{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:37:51Z","timestamp":1790347071390,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T00:00:00Z","timestamp":1620172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1822\/12 1086\/17"],"award-info":[{"award-number":["1822\/12 1086\/17"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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 <jats:italic>in vitro<\/jats:italic> by measuring <jats:italic>IL1\u03b2<\/jats:italic>, <jats:italic>IL6<\/jats:italic> and <jats:italic>TNF\u03b1<\/jats:italic> mRNA expression in primary macrophages, osteoclastogenesis in RANKL-induced bone marrow derived pre-osteoclasts and osteolysis <jats:italic>in vivo<\/jats:italic> 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 <jats:italic>in vitro<\/jats:italic>. In the bacterial infection model (LPS), SNV significantly reduced IL1\u03b2 expression, while VIP increased IL6 expression. In the aseptic models of osteolysis, SNV showed greater suppression of <jats:italic>in vitro<\/jats:italic> osteoclastogenesis than VIP, and significantly inhibited inflammation-induced osteolysis <jats:italic>in vivo<\/jats:italic>. 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.<\/jats:p>","DOI":"10.3389\/fphar.2021.638128","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T05:29:03Z","timestamp":1620192543000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Therapeutic Potential of Vasoactive Intestinal Peptide and its Derivative Stearyl-Norleucine-VIP in Inflammation-Induced Osteolysis"],"prefix":"10.3389","volume":"12","author":[{"given":"Michal","family":"Eger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Liron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar","family":"Hiram-Bab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zamzam","family":"Awida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliezer","family":"Giladi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Dangoor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mati","family":"Fridkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kohavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Illana","family":"Gozes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yankel","family":"Gabet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"151","DOI":"10.2174\/156802606775270288","article-title":"Neuropeptide mimetics and antagonists in the treatment of inflammatory disease: focus on VIP and PACAP","volume":"6","author":"Abad","year":"2006","journal-title":"Curr. 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