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Cell Dev. Biol."],"abstract":"<jats:p>This study aimed to investigate molecularly targeted therapy to revive bone remodeling and prevent BRONJ by local adipose-derived stem cells (ADSCs) transplantation. Clinical samples of BRONJ and healthy jawbones were used to examine the bone coupling-related cells and TGF-\u03b21 expression. Bone coupling-related cells and TGF-\u03b21 expression were also assessed in BRONJ-like animal model to confirm the results in clinical samples. ADSCs were locally administered <jats:italic>in vivo<\/jats:italic> and the therapeutic effects were evaluated by gross observation, radiological imaging, and histological examination. Furthermore, ADSCs-conditioned medium (ADSCs-CM) and neutralizing antibody were applied to assess the effects of ADSCs-derived TGF-\u03b21 on restoring bone coupling <jats:italic>in vivo<\/jats:italic>. Osteoclast formation and resorption assays were performed to evaluate the effects of ADSCs-derived TGF-\u03b21 on ZA-treated pre-osteoclasts. Cell migration was performed to assess the effects of ADSCs-derived TGF-\u03b21 on patients\u2019 bone marrow stem cells (BMSCs). The number of osteoclasts, Runx2-positive bone-lining cells (BLCs) and TGF-\u03b21 expression were decreased in BRONJ and animal model jaw bone samples. These reductions were significantly rescued and necrotic jawbone healing was effectively promoted by local ADSCs administration in BRONJ-like animal models. Mechanistically, ADSCs-CM mainly contributed to promoting bone coupling, while TGF-\u03b21 neutralizing antibody in the conditioned medium inhibited these effects. Besides, osteoclastogenesis and patients\u2019 BMSCs migration were also rescued by ADSCs-derived TGF-\u03b21. Furthermore, bone resorption-released bone matrix TGF-\u03b21, together with ADSCs-derived TGF-\u03b21, synergistically contributed to rescuing BMSCs migration. Collectively, ADSCs promoted bone healing of BRONJ by TGF-\u03b21-activated osteoclastogenesis and BMSCs migration capacities.<\/jats:p>","DOI":"10.3389\/fcell.2021.639590","type":"journal-article","created":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T14:03:00Z","timestamp":1620828180000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Adipose-Derived Stem Cells Promote Bone Coupling in Bisphosphonate-Related Osteonecrosis of the Jaw by TGF-\u03b21"],"prefix":"10.3389","volume":"9","author":[{"given":"Xian","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linhai","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"Zang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingang","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoping","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongsen","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ajpath.2013.03.006","article-title":"Understanding coupling between bone resorption and formation: are reversal cells the missing link?","volume":"183","author":"Andersen","year":"2013","journal-title":"Am. 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