Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a severe adverse reaction, which results in progressive bone destruction in the maxillofacial region of patients. To date, the pathological mechanisms remain largely unclear. Recently, we found that BRONJ patient had significantly deep periodontal pockets and severe periodontal bone defects before the exposed necrotic bone. Human periodontal ligament stem cells (hPDLSCs) play key roles in physiological maintenance and regeneration of periodontal tissues. However, the activities of hPDLSCs derived from BRONJ lesions and the role of hPDLSCs in BRONJ periodontal defect repair remain poorly understood. The aim of the present study was to elucidate the role of hPDLSCs in BRONJ. In this study, we found that the capacities of cell proliferation, adhesion, and migration of hPDLSCs derived from BRONJ lesions (BRONJ-hPDLSCs) were significantly decreased compared with control-hPDLSCs. BRONJ-hPDLSCs underwent early apoptosis compared with control-hPDLSCs. Importantly, we first demonstrated that BRONJ-hPDLSCs exhibited impaired osteogenic differentiation abilities in ectopic osteogenesis of nude mice. The above results suggested that the impaired BRONJ-hPDLSCs may be an important factor in deficient periodontal repair of BRONJ lesions and provide new insight into the underlying mechanism of BRONJ.
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References
1.
KhanAA, MorrisonA, HanleyDA, FelsenbergD, McCauleyLK, O'RyanF, ReidIR, RuggieroSL, TaguchiA, et al. (2015). Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res, 30:3–23.
2.
BakalO, TirnavaAA and SenH. (2015). Experience of pain in a patient with BRONJ. Clin Interv Aging, 10:1097–1098.
3.
MarxRE. (2003). Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg, 61:1115–1117.
4.
CampisiG, Di FedeO, MusciottoA, Lo CastoA, Lo MuzioL, FulfaroF, BadalamentiG, RussoA and GebbiaN. (2007). Bisphosphonate-related osteonecrosis of the jaw (BRONJ): run dental management designs and issues in diagnosis. Ann Oncol, 18 (Suppl 6):vi168–vi172.
5.
ManeaHC, UrechescuHC, BalicaNC, PricopMO, BadercaF, PoenaruM, HorhatID, JifcuEM, CloscaRM and SarauCA. (2018). Bisphosphonates-induced osteonecrosis of the jaw—epidemiological, clinical and histopathological aspects. Rom J Morphol Embryol, 59:825–831.
6.
WehrhanF, AmannK, MobiusP, WeberM, PreidlR, RiesJ and StockmannP. (2015). BRONJ-related jaw bone is associated with increased Dlx-5 and suppressed osteopontin-implication in the site-specific alteration of angiogenesis and bone turnover by bisphosphonates. Clin Oral Investig, 19:1289–1298.
7.
SoundiaA, HadayaD, EsfandiN, GkouverisI, ChristensenR, DrySM, BezouglaiaO, PirihF, NikitakisN, AghalooT and TetradisS. (2018). Zoledronate impairs socket healing after extraction of teeth with experimental periodontitis. J Dent Res, 97:312–320.
8.
Hamma-KourbaliY, Di BenedettoM, LedouxD, OudarO, LerouxY, LecouveyM and KraemerM. (2003). A novel non-containing-nitrogen bisphosphonate inhibits both in vitro and in vivo angiogenesis. Biochem Biophys Res Commun, 310:816–823.
9.
ZiebartT, HallingF, HeymannP, NeffA, BlattS, JungJ, PabstA, RighessoL and WalterC. (2016). Impact of soft tissue pathophysiology in the development and maintenance of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Dent J (Basel), 4:E36.
10.
BorbaTT, MolzP, SchlickmannDS, SantosC, OliveiraCF, PraD, NetoLK and FrankeSIR. (2019). Periodontitis: genomic instability implications and associated risk factors. Mutat Res Genet Toxicol Environ Mutagen, 840:20–23.
11.
TalakeyAA and BernabeE. (2019). Long-term regular dental attendance and tooth retention among British adults: a cross-sectional analysis of national survey data. Int J Dent Hyg, 17:64–70.
12.
MarxRE, SawatariY, FortinM and BroumandV. (2005). Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg, 63:1567–1575.
13.
AguirreJI, AkhterMP, KimmelDB, PingelJE, WilliamsA, JorgensenM, KesavaluL and WronskiTJ. (2012). Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis. J Bone Miner Res, 27:2130–2143.
14.
Thumbigere-MathV, MichalowiczBS, HodgesJS, TsaiML, SwensonKK, RockwellL and GopalakrishnanR. (2014). Periodontal disease as a risk factor for bisphosphonate-related osteonecrosis of the jaw. J Periodontol, 85:226–233.
15.
LiCL, LuWW, SeneviratneCJ, LeungWK, ZwahlenRA and ZhengLW. (2016). Role of periodontal disease in bisphosphonate-related osteonecrosis of the jaws in ovariectomized rats. Clin Oral Implants Res, 27:1–6.
16.
LiCL, SeneviratneCJ, HuoL, LuWW and ZhengLW. (2015). Impact of Actinomyces naeslundii on bisphosphonate-related osteonecrosis of the jaws in ovariectomized rats with periodontitis. J Craniomaxillofac Surg, 43:1662–1669.
17.
KrimmelM, RippergerJ, HairassM, HoefertS, KlubaS and ReinertS. (2014). Does dental and oral health influence the development and course of bisphosphonate-related osteonecrosis of the jaws (BRONJ)?. Oral Maxillofac Surg, 18:213–218.
18.
OteriG, BramantiE, NigroneV and CicciuM. (2013). Decayed, missing, and filled teeth index and periodontal health in osteoporotic patients affected by BRONJ: an observational study. J Osteoporos, 2013:231289.
19.
TsurushimaH, KokuryoS, SakaguchiO, TanakaJ and TominagaK. (2013). Bacterial promotion of bisphosphonate-induced osteonecrosis in Wistar rats. Int J Oral Maxillofac Surg, 42:1481–1487.
20.
OttoS, PautkeC, Martin JuradoO, NehrbassD, StoddartMJ, EhrenfeldM and ZeiterS. (2017). Further development of the MRONJ minipig large animal model. J Craniomaxillofac Surg, 45:1503–1514.
21.
AghalooTL, KangB, SungEC, ShoffM, RonconiM, GotcherJE, BezouglaiaO, DrySM and TetradisS. (2011). Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat. J Bone Miner Res, 26:1871–1882.
22.
HeLH, XiaoE, AnJG, HeY, ChenS, ZhaoL, ZhangT and ZhangY. (2017). Role of bone marrow stromal cells in impaired bone repair from BRONJ osseous lesions. J Dent Res, 96:539–546.
23.
Amghar-MaachS, Gay-EscodaC and Sanchez-GarcesMA. (2019). Regeneration of periodontal bone defects with dental pulp stem cells grafting: systematic review. J Clin Exp Dent, 11:e373–e381.
24.
IwasakiK, AkazawaK, NagataM, KomakiM, HondaI, MoriokaC, YokoyamaN, AyameH, YamakiK, et al. (2019). The fate of transplanted periodontal ligament stem cells in surgically created periodontal defects in rats. Int J Mol Sci, 20:E192.
25.
MoshaveriniaA, ChenC, XuX, AkiyamaK, AnsariS, ZadehHH and ShiS. (2014). Bone regeneration potential of stem cells derived from periodontal ligament or gingival tissue sources encapsulated in RGD-modified alginate scaffold. Tissue Eng Part A, 20:611–621.
26.
YanB, ZhangH, DaiT, GuY, QiuX, HuC, LiuY, WeiK and LiD. (2018). Necrostatin-1 promotes ectopic periodontal tissue like structure regeneration in LPS-treated PDLSCs. PLoS One, 13:e0207760.
27.
IkedaT, KuraguchiJ, KogashiwaY, YokoiH, SatomiT and KohnoN. (2015). Successful treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) patients with sitafloxacin: new strategies for the treatment of BRONJ. Bone, 73:217–222.
28.
ShapiroCL, YaromN, PetersonDE, BohlkeK and SaundersDP. (2019). Medication-related osteonecrosis of the jaw: MASCC/ISOO/ASCO Clinical Practice Guideline Summary. J Oncol Pract, 15:603–606.
29.
SchwartzHC. (2015). American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update and CTX. J Oral Maxillofac Surg, 73:377.
30.
AlbadawiH, HauraniMJ, OkluR, TrubianoJP, LaubPJ, YooHJ and WatkinsMT. (2013). Differential effect of zoledronic acid on human vascular smooth muscle cells. J Surg Res, 182:339–346.
31.
PrueterJ and DildeepA. (2016). Bisphosphonate related osteonecrosis of calvarial bone. Am J Otolaryngol, 37:470–472.
32.
KhanAM and SindwaniR. (2009). Bisphosphonate-related osteonecrosis of the skull base. Laryngoscope, 119:449–452.
33.
LongoR, CastellanaMA and GaspariniG. (2009). Bisphosphonate-related osteonecrosis of the jaw and left thumb. J Clin Oncol, 27:e242–e243.
34.
SanchisJM, BaganJV, MurilloJ, DiazJM and AsensioL. (2014). Risk of developing BRONJ among patients exposed to intravenous bisphosphonates following tooth extraction. Quintessence Int, 45:769–777.
35.
PushalkarS, LiX, KuragoZ, RamanathapuramLV, MatsumuraS, FleisherKE, GlickmanR, YanW, LiY and SaxenaD. (2014). Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw. Int J Oral Sci, 6:219–226.
36.
OttoS, TroltzschM, JambrovicV, PanyaS, ProbstF, RistowO, EhrenfeldM and PautkeC. (2015). Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development?. J Craniomaxillofac Surg, 43:847–854.
37.
SaadF, BrownJE, Van PoznakC, IbrahimT, StemmerSM, StopeckAT, DielIJ, TakahashiS, ShoreN, et al. (2012). Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol, 23:1341–1347.
38.
SoundiaA, HadayaD, EsfandiN, de MolonRS, BezouglaiaO, DrySM, PirihFQ, AghalooT and TetradisS. (2016). Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease. Bone, 90:133–141.
39.
KosM. (2014). Association of dental and periodontal status with bisphosphonate-related osteonecrosis of the jaws. A retrospective case controlled study. Arch Med Sci, 10:117–123.
40.
McCullochCA and BordinS. (1991). Role of fibroblast subpopulations in periodontal physiology and pathology. J Periodontal Res, 26:144–154.
41.
NanciA and BosshardtDD. (2006). Structure of periodontal tissues in health and disease. Periodontol 2000, 40:11–28.
42.
SchellerEL, BaldwinCM, KuoS, D'SilvaNJ, FeinbergSE, KrebsbachPH and EdwardsPC. (2011). Bisphosphonates inhibit expression of p63 by oral keratinocytes. J Dent Res, 90:894–899.
43.
CornishJ, BavaU, CallonKE, BaiJ, NaotD and ReidIR. (2011). Bone-bound bisphosphonate inhibits growth of adjacent non-bone cells. Bone, 49:710–716.
44.
LeeJS, YiJK, AnSY and HeoJS. (2014). Increased osteogenic differentiation of periodontal ligament stem cells on polydopamine film occurs via activation of integrin and PI3K signaling pathways. Cell Physiol Biochem, 34:1824–1834.
45.
Lima-JuniorRC, FigueiredoAA, FreitasHC, MeloML, WongDV, LeiteCA, MedeirosRP, Marques-NetoRD, ValeML, et al. (2012). Involvement of nitric oxide on the pathogenesis of irinotecan-induced intestinal mucositis: role of cytokines on inducible nitric oxide synthase activation. Cancer Chemother Pharmacol, 69:931–942.
46.
Lopez-JornetP, Camacho-AlonsoF, Martinez-CanovasA, Molina-MinanoF, Gomez-GarciaF and Vicente-OrtegaV. (2011). Perioperative antibiotic regimen in rats treated with pamidronate plus dexamethasone and subjected to dental extraction: a study of the changes in the jaws. J Oral Maxillofac Surg, 69:2488–2493.
47.
LesclousP, Abi NajmS, CarrelJP, BaroukhB, LombardiT, WilliJP, RizzoliR, SaffarJL and SamsonJ. (2009). Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation?. Bone, 45:843–852.
48.
MuratsuD, YoshigaD, TaketomiT, OnimuraT, SekiY, MatsumotoA and NakamuraS. (2013). Zoledronic acid enhances lipopolysaccharide-stimulated proinflammatory reactions through controlled expression of SOCS1 in macrophages. PLoS One, 8:e67906.
49.
NortonJT, HayashiT, CrainB, ChoJS, MillerLS, CorrM and CarsonDA. (2012). Cutting edge: nitrogen bisphosphonate-induced inflammation is dependent upon mast cells and IL-1. J Immunol, 188:2977–2980.
50.
KimS, WilliamsDW, LeeC, KimT, AraiA, ShiS, LiX, ShinKH, KangMK, ParkNH and KimRH. (2017). IL-36 induces bisphosphonate-related osteonecrosis of the jaw-like lesions in mice by inhibiting TGF-beta-mediated collagen expression. J Bone Miner Res, 32:309–318.
51.
ImGI, QureshiSA, KenneyJ, RubashHE and ShanbhagAS. (2004). Osteoblast proliferation and maturation by bisphosphonates. Biomaterials, 25:4105–4115.
52.
PanB, ToLB, FarrugiaAN, FindlayDM, GreenJ, GronthosS, EvdokiouA, LynchK, AtkinsGJ and ZannettinoAC. (2004). The nitrogen-containing bisphosphonate, zoledronic acid, increases mineralisation of human bone-derived cells in vitro. Bone, 34:112–123.
53.
ReinholzGG, GetzB, PedersonL, SandersES, SubramaniamM, IngleJN and SpelsbergTC. (2000). Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res, 60:6001–6007.
54.
Pujari-PalmerM, RoboC, PerssonC, ProcterP and EngqvistH. (2018). Influence of cement compressive strength and porosity on augmentation performance in a model of orthopedic screw pull-out. J Mech Behav Biomed Mater, 77:624–633.
55.
WangS, ZhaoJ, ZhangW, YeD, YuW, ZhuC, ZhangX, SunX, YangC, JiangX and ZhangZ. (2011). Maintenance of phenotype and function of cryopreserved bone-derived cells. Biomaterials, 32:3739–3749.
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