Osteoprotogerin (OPG) is a secreted member of the TNF receptor superfamily that was originally characterized based on its ability to suppress osteoclast formation [
1,
2]. OPG binds to the receptor activator of NF-κB ligand (RANKL) and functions as a soluble decoy receptor for RANKL. In bone, OPG inhibits osteoclastogenesis by preventing RANKL from binding to its receptor RANK and, consequently promotes apoptosis of osteoclast [
1]. OPG is critical for osteoclastogenesis and, therefore, homeostasis of bone remodeling and bone mass [
3]. In addition to its role in bone metabolism, OPG has been implicated in mucosal immunity [
4] and vascular systems. OPG is secreted by endothelial cells [
5,
6] and promotes both proliferation and migration of microvascular endothelial cells [
7,
8], and induces angiogenesis [
8‐
10]. OPG can also serve as survival factor for endothelial cells [
6,
8]. Furthermore, OPG acts as a decoy receptor of TNF-related apoptosis-inducing ligand (TRAIL) and neutralizes its function [
11,
12]. TRAIL belongs to the TNF family of cytokines and has emerged as a promising anticancer agent because of its ability to selectively induce apoptosis in a broad host of tumor cells [
13]. TRAIL binding to its receptors (TRAIL-R1 and TRAIL-R2) initiates the extrinsic pathway of apoptosis, resulting in recruitment of the adapter protein Fas-associated death domain (FADD) and procaspase-8 in the death inducing signaling complex (DISC). Caspase-8 can directly activate the effector caspases (caspase‒3, ‒6, ‒7) leading to the execution of apoptosis [
14]. However, in ovarian cancer cells, the apoptotic signal must be further amplified by engaging the intrinsic (mitochondrial) pathway [
15]. In this context, caspase-8 cleaves Bid to generate an active tBid, which in turn activates proapoptotic Bax or Bak proteins, and induces mitochondrial outer membrane permeabilization (MOMP). The mitochondria then release proapoptotic factors that promote effector caspases activation.
Several reports have shown that OPG is a survival factor that can block TRAIL-induced apoptosis in tumor cells. Human prostate cancer cells were shown to secrete OPG at concentrations sufficient to inhibit TRAIL-induced apoptosis
in vitro
[
16,
17]. Similarly, multiple myeloma cells were protected from TRAIL-induced apoptosis by OPG secreted from osteoblast-like cells and bone marrow stroma cells [
18]. OPG produced by breast cancer cells enhances tumor cell survival
in vitro and
in vivo by inhibiting TRAIL-induced apoptosis [
19‐
22]. The production of OPG in colorectal cancer cells and the addition of exogenous OPG to colorectal cancer cells both caused resistance to TRAIL-induced apoptosis [
23]. Exogenous addition of OPG also mediates resistance to TRAIL-induced apoptosis in ovarian cancer cells [
24].
Because OPG binds to TRAIL, OPG-mediated protection from TRAIL in various cancer cells has been assumed to be mainly related to its decoy function. However, the observations that OPG activates integrin/focal adhesion kinase (FAK)/ERK1/2 signaling in endothelial cells [
7,
8] to promote proliferation and migration suggest that OPG regulates cell function directly. Indeed, it was suggested that OPG-mediated proliferation and migration of endothelial cells occurs in a TRAIL-independent manner [
7,
25]. In ovarian cancer cells, activation of integrin/FAK and ERK1/2 signaling contribute to attenuate TRAIL-induced apoptosis [
26,
27]. Based on these observations, we hypothesize that OPG might attenuate TRAIL-induced apoptosis in a TRAIL binding-independent manner by activating survival signaling pathways in ovarian cancer cells. The purpose of this study was to investigate whether exogenous OPG can confer protection against TRAIL-induced apoptosis independent from its ability to act as a TRAIL decoy receptor.