (Liu et al, 2005) are major regulatory pathways for cytoprotective enzymes (Kanzaki et al, 2016a). Figure 2 summarizes the linking the periodontitis, the regulatory pathways of ROS scavenging enzymes, and the defense mechanism against tissue destruction.…”

TRAP-positive osteoclast precursors mediate ROS/NO-dependent bactericidal activity via TLR4

“…Interestingly, ROS produced by osteoclasts play a role in promoting the differentiation of these cells through Akt, NF-κB and ERK activation [37,38], suggesting that ROS function as a cell signaling mediator in osteoclastogenesis. Recent study reported that ROS-induced promotion of osteoclastogenesis is downmodulated by an antioxidant response system involving Nerf2 in the homeostatic context [39,40], indicating the presence of a sophisticated regulatory mechanism for ROS-associated osteoclastogenesis. On the other hand, low level of NO increases the generation of mature osteoclasts by up-regulating actin remodeling in mononuclear preosteoclasts, thereby promoting cell fusion processes required for multi-nucleation of OCm [32].…”