A Mini Review: Stem Cell Therapy for Osteonecrosis of the Femoral Head and Pharmacological Aspects

Author(s): Ding Zhao, Yijun Liu, Chi Ma, Guishan Gu*, Dong-Feng Han*

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 10 , 2019


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Abstract:

Osteonecrosis of the femoral head (ONFH) is a common disease that occurs frequently. Due to various etiologies, the blood supply directed to the femoral head is interrupted in patients with ONFH. This disease can result in degeneration and necrosis of the subchondral bone of the femoral head, which ultimately cause a collapse of the femoral head. Of note, ONFH can extremely affect the quality of living of patients with a high disability rate. Also, this disease often includes middle-aged and younger people. However, effective treatments of ONFH are still challenging in clinics. In recent years, stem cells have been profoundly studied and a relevant new technology has been developed rapidly and applied for regenerative medicine. A number of reports have demonstrated successful results of the treatment of ONFH by using stem cell transplantation. By the combination of minimally invasive hip decompression and injection of mesenchymal stem cells into the necrotic lesion, the retrospective analysis of patients treated revealed that significant pain relief was observed in 86% patients and they had no major complications after treatment. Thus, stem cell transplantation is anticipated to be applied as an innovative approach in the treatment of ONFH. This review will summarize results obtained from recent human and animal studies, which include the pathophysiological process of ONFH, current techniques and effects of using stem cells on the treatment of ONFH together with pharmacological aspects. Overall, the current evidence reveals the treatment of ONFH using stem cell technology as promising. Nonetheless, additional in-depth studies are necessary to better explore the application of this technology and seek more ideal approaches to minimize difficulties related to stem cells.

Keywords: Stem cell therapy, osteonecrosis of the femoral head, signal pathway, molecular mediator, etiologies, subchondral bone.

[1]
Guerado E, Caso E. The physiopathology of avascular necrosis of the femoral head: an update. Injury 2016; 47(Suppl. 6): S16-26.
[http://dx.doi.org/10.1016/S0020-1383(16)30835-X] [PMID: 28040082]
[2]
Moya-Angeler J, Gianakos AL, Villa JC, Ni A, Lane JM. Current concepts on osteonecrosis of the femoral head. World J Orthop 2015; 6(8): 590-601.
[http://dx.doi.org/10.5312/wjo.v6.i8.590] [PMID: 26396935]
[3]
Mont MA, Jones LC, Hungerford DS. Nontraumatic osteonecrosis of the femoral head: ten years later. J Bone Joint Surg Am 2006; 88(5): 1117-32.
[PMID: 16651589]
[4]
Petrigliano FA, Lieberman JR. Osteonecrosis of the hip: novel approaches to evaluation and treatment. Clin Orthop Relat Res 2007; 465(465): 53-62.
[PMID: 17906590]
[5]
Cardozo JB, Andrade DM, Santiago MB. The use of bisphosphonate in the treatment of avascular necrosis: a systematic review. Clin Rheumatol 2008; 27(6): 685-8.
[http://dx.doi.org/10.1007/s10067-008-0861-9] [PMID: 18270760]
[6]
Marker DR, Seyler TM, McGrath MS, Delanois RE, Ulrich SD, Mont MA. Treatment of early stage osteonecrosis of the femoral head. J Bone Joint Surg Am 2008; 90(Suppl. 4): 175-87.
[http://dx.doi.org/10.2106/JBJS.H.00671] [PMID: 18984729]
[7]
Gangji V, Hauzeur JP. Cellular-based therapy for osteonecrosis. Orthop Clin North Am 2009; 40(2): 213-21.
[http://dx.doi.org/10.1016/j.ocl.2008.10.009] [PMID: 19358906]
[8]
Hernigou P, Trousselier M, Roubineau F, et al. Stem Cell Therapy for the Treatment of Hip Osteonecrosis: A 30-Year Review of Progress. Clin Orthop Surg 2016; 8(1): 1-8.
[http://dx.doi.org/10.4055/cios.2016.8.1.1] [PMID: 26929793]
[9]
Jeong J, Shin K, Lee SB, Lee DR, Kwon H. Patient-tailored application for Duchene muscular dystrophy on mdx mice based induced mesenchymal stem cells. Exp Mol Pathol 2014; 97(2): 253-8.
[http://dx.doi.org/10.1016/j.yexmp.2014.08.001] [PMID: 25102299]
[10]
Ulrich D, Muralitharan R, Gargett CE. Toward the use of endometrial and menstrual blood mesenchymal stem cells for cell-based therapies. Expert Opin Biol Ther 2013; 13(10): 1387-400.
[http://dx.doi.org/10.1517/14712598.2013.826187] [PMID: 23930703]
[11]
Alfaro MP, Young PP. Lessons from genetically altered mesenchymal stem cells (MSCs): candidates for improved MSC-directed myocardial repair. Cell Transplant 2012; 21(6): 1065-74.
[http://dx.doi.org/10.3727/096368911X612477] [PMID: 22080676]
[12]
Hansson M, Tonning A, Frandsen U, et al. Artifactual insulin release from differentiated embryonic stem cells. Diabetes 2004; 53(10): 2603-9.
[http://dx.doi.org/10.2337/diabetes.53.10.2603] [PMID: 15448090]
[13]
Holtick U, Albrecht M, Chemnitz JM, et al. Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev 2014; (4): CD010189.
[http://dx.doi.org/10.1002/14651858.CD010189.pub2] [PMID: 24748537]
[14]
Pandur P, Maurus D, Kühl M. Increasingly complex: new players enter the Wnt signaling network. BioEssays 2002; 24(10): 881-4.
[http://dx.doi.org/10.1002/bies.10164] [PMID: 12325120]
[15]
Cook DA, Fellgett SW, Pownall ME, O’Shea PJ, Genever PG. Wnt-dependent osteogenic commitment of bone marrow stromal cells using a novel GSK3β inhibitor. Stem Cell Res (Amst) 2014; 12(2): 415-27.
[http://dx.doi.org/10.1016/j.scr.2013.10.002] [PMID: 24382458]
[16]
Colaianni G, Brunetti G, Faienza MF, Colucci S, Grano M. Osteoporosis and obesity: Role of Wnt pathway in human and murine models. World J Orthop 2014; 5(3): 242-6.
[http://dx.doi.org/10.5312/wjo.v5.i3.242] [PMID: 25035826]
[17]
Macsai CE, Foster BK, Xian CJ. Roles of Wnt signalling in bone growth, remodelling, skeletal disorders and fracture repair. J Cell Physiol 2008; 215(3): 578-87.
[http://dx.doi.org/10.1002/jcp.21342] [PMID: 18247365]
[18]
Ross SE, Hemati N, Longo KA, et al. Inhibition of adipogenesis by Wnt signaling. Science 2000; 289(5481): 950-3.
[http://dx.doi.org/10.1126/science.289.5481.950] [PMID: 10937998]
[19]
Evans CH, Huard J. Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol 2015; 11(4): 234-42.
[http://dx.doi.org/10.1038/nrrheum.2015.28] [PMID: 25776949]
[20]
Kuh SU, Zhu Y, Li J, et al. Can TGF-beta1 and rhBMP-2 act in synergy to transform bone marrow stem cells to discogenic-type cells? Acta Neurochir (Wien) 2008; 150(10): 1073-9.
[http://dx.doi.org/10.1007/s00701-008-0029-z] [PMID: 18781274]
[21]
Wilson CG, Martín-Saavedra FM, Vilaboa N, Franceschi RT. Advanced BMP gene therapies for temporal and spatial control of bone regeneration. J Dent Res 2013; 92(5): 409-17.
[http://dx.doi.org/10.1177/0022034513483771] [PMID: 23539558]
[22]
Herberg S, Susin C, Pelaez M, et al. Low-dose bone morphogenetic protein-2/stromal cell-derived factor-1β cotherapy induces bone regeneration in critical-size rat calvarial defects. Tissue Eng Part A 2014; 20(9-10): 1444-53.
[http://dx.doi.org/10.1089/ten.tea.2013.0442] [PMID: 24341891]
[23]
La WG, Jin M, Park S, et al. Delivery of bone morphogenetic protein-2 and substance P using graphene oxide for bone regeneration. Int J Nanomedicine 2014; 9(Suppl. 1): 107-16.
[PMID: 24872706]
[24]
White AP, Vaccaro AR, Hall JA, Whang PG, Friel BC, McKee MD. Clinical applications of BMP-7/OP-1 in fractures, nonunions and spinal fusion. Int Orthop 2007; 31(6): 735-41.
[http://dx.doi.org/10.1007/s00264-007-0422-x] [PMID: 17962946]
[25]
Hanada K, Solchaga LA, Caplan AI, et al. BMP-2 induction and TGF-beta 1 modulation of rat periosteal cell chondrogenesis. J Cell Biochem 2001; 81(2): 284-94.
[http://dx.doi.org/10.1002/1097-4644(20010501)81:2<284:AID-JCB1043>3.0.CO;2-D] [PMID: 11241668]
[26]
Mundy C, Gannon M, Popoff SN. Connective tissue growth factor (CTGF/CCN2) negatively regulates BMP-2 induced osteoblast differentiation and signaling. J Cell Physiol 2014; 229(5): 672-81.
[http://dx.doi.org/10.1002/jcp.24491] [PMID: 24127409]
[27]
Wang Y, Chen S, Deng C, et al. MicroRNA-204 Targets Runx2 to Attenuate BMP-2-induced Osteoblast Differentiation of Human Aortic Valve Interstitial Cells. J Cardiovasc Pharmacol 2015; 66(1): 63-71.
[http://dx.doi.org/10.1097/FJC.0000000000000244] [PMID: 25806689]
[28]
Rahman MS, Akhtar N, Jamil HM, Banik RS, Asaduzzaman SM. TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res 2015; 3: 15005.
[http://dx.doi.org/10.1038/boneres.2015.5] [PMID: 26273537]
[29]
Wang L, Park P, La Marca F, Than KD, Lin CY. BMP-2 inhibits tumor-initiating ability in human renal cancer stem cells and induces bone formation. J Cancer Res Clin Oncol 2015; 141(6): 1013-24.
[http://dx.doi.org/10.1007/s00432-014-1883-0] [PMID: 25431339]
[30]
Mizrahi O, Sheyn D, Tawackoli W, et al. BMP-6 is more efficient in bone formation than BMP-2 when overexpressed in mesenchymal stem cells. Gene Ther 2013; 20(4): 370-7.
[http://dx.doi.org/10.1038/gt.2012.45] [PMID: 22717741]
[31]
Simic P, Culej JB, Orlic I, et al. Systemically administered bone morphogenetic protein-6 restores bone in aged ovariectomized rats by increasing bone formation and suppressing bone resorption. J Biol Chem 2006; 281(35): 25509-21.
[http://dx.doi.org/10.1074/jbc.M513276200] [PMID: 16798745]
[32]
Street J, Bao M, deGuzman L, et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA 2002; 99(15): 9656-61.
[http://dx.doi.org/10.1073/pnas.152324099] [PMID: 12118119]
[33]
Ferrara N. VEGF-A: a critical regulator of blood vessel growth. Eur Cytokine Netw 2009; 20(4): 158-63.
[PMID: 20167554]
[34]
Moens S, Goveia J, Stapor PC, Cantelmo AR, Carmeliet P. The multifaceted activity of VEGF in angiogenesis - Implications for therapy responses. Cytokine Growth Factor Rev 2014; 25(4): 473-82.
[http://dx.doi.org/10.1016/j.cytogfr.2014.07.009] [PMID: 25169850]
[35]
Joensuu K, Uusitalo L, Alm JJ, Aro HT, Hentunen TA, Heino TJ. Enhanced osteoblastic differentiation and bone formation in co-culture of human bone marrow mesenchymal stromal cells and peripheral blood mononuclear cells with exogenous VEGF. Orthop Traumatol Surg Res 2015; 101(3): 381-6.
[http://dx.doi.org/10.1016/j.otsr.2015.01.014] [PMID: 25813558]
[36]
Ramazanoglu M, Lutz R, Rusche P, et al. Bone response to biomimetic implants delivering BMP-2 and VEGF: an immunohistochemical study. J Craniomaxillofac Surg 2013; 41(8): 826-35.
[http://dx.doi.org/10.1016/j.jcms.2013.01.037] [PMID: 23434516]
[37]
Zhang W, Zhu C, Wu Y, et al. VEGF and BMP-2 promote bone regeneration by facilitating bone marrow stem cell homing and differentiation. Eur Cell Mater 2014; 27: 1-11.
[http://dx.doi.org/10.22203/eCM.v027a01] [PMID: 24425156]
[38]
Kempen DH, Lu L, Heijink A, et al. Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. Biomaterials 2009; 30(14): 2816-25.
[http://dx.doi.org/10.1016/j.biomaterials.2009.01.031] [PMID: 19232714]
[39]
Peng H, Usas A, Olshanski A, et al. VEGF improves, whereas sFlt1 inhibits, BMP2-induced bone formation and bone healing through modulation of angiogenesis. J Bone Miner Res 2005; 20(11): 2017-27.
[http://dx.doi.org/10.1359/JBMR.050708] [PMID: 16234975]
[40]
Chen YX, Tao SC, Xu ZL, et al. Novel Akt activator SC-79 is a potential treatment for alcohol-induced osteonecrosis of the femoral head. Oncotarget 2017; 8(19): 31065-78.
[http://dx.doi.org/10.18632/oncotarget.16075] [PMID: 28415692]
[41]
Chen YX, Zhu DY, Xu ZL, et al. The Protective Effect of Cordycepin On Alcohol-Induced Osteonecrosis of the Femoral Head. Cell Physiol Biochem 2017; 42(6): 2391-403.
[http://dx.doi.org/10.1159/000480181] [PMID: 28848161]
[42]
Peng WX, Wang L. Adenovirus-Mediated Expression of BMP-2 and BFGF in Bone Marrow Mesenchymal Stem Cells Combined with Demineralized Bone Matrix For Repair of Femoral Head Osteonecrosis in Beagle Dogs. Cell Physiol Biochem 2017; 43(4): 1648-62.
[http://dx.doi.org/10.1159/000484026] [PMID: 29045937]
[43]
Han N, Li Z, Cai Z, Yan Z, Hua Y, Xu C. P-glycoprotein overexpression in bone marrow-derived multipotent stromal cells decreases the risk of steroid-induced osteonecrosis in the femoral head. J Cell Mol Med 2016; 20(11): 2173-82.
[http://dx.doi.org/10.1111/jcmm.12917] [PMID: 27396977]
[44]
Hang D, Wang Q, Guo C, Chen Z, Yan Z. Treatment of osteonecrosis of the femoral head with VEGF165 transgenic bone marrow mesenchymal stem cells in mongrel dogs. Cells Tissues Organs (Print) 2012; 195(6): 495-506.
[http://dx.doi.org/10.1159/000329502] [PMID: 22056983]
[45]
Zhang YL, Yin JH, Ding H, Zhang W, Zhang CQ, Gao YS. Vitamin K2 Prevents Glucocorticoid-induced Osteonecrosis of the Femoral Head in Rats. Int J Biol Sci 2016; 12(4): 347-58.
[http://dx.doi.org/10.7150/ijbs.13269] [PMID: 27019620]
[46]
Liu H, Liu H, Deng X, et al. CXCR4 antagonist delivery on decellularized skin scaffold facilitates impaired wound healing in diabetic mice by increasing expression of SDF-1 and enhancing migration of CXCR4-positive cells. Wound Repair Regen 2017; 25(4): 652-64.
[http://dx.doi.org/10.1111/wrr.12552] [PMID: 28783870]
[47]
Shafiq M, Kong D, Kim SH. SDF-1α peptide tethered polyester facilitates tissue repair by endogenous cell mobilization and recruitment. J Biomed Mater Res A 2017; 105(10): 2670-84.
[http://dx.doi.org/10.1002/jbm.a.36130] [PMID: 28571106]
[48]
Zhou W, Guo S, Liu M, Burow ME, Wang G. Targeting CXCL12/CXCR4 Axis in Tumor Immunotherapy. Curr Med Chem 2017.
[http://dx.doi.org/10.2174/0929867324666170830111531] [PMID: 28875842]
[49]
Kortesidis A, Zannettino A, Isenmann S, Shi S, Lapidot T, Gronthos S. Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood 2005; 105(10): 3793-801.
[http://dx.doi.org/10.1182/blood-2004-11-4349] [PMID: 15677562]
[50]
Tang CH, Chuang JY, Fong YC, Maa MC, Way TD, Hung CH. Bone-derived SDF-1 stimulates IL-6 release via CXCR4, ERK and NF-kappaB pathways and promotes osteoclastogenesis in human oral cancer cells. Carcinogenesis 2008; 29(8): 1483-92.
[http://dx.doi.org/10.1093/carcin/bgn045] [PMID: 18310089]
[51]
Toupadakis CA, Wong A, Genetos DC, et al. Long-term administration of AMD3100, an antagonist of SDF-1/CXCR4 signaling, alters fracture repair. J Orthop Res 2012; 30(11): 1853-9.
[http://dx.doi.org/10.1002/jor.22145] [PMID: 22592891]
[52]
Zhu W, Liang G, Huang Z, Doty SB, Boskey AL. Conditional inactivation of the CXCR4 receptor in osteoprecursors reduces postnatal bone formation due to impaired osteoblast development. J Biol Chem 2011; 286(30): 26794-805.
[http://dx.doi.org/10.1074/jbc.M111.250985] [PMID: 21636574]
[53]
Jones GN, Moschidou D, Lay K, et al. Upregulating CXCR4 in human fetal mesenchymal stem cells enhances engraftment and bone mechanics in a mouse model of osteogenesis imperfecta. Stem Cells Transl Med 2012; 1(1): 70-8.
[http://dx.doi.org/10.5966/sctm.2011-0007] [PMID: 23197643]
[54]
Liu C, Weng Y, Yuan T, et al. CXCL12/CXCR4 signal axis plays an important role in mediating bone morphogenetic protein 9-induced osteogenic differentiation of mesenchymal stem cells. Int J Med Sci 2013; 10(9): 1181-92.
[http://dx.doi.org/10.7150/ijms.6657] [PMID: 23935395]
[55]
Walenkamp AME, Lapa C, Herrmann K, Wester HJ. CXCR4 Ligands: The Next Big Hit? J Nucl Med 2017; 58(Suppl. 2): 77S-82S.
[http://dx.doi.org/10.2967/jnumed.116.186874] [PMID: 28864616]
[56]
Wang F, Schmidt H, Pavleska D, Wermann T, Seekamp A, Fuchs S. Crude Fucoidan Extracts Impair Angiogenesis in Models Relevant for Bone Regeneration and Osteosarcoma via Reduction of VEGF and SDF-1. Mar Drugs 2017; 15(6): 15.
[http://dx.doi.org/10.3390/md15060186] [PMID: 28632184]
[57]
Qin G, Chen Y, Li H, et al. Melittin inhibits tumor angiogenesis modulated by endothelial progenitor cells associated with the SDF-1α/CXCR4 signaling pathway in a UMR-106 osteosarcoma xenograft mouse model. Mol Med Rep 2016; 14(1): 57-68.
[http://dx.doi.org/10.3892/mmr.2016.5215] [PMID: 27177128]
[58]
Perrucci GL, Straino S, Corlianò M, et al. Cyclophilin A modulates bone marrow-derived CD117(+) cells and enhances ischemia-induced angiogenesis via the SDF-1/CXCR4 axis. Int J Cardiol 2016; 212: 324-35.
[http://dx.doi.org/10.1016/j.ijcard.2016.03.082] [PMID: 27057951]
[59]
Jia YB, Jiang DM, Ren YZ, Liang ZH, Zhao ZQ, Wang YX. Inhibitory effects of vitamin E on osteocyte apoptosis and DNA oxidative damage in bone marrow hemopoietic cells at early stage of steroid-induced femoral head necrosis. Mol Med Rep 2017; 15(4): 1585-92.
[http://dx.doi.org/10.3892/mmr.2017.6160] [PMID: 28259972]
[60]
Qi X, Zhang J, Yuan H, et al. Exosomes Secreted by Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Repair Critical-Sized Bone Defects through Enhanced Angiogenesis and Osteogenesis in Osteoporotic Rats. Int J Biol Sci 2016; 12(7): 836-49.
[http://dx.doi.org/10.7150/ijbs.14809] [PMID: 27313497]
[61]
Hernigou P, Beaujean F. Treatment of osteonecrosis with autologous bone marrow grafting. Clin Orthop Relat Res 2002; (405): 14-23.
[http://dx.doi.org/10.1097/00003086-200212000-00003] [PMID: 12461352]
[62]
Hernigou P, Poignard A, Zilber S, Rouard H. Cell therapy of hip osteonecrosis with autologous bone marrow grafting. Indian J Orthop 2009; 43(1): 40-5.
[http://dx.doi.org/10.4103/0019-5413.45322] [PMID: 19753178]
[63]
Martin JR, Houdek MT, Sierra RJ. Use of concentrated bone marrow aspirate and platelet rich plasma during minimally invasive decompression of the femoral head in the treatment of osteonecrosis. Croat Med J 2013; 54(3): 219-24.
[http://dx.doi.org/10.3325/cmj.2013.54.219] [PMID: 23771751]
[64]
Sen RK, Tripathy SK, Aggarwal S, Marwaha N, Sharma RR, Khandelwal N. Early results of core decompression and autologous bone marrow mononuclear cells instillation in femoral head osteonecrosis: a randomized control study. J Arthroplasty 2012; 27(5): 679-86.
[http://dx.doi.org/10.1016/j.arth.2011.08.008] [PMID: 22000577]
[65]
Potier E, Ferreira E, Andriamanalijaona R, et al. Hypoxia affects mesenchymal stromal cell osteogenic differentiation and angiogenic factor expression. Bone 2007; 40(4): 1078-87.
[http://dx.doi.org/10.1016/j.bone.2006.11.024] [PMID: 17276151]
[66]
Gangji V, De Maertelaer V, Hauzeur JP. Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: Five year follow-up of a prospective controlled study. Bone 2011; 49(5): 1005-9.
[http://dx.doi.org/10.1016/j.bone.2011.07.032] [PMID: 21821156]
[67]
Yan Z, Hang D, Guo C, Chen Z. Fate of mesenchymal stem cells transplanted to osteonecrosis of femoral head. J Orthop Res 2009; 27(4): 442-6.
[http://dx.doi.org/10.1002/jor.20759] [PMID: 18925660]


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VOLUME: 25
ISSUE: 10
Year: 2019
Published on: 04 August, 2019
Page: [1099 - 1104]
Pages: 6
DOI: 10.2174/1381612825666190527092948
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