The common use of dental and orthopedic implants calls for special attention to the immune response leading to peri-prosthetic bone loss and implant failure. In addition to the well-established microbial etiology for oral implant failure, wear debris and in particular
titanium (Ti) particles (TiP) in the implant vicinity are an important trigger of
inflammation and activation of
bone resorption around oral and orthopedic implants, presenting an unmet medical need. Here, we employed bacterial-derived
lipopolysaccharides (LPS) to model
infection and TiP to model aseptic
inflammation and
osteolysis. We assessed
inflammation in vitro by measuring IL1β,
IL6 and TNFα
mRNA expression in primary macrophages, osteoclastogenesis in RANKL-induced bone marrow derived pre-osteoclasts and
osteolysis in vivo in a mouse calvarial model. We also assessed the trans-epithelial penetrability and safety of the tested compound in rats. Our results show that a lipophilic super-active derivative of
vasoactive intestinal peptide (VIP), namely stearyl-
norleucine-VIP (SNV) presented superior anti-inflammatory and anti-osteoclastogenic effects compared to VIP in vitro. In the
bacterial infection model (LPS), SNV significantly reduced IL1β expression, while VIP increased
IL6 expression. In the aseptic models of
osteolysis, SNV showed greater suppression of in vitro osteoclastogenesis than VIP, and significantly inhibited
inflammation-induced
osteolysis in vivo. We also observed that expression levels of the
VIP receptor VPAC-2, but not that of VPAC-1, dramatically decreased during osteoclast differentiation. Importantly, SNV previously shown to have an increased stability compared to VIP, showed here significant trans-epithelial penetration and a clean toxicological profile, presenting a novel drug candidate that could be applied topically to counter both aseptic and
infection-related bone destruction.