Osteoprotegerin protects endothelial cells against apoptotic cell death induced byPorphyromonas gingivaliscysteine proteinases

Abstract

Osteoprotegerin (OPG) is a key regulator of osteoclastogenesis during the progression of periodontitis. Recent reports suggest that osteoprotegerin may also prevent arterial calcification and contribute to endothelial cell survival. To determine whether the vascular functions of osteoprotegerin are involved in periodontitis, we examined whether osteoprotegerin contributed to the survival of endothelial cells damaged by Porphyromonas gingivalis cysteine proteinases (gingipains). Gingipain proteinases cleave a broad range of host proteins, and are important virulence factors of P. gingivalis, a major causative bacterium of adult periodontitis. Human microvascular endothelial cells (HMVEC) were exposed to activated gingipain extracts from P. gingivalis 381, with and without pretreatment with osteoprotegerin. Cell viability was quantified by the tetrazolium (WST-8) reduction assay, and apoptosis was examined using Hoechst 33342 nuclear staining. After 16 h of treatment with activated gingipain extracts, HMVEC showed near-complete detachment from the tissue culture dish, and apoptosis was evident by 24 h. Pretreatment of HMVEC with osteoprotegerin reduced the extent of both cellular detachment and apoptotic cell death. Our results indicated that osteoprotegerin pretreatment protected HMVEC against detachment and apoptotic cell death induced by gingipain-active bacterial cell extracts. These results also suggest that osteoprotegerin may function as a survival factor for endothelial cells during periodontitis.

RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases

“…2c). The OPG survival effect has also been demonstrated in pathological conditions such as periodontitis [171]. Indeed, OPG produced by microvascular endothelial cells controls endothelial cell survival and bone remodeling during this pathology [172].…”

Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells

“…Several studies 2,[6][7][8][9][10] have demonstrated that recombinant OPG supports the survival of both normal and tumor-associated For personal use only. on March 31, 2019.…”

“…[3][4][5] More importantly, for the purpose of this study, it has also been shown that OPG is produced in vitro by vascular endothelial cells, is overexpressed by tumor-associated endothelial cells, and is able to promote the survival/proliferation of endothelial cells in a paracrine or autocrine manner. [6][7][8][9][10] Moreover, elevated levels of serum OPG have been detected in both solid tumors and hematologic malignancies. 11 Although the relative contribution of both normal and tumor-associated endothelial cells to serum OPG remains to be established, 2 both the stromal and the tumoral vasculature is engaged in extensive interactions with the cancer cells, probably contributing to the growth and invasiveness of the tumor.…”

Osteoprotegerin: Multiple partners for multiple functions

“…As mentioned above, OPG exerts an antiapoptotic effect towards TRAIL and decreases in consequence the number of apoptotic bodies that may serve as nucleation sites for passive mineralization (Fleishman et al 1990;Benslimane-Ahmim et al 2011). Several studies have shown also that recombinant OPG can promote the survival/proliferation of mature vascular endothelial cells (Malyankar et al 2000;Pritzker et al 2004;Cross et al 2006;Kobayashi-Sakamoto et al 2006;McGonigle et al 2009). Similarly, Lawrie et al showed OPG promotes the proliferation and the migration of pulmonary artery smooth muscle cell, and thus evidenced an important role of OPG in the pathogenesis of pulmonary arterial hypertension (Lawrie et al 2008).…”