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Adipose tissue plays a role in pro\u2010inflammatory diseases by releasing cytokines with a catabolic effect on bone, such as tumor necrosis factor\u2010alpha (TNF\u2010\u03b1). Thus, we hypothesized that endogenous TNF\u2010\u03b1 could have a negative effect on at\u2010MSC differentiation into osteoblasts. Short interfering RNAs (siRNAs) targeting TNF\u2010\u03b1 receptors (siR1, siR2, and si1R\/R2) were transfected into at\u2010MSCs, and cell differentiation was assessed by measuring the expression of bone markers, ALP activity, and mineralized matrix. Scrambled was used as Control. Knockout at\u2010MSCs (KOR1\/R2) was injected in mice calvaria defects, and bone formation was evaluated by microtomography and histological analysis. Data were compared by Kruskal\u2013Wallis or analysis of variance (5%). The expression of bone markers confirmed that at\u2010MSCs differentiate less than bone marrow MSCs. In silenced cells, the expression of <jats:italic>Alp, Runx2<\/jats:italic>, and <jats:italic>Opn<\/jats:italic> was generally higher compared to Control. ALP, RUNX2, and OPN were expressed at elevated levels in silenced groups, most notably at\u2010MSCs\u2010siR1\/R2. ALP was detected at high levels in at\u2010MSCs\u2010siR1\/R2 and in\u2010MSCs\u2010siR1, followed by an increase in mineralized nodules in at\u2010MSCs\u2010siR1\/R2. As the morphometric parameters increased, the groups treated with KOR1\/R2 exhibited slight bone formation near the edges of the defects. Endogenous TNF\u2010\u03b1 inhibits osteoblast differentiation and activity in at\u2010MSCs, and its disruption increases bone formation. While opening a path of investigation, that may lead to the development of new treatments for bone regeneration using at\u2010MSC\u2010based therapies.<\/jats:p>","DOI":"10.1002\/bit.28468","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T03:02:50Z","timestamp":1686798170000},"page":"3067-3078","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Disruption of TNF\u2010\u03b1 signaling improves osteoblastic differentiation of adipose\u2010derived mesenchymal stem cells and bone repair"],"prefix":"10.1002","volume":"120","author":[{"given":"Rayana L.","family":"Bighetti\u2010Trevisan","sequence":"first","affiliation":[{"name":"Bone Research Lab, School of Dentistry of Ribeir\u00e3o Preto University of S\u00e3o Paulo Ribeir\u00e3o Preto S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nat\u00e1lia P.","family":"Bueno","sequence":"additional","affiliation":[{"name":"School of Dentistry University of S\u00e3o Paulo S\u00e3o Paulo S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alann T. 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