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Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H<jats:sub>2<\/jats:sub>S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-\u03b1. Clodronate significantly modulated iNOS expression elicited by TNF-\u03b1. Inflammatory markers induced by TNF-\u03b1, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H<jats:sub>2<\/jats:sub>S, together with the reduction in CSE expression associated with TNF-\u03b1 treatment, was reverted by clodronate, thus rescuing endogenous H<jats:sub>2<\/jats:sub>S pathway activity. Clodronate displays antinflammatory properties through the modulation of H<jats:sub>2<\/jats:sub>S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H<jats:sub>2<\/jats:sub>S pathway, here we showed for the first the involvement of H<jats:sub>2<\/jats:sub>S in the additive beneficial effects observed following clodronate therapy.<\/jats:p>","DOI":"10.1038\/s41598-021-94228-y","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T10:26:57Z","timestamp":1626776817000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["In vitro evidence for the involvement of H2S pathway in the effect of clodronate during inflammatory response"],"prefix":"10.1038","volume":"11","author":[{"given":"Rosangela","family":"Montanaro","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessio","family":"D\u2019Addona","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Izzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Ruosi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Brancaleone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,7,20]]},"reference":[{"key":"94228_CR1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.bone.2011.01.014","volume":"49","author":"S Cremers","year":"2011","unstructured":"Cremers, S. & Papapoulos, S. 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