Abstract
Osteoprotegerin (OPG) is known to inhibit differentiation and activation of osteoclasts (OCs) by functioning as a decoy receptor blocking interactions between RANK and RANKL. However, the exact role of OPG in the survival/apoptosis of OCs remains unclear. OPG caused increased rates of apoptosis of both OCs and osteoclast precursor cells (OPCs). The expression of Fas and activated caspase-8 was increased by both 20 ng/mL and 40 ng/mL of OPG, but was markedly decreased at 80 ng/mL. Interestingly, we noted that while levels of Fas ligand (FasL) increased with increasing doses of OPG, the soluble form of FasL in the supernatant decreased. The results of a co-immunoprecipitation assay suggested that the decrease of sFasL might be caused by the binding of OPG. This would block the inhibition of the apoptosis of OCs and OPCs. Furthermore, changes in expression levels of Bax/Bcl-2, cleaved-caspase-9, cleaved-caspased-3 and the translocation of cytochrome c, illustrated that OPG induced apoptosis of OCs and OPCs via the classic Fas/FasL apoptosis pathway, and was mediated by mitochondria. Altogether, our results demonstrate that OPG induces OCs and OPCs apoptosis partly by the Fas/FasL signaling pathway.
Highlights
Since the discovery of the first tumor necrosis factor, tumor necrosis factor alpha (TNFα), members of TNF superfamily [1] have been found, many TNF family members have shown promise in several therapeutic applications including cancer, infectious disease, transplantation and autoimmunity [2].Osteoprotegerin (OPG), a member of the TNF family, is a secreted glycoprotein that prevents receptor activator of nuclear factor kappaB ligand (RANKL) from binding to receptor activator of nuclear factor kappa B (RANK), thereby leading to the inhibition of osteoclast differentiation and activation [3]
It is known that RANKL is essential for osteoclast survival [9], and the binding of RANKL to RANK would elicit a complex signalization cascade resulting in osteoclast-specific gene transcription and survival pathway activation [10], there is no evidence that the decoy receptor role of OPG would impede the survival pathway, even lead to the apoptosis of osteoclasts (OCs)
We report the novel function of Fas ligand (FasL)/Fas in OCs and osteoclast precursor cells (OPCs) apoptosis induced by OPG
Summary
Since the discovery of the first tumor necrosis factor, tumor necrosis factor alpha (TNFα), members of TNF superfamily [1] have been found, many TNF family members have shown promise in several therapeutic applications including cancer, infectious disease, transplantation and autoimmunity [2]. The mitochondrial component of the apoptotic process is mediated by truncated BH3 interacting domain death agonist (BID) translocation to the mitochondria from the cytosol and subsequent cytochrome c release [16]. It has been known for many years that the correct functioning of the immune system requires it to maintain an equilibrium. It is well known that the Fas/FasL system is the major apoptotic mediator in the immune system, and in recent years, there have been many studies demonstrating that the Fas/FasL system has an effect on the regulation of bone turnover[19, 20] and osteoclast progenitor apoptosis [21]. We report the novel function of FasL/Fas in OCs and osteoclast precursor cells (OPCs) apoptosis induced by OPG
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