Advertisement

Effects of prostaglandin E2 and D2 on cell proliferation and osteogenic capacity of human mesenchymal stem cells

Published:September 13, 2019DOI:https://doi.org/10.1016/j.plefa.2019.09.005

      Highlights

      • Our study shows that PGE2 and PGD2, which are known to be present in higher concentrations in periodontitis affected tissues, hinder proliferation and osteogenic differentiation of hMSC. PGE2 induced a higher growth rate during the first week, as early response of the tissue against an inflammatory stimulus.
      • With a continuous inflammatory challenge of PGE2, a decrease of the proliferation capacity of hMSCs that mediate tissue regeneration resulted.

      Abstract

      The manifestation of periodontitis-related inflammatory reaction is inevitably bound to the production of prostaglandins E2 and D2 which have been suggested to mediate osteoclastic and osteogenic effects within the affected tissue.
      We demonstrated the presence of PGE2 and PGD2 receptors on hMSCs on RNA level and with immunofluorescence. For each Prostaglandin, three concentrations were studied: 0.1; 0.5 or 1.0 µg/ml. A lower expression of EP1 and EP4 (PGE2 receptors 1 and 4) after stimulation with PGE2 was shown, thus a tendency to compromise osteogenic differentiation and metabolism. PGE2 induced a higher growth-rate during the first week, while a continuous inflammatory challenge determined a decrease of the proliferation of hMSCs. PGD2 inhibited cell growth irrespective of the duration of the stimulation. PGE2 and PGD2 have also negative effects on calcium deposition osteogenic, thus on differentiation of hMSCs. PGE2 and PGD2 seem to induce bone resorption also having indirectly a negative impact on the osteogenic differentiation of hMSCs. Thus, inhibitors of PGE2 and PGD2 can be used as adjunct to mechanical periodontal treatment.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Prostaglandins, Leukotrienes and Essential Fatty Acids
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Pihlstrom B.L.
        • Michalowicz B.S.
        • Johnson N.W.
        Periodontal diseases.
        Lancet. 2005; 366: 1809-1820https://doi.org/10.1016/S0140-6736(05)67728-8
        • Eke P.I.
        • Thornton-Evans G.O.
        • Wei L.
        • et al.
        Periodontitis in US adults: national health and nutrition examination survey 2009–2014.
        J. Am. Dent. Assoc. 2018; 149 (e6): 576-588https://doi.org/10.1016/j.adaj.2018.04.023
        • Kassebaum N.J.
        • Bernabe E.
        • Dahiya M.
        • et al.
        Global burden of severe periodontitis in 1990–2010: a systematic review and meta-regression.
        J. Dent. Res. 2014; 93: 1045-1053https://doi.org/10.1177/0022034514552491
        • Noguchi K.
        • Ishikawa I.
        The roles of cyclooxygenase-2 and prostaglandin E2 in periodontal disease.
        Periodontol 2000. 2007; 43: 85-101https://doi.org/10.1111/j.1600-0757.2006.00170.x
        • Ern C.
        • Berger T.
        • Frasheri I.
        • et al.
        Differentiation of hMSC and hPDLSC induced by PGE2 or BMP-7 in 3D models.
        Prostaglandins Leukot. Essent. Fatty Acids. 2017; 122: 30-37https://doi.org/10.1016/j.plefa.2017.06.005
        • Hienz S.A.
        • Paliwal S.
        • Ivanovski S.
        Mechanisms of bone resorption in periodontitis.
        J. Immunol. Res. 2015; 2015615486https://doi.org/10.1155/2015/615486
        • Offenbacher S.
        • Odle B.M.
        • Gray R.C.
        • et al.
        Crevicular fluid prostaglandin E levels as a measure of the periodontal disease status of adult and juvenile periodontitis patients.
        J. Periodontal Res. 1984; 19: 1-13
        • Ohm K.
        • Albers H.K.
        • Lisboa B.P.
        Measurement of eight prostaglandins in human gingival and periodontal disease using high pressure liquid chromatography and radioimmunoassay.
        J. Periodontal Res. 1984; 19: 501-511
        • Tsai C.C.
        • Hong Y.C.
        • Chen C.C.
        • et al.
        Measurement of prostaglandin E2 and leukotriene B4 in the gingival crevicular fluid.
        J. Dent. 1998; 26: 97-103
        • Sanchez G.A.
        • Miozza V.A.
        • Delgado A.
        • et al.
        Salivary IL-1beta and PGE2 as biomarkers of periodontal status, before and after periodontal treatment.
        J. Clin. Periodontol. 2013; 40: 1112-1117https://doi.org/10.1111/jcpe.12164
        • Baser U.
        • Oztekin G.
        • Ademoglu E.
        • et al.
        Is the severity of periodontitis related to gingival crevicular fluid and serum high-sensitivity C-reactive protein concentrations?.
        Clin. Lab. 2014; 60: 1653-1658
        • Liao C.H.
        • Fei W.
        • Shen Z.H.
        • et al.
        Expression and distribution of TNF-alpha and PGE2 of periodontal tissues in rat periodontitis model.
        Asian Pac. J. Trop. Med. 2014; 7: 412-416https://doi.org/10.1016/S1995-7645(14)60067-5
        • Miyauchi M.
        • Ijuhin N.
        • Nikai H.
        • et al.
        Effect of exogenously applied prostaglandin E2 on alveolar bone loss–histometric analysis.
        J. Periodontol. 1992; 63: 405-411https://doi.org/10.1902/jop.1992.63.5.405
        • Yang R.S.
        • Liu T.K.
        • Lin-Shiau S.Y.
        Increased bone growth by local prostaglandin E2 in rats.
        Calcif. Tissue Int. 1993; 52: 57-61
        • Machwate M.
        • Harada S.
        • Leu C.T.
        • et al.
        Prostaglandin receptor EP(4) mediates the bone anabolic effects of PGE(2).
        Mol. Pharmacol. 2001; 60: 36-41
        • Tian X.Y.
        • Zhang Q.
        • Zhao R.
        • et al.
        Continuous PGE2 leads to net bone loss while intermittent PGE2 leads to net bone gain in lumbar vertebral bodies of adult female rats.
        Bone. 2008; 42: 914-920https://doi.org/10.1016/j.bone.2007.12.228
        • Li M.
        • Thompson D.D.
        • Paralkar V.M.
        Prostaglandin E(2) receptors in bone formation.
        Int. Orthop. 2007; 31: 767-772https://doi.org/10.1007/s00264-007-0406-x
        • Tang C.H.
        • Yang R.S.
        • Fu W.M.
        Prostaglandin E2 stimulates fibronectin expression through EP1 receptor, phospholipase C, protein kinase Calpha, and c-Src pathway in primary cultured rat osteoblasts.
        J. Biol. Chem. 2005; 280: 22907-22916https://doi.org/10.1074/jbc.M500130200
        • Kamoshita E.
        • Ikeda Y.
        • Fujita M.
        • et al.
        Recruitment of a prostaglandin E receptor subtype, EP3-expressing bone marrow cells is crucial in wound-induced angiogenesis.
        Am. J. Pathol. 2006; 169: 1458-1472https://doi.org/10.2353/ajpath.2006.051358
        • Sakuma Y.
        • Tanaka K.
        • Suda M.
        • et al.
        Crucial involvement of the EP4 subtype of prostaglandin E receptor in osteoclast formation by proinflammatory cytokines and lipopolysaccharide.
        J. Bone Mineral Res. 2000; 15: 218-227https://doi.org/10.1359/jbmr.2000.15.2.218
        • Yoshida K.
        • Oida H.
        • Kobayashi T.
        • et al.
        Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation.
        Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4580-4585https://doi.org/10.1073/pnas.062053399
        • Garcia-Solaesa V.
        • Sanz-Lozano C.
        • Padron-Morales J.
        • et al.
        The prostaglandin D2 receptor (PTGDR) gene in asthma and allergic diseases.
        Allergol. Immunopathol. (Madr.). 2014; 42: 64-68https://doi.org/10.1016/j.aller.2012.12.002
        • Weschenfelder J.
        • Sander C.
        • Kluge M.
        • et al.
        The influence of cytokines on wakefulness regulation: clinical relevance, mechanisms and methodological problems.
        Psychiatr. Danub. 2012; 24: 112-126
        • Matsuoka T.
        • Narumiya S.
        Prostaglandin receptor signaling in disease.
        Sci. World J. 2007; 7: 1329-1347https://doi.org/10.1100/tsw.2007.182
        • Takagi T.
        • Yamamoto T.
        • Asano S.
        • et al.
        Effect of prostaglandin D2 on the femoral bone mineral density in ovariectomized rats.
        Calcif. Tissue Int. 1993; 52: 442-446
        • Koshihara Y.
        • Kawamura M.
        Prostaglandin D2 stimulates calcification of human osteoblastic cells.
        Biochem. Biophys. Res. Commun. 1989; 159: 1206-1212
        • Durand M.
        • Gallant M.A.
        • de Brum-Fernandes A.J.
        Prostaglandin D2 receptors control osteoclastogenesis and the activity of human osteoclasts.
        J. Bone Mineral Res. 2008; 23: 1097-1105https://doi.org/10.1359/jbmr.080228
        • Pettipher R.
        • Hansel T.T.
        • Armer R.
        Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases.
        Nat. Rev. Drug Discov. 2007; 6: 313-325https://doi.org/10.1038/nrd2266
        • Gallant M.A.
        • Samadfam R.
        • Hackett J.A.
        • et al.
        Production of prostaglandin D(2) by human osteoblasts and modulation of osteoprotegerin, RANKL, and cellular migration by DP and CRTH2 receptors.
        J. Bone Mineral Res. 2005; 20: 672-681https://doi.org/10.1359/JBMR.041211
        • Preshaw P.M.
        Host modulation therapy with anti-inflammatory agents.
        Periodontol 2000. 2018; 76: 131-149https://doi.org/10.1111/prd.12148
        • Moro M.G.
        • Oliveira M.
        • Oliveira L.R.
        • et al.
        Effects of selective versus non-selective COX-2 inhibition on experimental periodontitis.
        Braz. Dent. J. 2019; 30: 133-138https://doi.org/10.1590/0103-6440201902241
        • Kirschneck C.
        • Kuchler E.C.
        • Wolf M.
        • et al.
        Effects of the highly COX-2-selective analgesic NSAID etoricoxib on human periodontal ligament fibroblasts during compressive orthodontic mechanical strain.
        Mediators Inflamm. 2019; 20192514956https://doi.org/10.1155/2019/2514956
        • Sanchez-Lara P.A.
        • Warburton D.
        Impact of stem cells in craniofacial regenerative medicine.
        Front. Physiol. 2012; 3: 188https://doi.org/10.3389/fphys.2012.00188
        • Maeda H.
        • Tomokiyo A.
        • Fujii S.
        • et al.
        Promise of periodontal ligament stem cells in regeneration of periodontium.
        Stem Cell Res. Ther. 2011; 2: 33https://doi.org/10.1186/scrt74
        • Ern C.
        • Krump-Konvalinkova V.
        • Docheva D.
        • et al.
        Interactions of human endothelial and multipotent mesenchymal stem cells in cocultures.
        Open Biomed. Eng. J. 2010; 4: 190-198https://doi.org/10.2174/1874120701004010190
        • Suzawa T.
        • Miyaura C.
        • Inada M.
        • et al.
        The role of prostaglandin E receptor subtypes (EP1, EP2, EP3, and EP4) in bone resorption: an analysis using specific agonists for the respective EPs.
        Endocrinology. 2000; 141: 1554-1559https://doi.org/10.1210/endo.141.4.7405
        • Noack C.
        • Hempel U.
        • Preissler C.
        • et al.
        Prostaglandin E2 impairs osteogenic and facilitates adipogenic differentiation of human bone marrow stromal cells.
        Prostaglandins Leukot. Essent. Fatty Acids. 2015; 94: 91-98https://doi.org/10.1016/j.plefa.2014.11.008
        • Hock J.
        Gingival vasculature around erupting deciduous teeth of dogs and cats.
        J. Clin. Periodontol. 1975; 2: 44-50
        • Hock J.
        Vascular morphology in noninflamed healed gingiva of dogs.
        J. Clin. Periodontol. 1979; 6: 37-44
        • Scutt A.
        • Bertram P.
        • Brautigam M.
        The role of glucocorticoids and prostaglandin E2 in the recruitment of bone marrow mesenchymal cells to the osteoblastic lineage: positive and negative effects.
        Calcif. Tissue Int. 1996; 59: 154-162
        • Flanagan A.M.
        • Chambers T.J.
        Stimulation of bone nodule formation in vitro by prostaglandins E1 and E2.
        Endocrinology. 1992; 130: 443-448https://doi.org/10.1210/endo.130.1.1309342
        • Nagata T.
        • Kaho K.
        • Nishikawa S.
        • et al.
        Effect of prostaglandin E2 on mineralization of bone nodules formed by fetal rat calvarial cells.
        Calcif. Tissue Int. 1994; 55: 451-457
        • Fujitani Y.
        • Aritake K.
        • Kanaoka Y.
        • et al.
        Pronounced adipogenesis and increased insulin sensitivity caused by overproduction of prostaglandin D2 in vivo.
        FEBS J. 2010; 277: 1410-1419https://doi.org/10.1111/j.1742-4658.2010.07565.x