10 March 2021: Hypothesis
Med Sci Monit 2021; 27:e929684
ABSTRACT: The treatment measures of medication-related osteonecrosis of the jaw (MRONJ) is a worldwide challenge in oral and maxillofacial surgery because of its unclear pathogenesis. Previous studies suggested that mesenchymal stem cells played important roles in promoting MRONJ lesion healing, but the detailed mechanisms were unknown. Increasing numbers of studies have demonstrated that exosomes derived from mesenchymal stem cells, especially adipose-derived stem cells, have key roles in stem cell-based therapies by accelerating bone remodeling, facilitating angiogenesis, and promoting wound healing. We hypothesized that exosomes derived from adipose-derived stem cells can prevent MRONJ by accelerating gingival healing and enhancing bone remodeling processes. Our results may provide a promising therapeutic option for MRONJ clinical therapy.
Keywords: Bisphosphonate-Associated Osteonecrosis of the Jaw, Bone Remodeling, mesenchymal stromal cells, Wound Healing, Adipocytes, Adipose Tissue, exosomes, Gingiva, Mesenchymal Stem Cell Transplantation
THERAPEUTIC POTENTIAL OF ADIPOSE-DERIVED STEM CELLS ON BONE AND SOFT TISSUES:
Adipose-derived stem cells (ASCs), a kind of self-renewing multipotent stem cell, seem to be the most advantageous adult stem cells for cell therapy. These cells are abundant and accessible, and their collection is associated with low donor morbidity . Accumulated studies have shown that ASC-derived cellular therapy exerts important functions in the treatment of various human skeletal and soft tissue diseases, such as osteoporosis, bone nonunion, and skin wounds, by differentiating into the types of cells that are damaged and by secreting paracrine factors or regulatory mediators of immune function [8–10]. Previous research suggested that the local implantation of allogeneic ASCs directly participated in osteogenesis and enhanced rehabilitation within bone defects . Wagner et al  found that local application of ASCs repaired bone defects by enhancing bone regeneration after sufficient debridement of infected bone tissue in posttraumatic osteomyelitis . Furthermore, ASCs were reported to upregulate bone morphogenetic protein (BMP)-2 and vascular endothelial growth factor (VEGF) in perifracture tissues, differentiate into osteoblasts or endothelial cells, and promote M2 macrophage polarization, thus effectively accelerating fracture healing [13,14]. Previous research also suggested that the systemic transplantation of ASCs improved bone quality in ovariectomized-induced osteoporosis in vivo, and the conditioned medium derived from ASCs promoted proliferation and differentiation of osteoblasts and stimulated survival and differentiation of osteoclasts in vitro . In rheumatoid arthritis, systemic administration of ASCs alleviated the progression of arthritis by reducing the total number of pathogenic GM-Th17 cells and increasing the number of regulatory T cells . Interestingly, Alonso-Rodriguez et al  and Barba-Recreo et al  reported ASCs effectively promoted vascularization, bone remodeling, and regeneration, and prevented the onset of MRONJ.
Aside from the bone repair process, ASCs were also shown to play important roles in cutaneous wound healing and regeneration [18–20]. Altman et al  confirmed that local administration of ASCs significantly accelerated full-thickness skin wound healing by endothelial and fibroblastic differentiation. Apart from direct differentiation, accumulated studies have shown that ASCs can secrete various cytokines and chemokines, such as VEGF, basic fibroblast growth factor (b-FGF), interleukin (IL)-6, IL-8, and hepatocyte growth factor (HGF) to regulate angiogenesis and immunity during wound healing [10,22]. Oryan et al  reported that ASCs suppressed the expression of IL-1β on the 7th day after injury, increased the level of TGF-β1 on the 14th day after injury, upregulated the level of TGF-β1 and bFGFs on the 28th day after injury, and promoted burn wound healing . Furthermore, ASCs were shown to accelerate diabetic wound healing by secreting VEGF, b-FGF, and HGF, which may have enhanced the epithelialization rate and granulation tissue formation . With regard to MRONJ, our previous study suggested that local administration of ASCs accelerated gingival closure via TGF-β1 in zoledronate-treated mice and could prevent MRONJ . Hence, ASCs are a useful source of stem cell therapies for bone and soft tissue wound healing.
EXOSOMES EXERT IMPORTANT ROLES IN ASC-BASED THERAPY FUNCTION:
Exosomes are 30- to 100-nm extracellular vesicles that contain various proteins, nucleic acids, and lipids, and they have attracted much attention as acellular therapy . Recently, studies have increasingly suggested that transplanted stem cells are more likely to secrete extracellular vesicles as cell-to-cell communicators to exert their influence on targeted tissues, rather than home in on the injured sites and subsequently differentiate into the target cells [27,28]. Many exosomal proteins from ASCs, some of which are associated with cell migration and regeneration, have been identified by proteomic analysis . In addition, the use of ASC-derived exosomes (ASC-Exos) may avoid the biosafety and ethics problems associated with direct cell transplantation. Stem cell therapy is potentially controversial due to the risks of pulmonary embolism and tumorigenicity [30,31]. Furthermore, ASC-Exos have the advantage of being more easily manufactured, handled, characterized, and stored than stem cells . In the past few years, accumulated studies have demonstrated that ASC-Exos play important roles in wound healing, bone repair, myocardial repair, hepatic repair, and other aspects of diseases [33–35]. ASC-Exos were found to deliver miR-21, miR-181b, MMPs, MFG-E8, and ANGPTL1 to activate intercellular signaling pathways in endothelial cells and promote vascularization in soft tissue repair [36–38]; to transmit miR-375 to help induce osteoblast differentiation and bone regeneration in bone defects ; and to transfer miR-126 to inhibit inflammation and fibrosis and to promote neovascularization to alleviate myocardial damage in acute myocardial ischemic animal models . Therefore, exosomes from ASCs show great potential as acellular factors for various disease therapies.
MRONJ is a disease of obvious clinical manifestation with persistent gingival nonhealing and osteonecrotic bone exposure. Several theories have been reported regarding the main pathogenesis of MRONJ, including oversuppression of jawbone remodeling, soft tissue toxicity, and anti-angiogenesis [41–43]. Based on a brief review of recent studies of the effects of ASCs and exosomes on bone and soft tissue wound healing as well as angiogenesis, we hypothesize that exosomes from ASCs might contribute to preventing MRONJ by enhancing bone remodeling, accelerating gingival wound healing, and promoting angiogenesis.
Evaluation of the Hypothesis
EXOSOMES DERIVED FROM ASCS ENHANCED BONE REMODELING:
Bone remodeling is a lifelong process that serves to adjust the skeleton’s architecture and repair microdamage to maintain functional integrity . This process is characterized by coupling of bone remodeling-related cells, osteoclasts for bone resorption and osteoblasts for bone formation, which are organized in bone multicellular units . Since exosomes are considered primary paracrine effectors of intercellular messengers, they have attracted considerable attention in the context of bone physiology and diseases . Physiologically, exosomal miRNAs derived from MSCs have been found to be enriched in bone coupling-related signaling and proteins (Wnt/β-catenin, BMP/Smad, TGF-β, mTOR) [46,47], which not only transmit signals to mediate bone resorption and formation and promote the proliferation, differentiation, and activity of most bone remodeling-related cells, but also play a pivotal part in extracellular matrix mineralization [34,46–49]. In the process of bone resorption, exosomal miR-31a-5p from bone marrow-derived MSCs promoted osteoclastic differentiation and bone resorption activity by directly binding to the 3′UTR of RhoA . In the process of bone formation, exosomes from ASCs contained let-7i-5p, miR-22-3p, miR-17, miR-20a, miR-20b, and miR-106a, which are capable of promoting bone MSC migration and homing to bone defects, thereby remarkably enhancing bone regeneration [51,52]. Taken together, the evidence suggests that exosomes from ASCs might exert important functions in promoting bone remodeling and might be a promising tool to rescue bone remodeling suppression in MRONJ.
EXOSOMES FROM ASCS ACCELERATING WOUND HEALING:
An increasing number of studies have demonstrated that exosomes from ASCs can promote healing of wounds, such as diabetic foot ulcers and chronic cutaneous ulceration [53,54]. Wound healing includes 4 phases: hemostasis, inflammation, proliferation, and tissue remodeling . Zhao et al  found that exosome-borne active STAT3 from ASCs could induce macrophages into M2 phenotypes and significantly suppress the secretion of proinflammatory factor tumor necrosis factor-α, while increasing the anti-inflammatory factor IL-10. In a separate study, Zhang et al  showed that ASC-derived exosomes can promote fibroblast proliferation and migration and optimize collagen deposition via the PI3K/Akt signaling pathway to further accelerate full-thickness skin wound healing. Furthermore, ASC-Exos were reported to promote re-epithelialization and inhibit apoptosis of HaCat cells via upregulating the Wnt/β-catenin signaling pathway . Thus, exosome-derived ASCs showed potent abilities to promote wound healing.
EXOSOMES FROM ASCS PROMOTE ANGIOGENESIS:
Multiple studies have suggested that exosomes could promote cutaneous wound healing or bone healing by accelerating angiogenesis, which is a vital factor determining the outcome of healing [59,60]. Exosomes from MSCs have been found to contain pro-angiogenic factors (VEGF, TGF-β1, IL-8, HGF, and multiple microRNAs) that induce vascularization by promoting endothelial cell proliferation and migration . Huang et al  reported that systemic administration of MSC-Exos enhanced microvessel density, and reduced target cell apoptosis and tissue inflammatory infiltration in a rat spinal cord injury model. Another study showed that ASC-Exos enhanced endothelial cell tube formation both in vitro and in vivo through miR-125a inhibiting the expression of the angiogenesis inhibitor delta-like 4 (DLL4) . Consistent with these findings, Xue et al  also showed that ASC-derived exosomes induced neovascularization and accelerated wound healing by overexpressing the transcription factor nuclear factor-E2-related factor 2 (Nrf2) in a diabetic foot ulcer rat model. In a study of experimental ischemia-reperfusion injury, ASC-Exos protected skin flap survival through enhanced neovascularization and reduced the inflammation and apoptosis in the skin flap . Taken together, these studies suggested exosomes from ASCs might play key roles in stimulating vascularization owing to their enriched angiogenesis-related factors. Nevertheless, the definitive mechanisms of the interaction between exosomes and endothelial cells still need to be explored.
Promoting gingival healing, bone remodeling, and angiogenesis are key interventions to prevent the development of MRONJ. Over the past few years, therapies based on stem cells have arisen as a very promising approach to prevent MRONJ development [16,17,25]. Our previous study suggested that the local administration of ASCs prevented the occurrence of MRONJ through secreting TGF-β1, inducing primary gingival closure, and rescuing the bone regeneration process in the alveolar sockets . However, MRONJ predominantly occurs in patients with malignant underlying diseases . ASC-based treatment may increase the risks of systemic immunosuppression . Furthermore, the efficiency of stem cell-based therapies is often influenced by many factors, such as high cell passages and cells being derived from aged or diseased patients [65,66]. Thus, it is necessary to find a more secure way to prevent the development of MRONJ.
Extensive evidence exists in the literature that shows that ASCs predominantly act in a paracrine manner, with secretory factors being the mediators of soft tissue repair and bone remodeling [34,55,67]. Exosomes from ASCs might exert a similar function in promoting wound healing in both bone tissues and soft tissues, as they are one of the key factors released by MSCs . Furthermore, exosome-based therapy has its advantages as an acellular therapy compared with direct treatment with ASCs. Therefore, exosomes may be a promising therapy in the treatment of MRONJ by enhancing bone remodeling, gingival healing, and angiogenesis. To achieve a higher concentration and more effective action in the targeted area and to eliminate the adverse effects on systemic immunomodulation, we generally apply the exosomes locally at the same time as dental surgery or dental extractions. Future studies are needed to focus on the therapeutic effects of exosomes on MRONJ and the therapeutic mechanisms.
The pathogenesis of MRONJ is now widely accepted as having a multifactorial etiology, including oversuppression of jawbone remodeling, soft tissue toxicity, and anti-angiogenesis. ASC-derived exosomes have potential for promoting bone remodeling and enhancing soft tissue wound healing and angiogenesis. As such, exosomes from ASCs might contribute to preventing MRONJ.
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