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Adipose-Derived Stem Cells Promote Bone Coupling in Bisphosphonate-Related Osteonecrosis of the Jaw by TGF-β1.

ABSTRACT: 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-β1 expression. Bone coupling-related cells and TGF-β1 expression were also assessed in BRONJ-like animal model to confirm the results in clinical samples. ADSCs were locally administered in vivo 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-β1 on restoring bone coupling in vivo. Osteoclast formation and resorption assays were performed to evaluate the effects of ADSCs-derived TGF-β1 on ZA-treated pre-osteoclasts. Cell migration was performed to assess the effects of ADSCs-derived TGF-β1 on patients' bone marrow stem cells (BMSCs). The number of osteoclasts, Runx2-positive bone-lining cells (BLCs) and TGF-β1 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-β1 neutralizing antibody in the conditioned medium inhibited these effects. Besides, osteoclastogenesis and patients' BMSCs migration were also rescued by ADSCs-derived TGF-β1. Furthermore, bone resorption-released bone matrix TGF-β1, together with ADSCs-derived TGF-β1, synergistically contributed to rescuing BMSCs migration. Collectively, ADSCs promoted bone healing of BRONJ by TGF-β1-activated osteoclastogenesis and BMSCs migration capacities.

SUBMITTER: Dong X

PROVIDER: S-EPMC8154543 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDue to its complex pathogenesis and low clinical cure rate, bisphosphonate-related osteonecrosis of the jaw (BRONJ) poses a substantial challenge for oral and maxillofacial surgeons. Therefore, the treatment of BRONJ should focus on prevention. In clinical studies, primary wound closure can significantly reduce the incidence of BRONJ. Whether local stem cell transplantation can promote primary gingival healing in patients with a medication history and prevent BRONJ has not been reported.MethodsIn this study, animals were divided into a healthy group (non-drug treatment), a BP group, a hydroxyapatite (HA) group, and an adipose-derived stem cell (ADSC) group. All groups except the healthy group were treated with BPs and immunosuppressive drugs once per week for 8 weeks, simulating clinical use for the treatment of cancer patients with bone metastasis, to induce BRONJ-like animals. After the sixth drug treatment, the bilateral premolars were extracted in all groups. In contrast to the healthy and BP groups, the extraction sockets in the HA and ADSC groups were filled with HA or HA + ADSCs simultaneously post extraction to observe the preventive effect of ADSCs on the occurrence of BRONJ. At 2 and 8 weeks post extraction, animals from all groups were sacrificed.ResultsAt 8 weeks post transplantation, ADSCs prevented the occurrence of BRONJ, mainly through accelerating healing of the gingival epithelium at 2 weeks post extraction. We also found that ADSCs could upregulate the expression of transforming growth factor β1 (TGF-β1) and fibronectin in tissue from animals with a medication history by accelerating gingival healing of the extraction socket. A rescue assay further demonstrated that TGF-β1 and fibronectin expression decreased in TGF-β1-deficient ADSC-treated animals, which partially abolished the preventive effect of ADSCs on the onset of BRONJ.ConclusionADSCs prevent the onset of BRONJ, mainly by upregulating the expression of TGF-β1 and fibronectin to promote primary gingival healing, ultimately leading to bone regeneration in the tooth extraction socket. Our new findings provide a novel stem cell treatment for the prevention of BRONJ.

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Adipose-Derived Stem Cells Promote Bone Coupling in Bisphosphonate-Related Osteonecrosis of the Jaw by TGF-β1.

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