Dataset Information

Adipose-derived stem cells prevent the onset of bisphosphonate-related osteonecrosis of the jaw through transforming growth factor ?-1-mediated gingival wound healing.

ABSTRACT:

Background

Due 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.

Methods

In 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.

Results

At 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 ?1 (TGF-?1) 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-?1 and fibronectin expression decreased in TGF-?1-deficient ADSC-treated animals, which partially abolished the preventive effect of ADSCs on the onset of BRONJ.

Conclusion

ADSCs prevent the onset of BRONJ, mainly by upregulating the expression of TGF-?1 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.

SUBMITTER: Zang X

PROVIDER: S-EPMC6567445 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Adipose-derived stem cells prevent the onset of bisphosphonate-related osteonecrosis of the jaw through transforming growth factor β-1-mediated gingival wound healing.

Zang Xiaolong X He Linhai L Zhao Lu L He Yang Y Xiao E E Zhang Yi Y

Stem cell research & therapy 20190613 1

<h4>Background</h4>Due 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 bee ...[more]

PMID: 31196208

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Project description:BackgroundMedication-related osteonecrosis of the jaw (MRONJ) is a serious debilitating disease caused by anti-resorption and anti-angiogenesis drugs, significantly affecting patients' quality of life. Recent studies suggested that primary gingival wound healing may effectively prevent the development of MRONJ. This study aimed to evaluate the effects of low-level light therapy (LLLT) on promoting gingival wound healing in extraction sockets of MRONJ-like mice and preventing the occurrence of MRONJ. Furthermore, we explored underlying mechanisms.MethodsMice were randomly divided into the Ctrl, Zol, and Zol + LLLT groups. Administration of zoledronate and tooth extraction of bilateral maxillary second molars were used to build the MRONJ model, and LLLT was locally administered into the tooth sockets to examine the effect of LLLT. Next, to explore the function of IL-1RA, we performed LLLT with interleukin-1 receptor antagonist (IL-1RA) neutralizing antibody (named Zol + LLLT + IL-1RA NAb group) or negative control antibodies for tooth extraction in subsequent rescue animal experiments. Stereoscope observations, micro-computed tomography, and histological examination were conducted to evaluate gingival wound healing and bone regeneration in tooth sockets. The effects of LLLT on the migration capacities of zoledronate-treated epithelial cells were assessed in vitro.ResultsLLLT promoted primary gingival wound healing without exposed necrotic bone. Micro-computed tomography results showed higher bone volume and mineral density of the tooth sockets after LLLT. Histology analysis showed complete gingival coverage, obvious bone regeneration, and reduced soft tissue inflammation, with down-regulated pro-inflammation cytokines, like interleukin-1 beta (IL-1β) and tumor necrosis factor-α (TNF-α), and up-regulated IL-1RA expression in the gingival tissue in the LLLT group. The rescue assay further showed that the effects of LLLT promoting gingival wound healing and preventing MRONJ might be partially abolished by IL-1RA neutralizing antibodies. In vitro studies demonstrated that LLLT accelerated zoledronate-treated epithelial cell migration.ConclusionsLLLT might promote primary gingival wound healing and contribute to subsequent bone regeneration of the tooth extractions in MRONJ-like lesions via IL-1RA-mediated pro-inflammation signaling suppression.