Abstract
Objectives
We previously suggested an ovariectomy (OVX)-induced osteoporotic rat model showing an impaired alveolar bone defect healing. This study aimed to evaluate and compare the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) and recombinant human platelet-derived growth factor-BB (rhPDGF-BB) on alveolar bone defect healing in OVX-induced osteoporotic rats.
Materials and Methods
A total of forty-one female rats were divided into four groups: a collagen group (n=10), a PDGF-BB group (n=11), a BMP-2 group (n=10), and a control group (n=10). Four months after OVX, alveolar bone drill-hole defects were created and grafted with collagen gel, rhPDGF-BB/collagen gel, or rhBMP-2/collagen gel. The defects in the control group were not grafted with any material. Defect healing was evaluated by histological, histomorphometric, and microcomputed tomographic (micro-CT) analyses at 2 and 4 weeks.
Results
According to the micro-CT analysis, the BMP-2 group exhibited the greatest bone volume fraction among all groups, while the PDGF-BB group did not show significant differences compared with the collagen group. The histomorphometric analysis showed a significantly larger amount of new bone area in the BMP-2 group than in the control and collagen groups at 4 weeks; however, the PDGF-BB group did not reach significant superiority compared with the other groups.
Conclusions
Alveolar bone regeneration was significantly enhanced by the local use of rhBMP-2/collagen gel compared with the use of rhPDGF-BB/collagen gel in OVX-induced osteoporotic rats.
Clinical Relevance
A treatment modality using rhBMP-2 may be a promising approach to promote alveolar bone regeneration in patients suffering from postmenopausal osteoporosis.
Similar content being viewed by others
References
Kanis JA (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int 4(6):368–381
Nih Consensus Development Panel on Osteoporosis Prevention D, Therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285(6):785–795. https://doi.org/10.1001/jama.285.6.785
Reinhardt RA, Payne JB, Maze CA, Patil KD, Gallagher SJ, Mattson JS (1999) Influence of estrogen and osteopenia/osteoporosis on clinical periodontitis in postmenopausal women. J Periodontol 70(8):823–828. https://doi.org/10.1902/jop.1999.70.8.823
Tezal M, Wactawski-Wende J, Grossi SG, Ho AW, Dunford R, Genco RJ (2000) The relationship between bone mineral density and periodontitis in postmenopausal women. J Periodontol 71(9):1492–1498. https://doi.org/10.1902/jop.2000.71.9.1492
Krall EA, Garcia RI, Dawson-Hughes B (1996) Increased risk of tooth loss is related to bone loss at the whole body, hip, and spine. Calcif Tissue Int 59(6):433–437. https://doi.org/10.1007/bf00369206
He YX, Zhang G, Pan XH, Liu Z, Zheng LZ, Chan CW, Lee KM, Cao YP, Li G, Wei L, Hung LK, Leung KS, Qin L (2011) Impaired bone healing pattern in mice with ovariectomy-induced osteoporosis: a drill-hole defect model. Bone 48(6):1388–1400. https://doi.org/10.1016/j.bone.2011.03.720
Kim HJ, Kim KH, Lee YM, Ku Y, Heo SJ, Rhyu IC, Seol YJ (2020) Ovariectomy and timing of impaired maxillary alveolar bone regeneration: an experimental study in rats. J Periodontol. 91:1357–1366. https://doi.org/10.1002/JPER.19-0537
Makhdom AM, Hamdy RC (2013) The role of growth factors on acceleration of bone regeneration during distraction osteogenesis. Tissue Eng Part B Rev 19(5):442–453. https://doi.org/10.1089/ten.TEB.2012.0717
Caplan AI, Correa D (2011) PDGF in bone formation and regeneration: new insights into a novel mechanism involving MSCs. J Orthop Res 29(12):1795–1803. https://doi.org/10.1002/jor.21462
Kanczler JM, Oreffo RO (2008) Osteogenesis and angiogenesis: the potential for engineering bone. Eur Cell Mater 15:100–114. https://doi.org/10.22203/ecm.v015a08
Bayer EA, Fedorchak MV, Little SR (2016) The influence of platelet-derived growth factor and bone morphogenetic protein presentation on tubule organization by human umbilical vascular endothelial cells and human mesenchymal stem cells in coculture. Tissue Eng Part A 22(21-22):1296–1304. https://doi.org/10.1089/ten.TEA.2016.0163
Devescovi V, Leonardi E, Ciapetti G, Cenni E (2008) Growth factors in bone repair. Chir Organi Mov 92(3):161–168. https://doi.org/10.1007/s12306-008-0064-1
Kempen DH, Lu L, Heijink A, Hefferan TE, Creemers LB, Maran A et al (2009) Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. Biomaterials 30(14):2816–2825. https://doi.org/10.1016/j.biomaterials.2009.01.031
Moreno-Miralles I, Schisler JC, Patterson C (2009) New insights into bone morphogenetic protein signaling: focus on angiogenesis. Curr Opin Hematol 16(3):195–201. https://doi.org/10.1097/MOH.0b013e32832a07d6
Hollinger JO, Hart CE, Hirsch SN, Lynch S, Friedlaender GE (2008) Recombinant human platelet-derived growth factor: biology and clinical applications. J Bone Joint Surg Am 90(Suppl 1):48–54. https://doi.org/10.2106/JBJS.G.01231
Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79(4):1283–1316. https://doi.org/10.1152/physrev.1999.79.4.1283
Hsu YT, Al-Hezaimi K, Galindo-Moreno P, O'Valle F, Al-Rasheed A, Wang HL (2017) Effects of recombinant human bone morphogenetic protein-2 on vertical bone augmentation in a canine model. J Periodontol 88(9):896–905. https://doi.org/10.1902/jop.2017.160516
Pelaez M, Susin C, Lee J, Fiorini T, Bisch FC, Dixon DR, McPherson JC III, Buxton AN, Wikesjö UME (2014) Effect of rhBMP-2 dose on bone formation/maturation in a rat critical-size calvarial defect model. J Clin Periodontol 41(8):827–836. https://doi.org/10.1111/jcpe.12270
Thoma DS, Cha JK, Sapata VM, Jung RE, Husler J, Jung UW (2017) Localized bone regeneration around dental implants using recombinant bone morphogenetic protein-2 and platelet-derived growth factor-BB in the canine. Clin Oral Implants Res 28(11):1334–1341. https://doi.org/10.1111/clr.12989
Thoma DS, Lim HC, Sapata VM, Yoon SR, Jung RE, Jung UW (2017) Recombinant bone morphogenetic protein-2 and platelet-derived growth factor-BB for localized bone regeneration. Histologic and radiographic outcomes of a rabbit study. Clin Oral Implants Res 28(11):e236–e243. https://doi.org/10.1111/clr.13002
Pountos I, Georgouli T, Henshaw K, Bird H, Jones E, Giannoudis PV (2010) The effect of bone morphogenetic protein-2, bone morphogenetic protein-7, parathyroid hormone, and platelet-derived growth factor on the proliferation and osteogenic differentiation of mesenchymal stem cells derived from osteoporotic bone. J Orthop Trauma 24(9):552–556. https://doi.org/10.1097/BOT.0b013e3181efa8fe
Prall WC, Haasters F, Heggebo J, Polzer H, Schwarz C, Gassner C et al (2013) Mesenchymal stem cells from osteoporotic patients feature impaired signal transduction but sustained osteoinduction in response to BMP-2 stimulation. Biochem Biophys Res Commun 440(4):617–622. https://doi.org/10.1016/j.bbrc.2013.09.114
Lasota A, Danowska-Klonowska D (2004) Experimental osteoporosis--different methods of ovariectomy in female white rats. Rocz Akad Med Bialymst 49(Suppl 1):129–131
Park SY, Kim KH, Shin SY, Koo KT, Lee YM, Seol YJ (2013) Dual delivery of rhPDGF-BB and bone marrow mesenchymal stromal cells expressing the BMP2 gene enhance bone formation in a critical-sized defect model. Tissue Eng Part A 19(21-22):2495–2505. https://doi.org/10.1089/ten.tea.2012.0648
Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R et al (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 84(12):2123–2134. https://doi.org/10.2106/00004623-200212000-00001
Katayama Y, Matsuyama Y, Yoshihara H, Sakai Y, Nakamura H, Imagama S, Ito Z, Wakao N, Kamiya M, Yukawa Y, Kanemura T, Sato K, Iwata H, Ishiguro N (2009) Clinical and radiographic outcomes of posterolateral lumbar spine fusion in humans using recombinant human bone morphogenetic protein-2: an average five-year follow-up study. Int Orthop 33(4):1061–1067. https://doi.org/10.1007/s00264-008-0600-5
Jovanovic SA, Hunt DR, Bernard GW, Spiekermann H, Wozney JM, Wikesjo UM (2007) Bone reconstruction following implantation of rhBMP-2 and guided bone regeneration in canine alveolar ridge defects. Clin Oral Implants Res 18(2):224–230. https://doi.org/10.1111/j.1600-0501.2006.01324.x
Wikesjo UM, Qahash M, Thomson RC, Cook AD, Rohrer MD, Wozney JM et al (2004) rhBMP-2 significantly enhances guided bone regeneration. Clin Oral Implants Res 15(2):194–204. https://doi.org/10.1111/j.1600-0501.2004.00971.x
Al-Zube L, Breitbart EA, O'Connor JP, Parsons JR, Bradica G, Hart CE et al (2009) Recombinant human platelet-derived growth factor BB (rhPDGF-BB) and beta-tricalcium phosphate/collagen matrix enhance fracture healing in a diabetic rat model. J Orthop Res 27(8):1074–1081. https://doi.org/10.1002/jor.20842
Thoma DS, Jung RE, Hanseler P, Hammerle CH, Cochran DL, Weber FE (2012) Impact of recombinant platelet-derived growth factor BB on bone regeneration: a study in rabbits. Int J Periodontics Restorative Dent 32(2):195–202
Zarrinkalam MR, Schultz CG, Ardern DW, Vernon-Roberts B, Moore RJ (2013) Recombinant human bone morphogenetic protein-type 2 (rhBMP-2) enhances local bone formation in the lumbar spine of osteoporotic sheep. J Orthop Res 31(9):1390–1397. https://doi.org/10.1002/jor.22387
Wu ZX, Liu D, Wan SY, Cui G, Zhang Y, Lei W (2011) Sustained-release rhBMP-2 increased bone mass and bone strength in an ovine model of postmenopausal osteoporosis. J Orthop Sci 16(1):99–104. https://doi.org/10.1007/s00776-010-0019-x
Kim RY, Yang HJ, Song YM, Kim IS, Hwang SJ (2015) estrogen modulates bone morphogenetic protein-induced sclerostin expression through the Wnt signaling pathway. Tissue Eng Part A 21(13-14):2076–2088. https://doi.org/10.1089/ten.TEA.2014.0585
Yamamoto T, Saatcioglu F, Matsuda T (2002) Cross-talk between bone morphogenic proteins and estrogen receptor signaling. Endocrinology 143(7):2635–2642. https://doi.org/10.1210/endo.143.7.8877
Wang Q, Zhao B, Li C, Rong JS, Tao SQ, Tao TZ (2014) Decreased proliferation ability and differentiation potential of mesenchymal stem cells of osteoporosis rat. Asian Pac J Trop Med 7(5):358–363. https://doi.org/10.1016/S1995-7645(14)60055-9
Abreu FA, Ferreira CL, Silva GA, Paulo Cde O, Miziara MN, Silveira FF et al (2013) Effect of PDGF-BB, IGF-I growth factors and their combination carried by liposomes in tooth socket healing. Braz Dent J 24(4):299–307. https://doi.org/10.1590/0103-6440201302238
King GN, King N, Cruchley AT, Wozney JM, Hughes FJ (1997) Recombinant human bone morphogenetic protein-2 promotes wound healing in rat periodontal fenestration defects. J Dent Res 76(8):1460–1470. https://doi.org/10.1177/00220345970760080801
Stancoven BW, Lee J, Dixon DR, McPherson JC 3rd, Bisch FC, Wikesjo UM et al (2013) Effect of bone morphogenetic protein-2, demineralized bone matrix and systemic parathyroid hormone (1-34) on local bone formation in a rat calvaria critical-size defect model. J Periodontal Res 48(2):243–251. https://doi.org/10.1111/jre.12001
Catoira MC, Fusaro L, Di Francesco D, Ramella M, Boccafoschi F (2019) Overview of natural hydrogels for regenerative medicine applications. J Mater Sci Mater Med 30(10):115. https://doi.org/10.1007/s10856-019-6318-7
Brown RA, Phillips JB (2007) Cell responses to biomimetic protein scaffolds used in tissue repair and engineering. Int Rev Cytol 262:75–150. https://doi.org/10.1016/S0074-7696(07)62002-6
Xu L, Zhang W, Lv K, Yu W, Jiang X, Zhang F (2016) Peri-implant bone regeneration using rhPDGF-BB, BMSCs, and beta-TCP in a canine model. Clin Implant Dent Relat Res 18(2):241–252. https://doi.org/10.1111/cid.12259
Nash TJ, Howlett CR, Martin C, Steele J, Johnson KA, Hicklin DJ (1994) Effect of platelet-derived growth factor on tibial osteotomies in rabbits. Bone 15(2):203–208. https://doi.org/10.1016/8756-3282(94)90709-9
Nevins M, Kao RT, McGuire MK, McClain PK, Hinrichs JE, McAllister BS et al (2013) Platelet-derived growth factor promotes periodontal regeneration in localized osseous defects: 36-month extension results from a randomized, controlled, double-masked clinical trial. J Periodontol 84(4):456–464. https://doi.org/10.1902/jop.2012.120141
Li DQ, Wan QL, Pathak JL, Li ZB (2017) Platelet-derived growth factor BB enhances osteoclast formation and osteoclast precursor cell chemotaxis. J Bone Miner Metab 35(4):355–365. https://doi.org/10.1007/s00774-016-0773-8
Marden LJ, Fan RS, Pierce GF, Reddi AH, Hollinger JO (1993) Platelet-derived growth factor inhibits bone regeneration induced by osteogenin, a bone morphogenetic protein, in rat craniotomy defects. J Clin Invest 92(6):2897–2905. https://doi.org/10.1172/JCI116912
Luvizuto ER, Tangl S, Dobsak T, Reich K, Gruber R, Sonoda CK, Okamoto R (2016) Effect of recombinant PDGF-BB on bone formation in the presence of beta-tricalcium phosphate and bovine bone mineral matrix: a pilot study in rat calvarial defects. BMC Oral Health 16(1):52. https://doi.org/10.1186/s12903-016-0210-3
Kumar A, Salimath BP, Stark GB, Finkenzeller G (2010) Platelet-derived growth factor receptor signaling is not involved in osteogenic differentiation of human mesenchymal stem cells. Tissue Eng Part A 16(3):983–993. https://doi.org/10.1089/ten.TEA.2009.0230
Yu X, Hsieh SC, Bao W, Graves DT (1997) Temporal expression of PDGF receptors and PDGF regulatory effects on osteoblastic cells in mineralizing cultures. Am J Physiol 272(5 Pt 1):C1709–C1716. https://doi.org/10.1152/ajpcell.1997.272.5.C1709
Tokunaga A, Oya T, Ishii Y, Motomura H, Nakamura C, Ishizawa S, Fujimori T, Nabeshima YI, Umezawa A, Kanamori M, Kimura T, Sasahara M (2008) PDGF receptor beta is a potent regulator of mesenchymal stromal cell function. J Bone Miner Res 23(9):1519–1528. https://doi.org/10.1359/jbmr.080409
Sanchez-Fernandez MA, Gallois A, Riedl T, Jurdic P, Hoflack B (2008) Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling. PLoS One 3(10):e3537. https://doi.org/10.1371/journal.pone.0003537
Huang Y, Yin Y, Gu Y, Gu Q, Yang H, Zhou Z, Shi Q (2020) Characterization and immunogenicity of bone marrow-derived mesenchymal stem cells under osteoporotic conditions. Sci China Life Sci 63(3):429–442. https://doi.org/10.1007/s11427-019-1555-9
Justesen J, Stenderup K, Eriksen EF, Kassem M (2002) Maintenance of osteoblastic and adipocytic differentiation potential with age and osteoporosis in human marrow stromal cell cultures. Calcif Tissue Int 71(1):36–44. https://doi.org/10.1007/s00223-001-2059-x
Kaipel M, Schutzenberger S, Schultz A, Ferguson J, Slezak P, Morton TJ et al (2012) BMP-2 but not VEGF or PDGF in fibrin matrix supports bone healing in a delayed-union rat model. J Orthop Res 30(10):1563–1569. https://doi.org/10.1002/jor.22132
Kang W, Liang Q, Du L, Shang L, Wang T, Ge S (2019) Sequential application of bFGF and BMP-2 facilitates osteogenic differentiation of human periodontal ligament stem cells. J Periodontal Res 54(4):424–434. https://doi.org/10.1111/jre.12644
Zara JN, Siu RK, Zhang X, Shen J, Ngo R, Lee M, Li W, Chiang M, Chung J, Kwak J, Wu BM, Ting K, Soo C (2011) High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo. Tissue Eng Part A 17(9-10):1389–1399. https://doi.org/10.1089/ten.TEA.2010.0555
Minier K, Toure A, Fusellier M, Fellah B, Bouvy B, Weiss P et al (2014) BMP-2 delivered from a self-crosslinkable CaP/hydrogel construct promotes bone regeneration in a critical-size segmental defect model of non-union in dogs. Vet Comp Orthop Traumatol 27(6):411–421. https://doi.org/10.3415/VCOT-14-03-0036
James AW, LaChaud G, Shen J, Asatrian G, Nguyen V, Zhang X, Ting K, Soo C (2016) A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng Part B Rev 22(4):284–297. https://doi.org/10.1089/ten.TEB.2015.0357
Acknowledgements
The authors appreciate Ms. Mi-Jung Kang’s remarkable technical help.
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. NRF-2020R1A2C1007536).
Author information
Authors and Affiliations
Contributions
Hyun Ju Kim and Kyoung-Hwa Kim contributed equally to this work. HJK carried out all animal experiments and radiographic analyses and drafted the manuscript. KHK participated in all animal experiments and carried out the histological and histomorphometric analyses, including tissue sample preparation. YML participated in the study design and helped revise the manuscript. YK advised on the data analysis and helped revise the manuscript. ICR participated in the study design and reviewed the manuscript. YJS conceived the study, designed the study protocol, and helped draft and revise the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethical approval
This study was performed in accordance with the guidelines of the Seoul National University Institutional Animal Care and Use Committee and Animal Research: Reporting In Vivo Experiments (ARRIVE). The experimental protocols were approved by the Institute of Laboratory Animal Resources, Seoul National University (SNU-180626-2). All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Informed consent
For this type of study, formal consent is not required.
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
ESM 1
(PDF 333 kb)
Rights and permissions
About this article
Cite this article
Kim, H.J., Kim, KH., Lee, YM. et al. In ovariectomy-induced osteoporotic rat models, BMP-2 substantially reversed an impaired alveolar bone regeneration whereas PDGF-BB failed. Clin Oral Invest 25, 6159–6170 (2021). https://doi.org/10.1007/s00784-021-03915-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00784-021-03915-7