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

Xian Dong,Yang He,Hongsen Bi,Linhai He,Jingang An,Xinhua Liu,Xiaolong Zang,Yi Zhang,E Xiao,Baoping Wu

doi:10.3389/fcell.2021.639590

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.

Highlights

MATERIALS AND METHODSBisphosphonate-related osteonecrosis of the jaw (BRONJ) has become a predominant side-effect of bisphosphonate therapy which is often administered to patients with malignant disease (Ruggiero et al, 2014)
TGF-β1 Expression, Osteoclasts, and Runx2-Positive bonelining cells (BLCs) Are Decreased in BRONJ Patients and Rabbit Model
Removal of TGF-β1 from the adipose-derived stem cells (ADSCs)-Conditioned medium (CM) significantly inhibited the CM-induced migration (TGF-β1 NAb treated group vs. ADSCs-CM treated group, 0.2924 ± 0.0373% vs. 0.7109 ± 0.0178%, n=4) (Figure 4B). These results indicated that TGF-β1 from ADSCs contributed to the increased number of Runx2-positive BLCs after ADSCs-CM or ADSCs treatment in the BRONJ-like animal model

Summary

Introduction

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has become a predominant side-effect of bisphosphonate therapy which is often administered to patients with malignant disease (Ruggiero et al, 2014). It has been estimated that from 2004–2014, BRONJ has affected over 11,440–17,160 patients/year worldwide, and the incidence is still rising (Khan et al, 2015; Silva et al, 2016). The diagnostic criteria provided by the American Association of Oral and Maxillofacial Surgeons were up to date in 2014. BRONJ is still a big challenge for oral and maxillafacial surgeon due to the not quite clear pathological mechanisms. Though deficiency in osteoclasts and bone remodeling is considered one of the most important mechanisms (Reid, 2009; Ruggiero et al, 2014), there are still no much effective therapies to prevent BRONJ

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Conclusion