Therapeutic Potential of Vasoactive Intestinal Peptide and its Derivative Stearyl-Norleucine-VIP in Inflammation-Induced Osteolysis

Michal Eger; Tamar Liron; Sahar Hiram-Bab; Zamzam Awida; Eliezer Giladi; David Dangoor; Mati Fridkin; David Kohavi; Illana Gozes; Yankel Gabet

doi:10.3389/fphar.2021.638128

Therapeutic Potential of Vasoactive Intestinal Peptide and its Derivative Stearyl-Norleucine-VIP in Inflammation-Induced Osteolysis

Front Pharmacol. 2021 May 5:12:638128. doi: 10.3389/fphar.2021.638128. eCollection 2021.

Authors

Michal Eger^{1

2}, Tamar Liron¹, Sahar Hiram-Bab¹, Zamzam Awida^{1

3}, Eliezer Giladi⁴, David Dangoor⁴, Mati Fridkin⁵, David Kohavi², Illana Gozes^{4

6}, Yankel Gabet^{1

6}

Affiliations

¹ Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
² Department of Prosthodontics, Goldschleger School of Dental Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³ Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁴ Department of Human Molecular Genetics and Biochemistry, Elton Laboratory of Molecular Neuroendocrinology, Sackler Faculty of Medicine, Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv, Israel.
⁵ Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
⁶ Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.

Abstract

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.

Keywords: aseptic implant loosening; implant infection; implant wear debris; osteoclasts; periimplantitis; periodontitis; topical agents.