Intraarticular injection of bone marrow-derived mesenchymal stem cells enhances regeneration in knee osteoarthritis

Emily Claire Doyle, Nicholas Martin Wragg, Samantha Louise Wilson, Emily Claire Doyle, Nicholas Martin Wragg, Samantha Louise Wilson

Abstract

Purpose: This review aimed to evaluate the efficacy of intra-articular injections of bone marrow derived mesenchymal stem cells (BM-MSCs) for the treatment of knee osteoarthritis (KOA).

Methods: This narrative review evaluates recent English language clinical data and published research articles between 2014 and 2019. Key word search strings of ((("bone marrow-derived mesenchymal stem cell" OR "bone marrow mesenchymal stromal cell" OR "bone marrow stromal cell")) AND ("osteoarthritis" OR "knee osteoarthritis")) AND ("human" OR "clinical"))) AND "intra-articular injection" were used to identify relevant articles using PMC, Cochrane Library, Web Of Science and Scopus databases.

Results: Pre-clinical studies have demonstrated successful, safe and encouraging results for articular cartilage repair and regeneration. This is concluded to be due to the multilineage differential potential, immunosuppressive and self-renewal capabilities of BM-MSCs, which have shown to augment pain and improve functional outcomes. Subsequently, clinical applications of intra-articular injections of BM-MSCs are steadily increasing, with most studies demonstrating a decrease in poor cartilage index, improvements in pain, function and Quality of Life (QoL); with moderate-to-high level evidence regarding safety for therapeutic administration. However, low confidence in clinical efficacy remains due to a plethora of heterogenous methodologies utilised, resulting in challenging study comparisons. A moderate number of cells (40 × 106) were identified as most likely to achieve optimal responses in individuals with grade ≥ 2 KOA. Likewise, significant improvements were reported when using lower (24 × 106) and higher (100 × 106) cell numbers, although adverse effects including persistent pain and swelling were a consequence.

Conclusion: Overall, the benefits of intra-articular injections of BM-MSCs were deemed to outweigh the adverse effects; thus, this treatment be considered as a future therapy strategy. To realise this, long-term large-scale randomised clinical trials are required to enable improved interpretations, to determine the validity of efficacy in future studies.

Level of evidence: IV.

Keywords: Allogenic; Autologous; Cell therapies; Clinical efficacy; Immunomodulation; Mesenchymal stem cells; Optimal dosage; Osteoarthritis.

Conflict of interest statement

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript. There is no funding to report related to the production of this manuscript.

Figures

Fig. 1
Fig. 1
The function of MSCs play a significant role in the repair and regeneration process and are identified in this diagram. These include the reduction of cell death to continually replace lost cells, the secretion of trophic factors which stabilise the extracellular matrix and the suppression of immune cell activation to prevent inflammation. Adapted from: BioExplorer.net [63]
Fig. 2
Fig. 2
PRISMA flowchart of study selection criteria

References

    1. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1323–1330.
    1. Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015;386(9995):743–800.
    1. Antony B, Jones G, Jin X, Ding C. Do early life factors affect the development of knee osteoarthritis in later life: a narrative review. Arthritis Res Ther. 2016;18(1):1–40.
    1. Kiadaliri AA, Lamm CJ, de Verdier MG, Engström G, Turkiewicz A, Lohmander LS, et al. Association of knee pain and different definitions of knee osteoarthritis with health-related quality of life: a population-based cohort study in southern Sweden. Health Qual Life Outcomes. 2016;14(1):1–7.
    1. Murphy L, Schwartz TA, Helmick CG, Renner JB, Tudor G, Koch G, et al. Lifetime risk of symptomatic knee osteoarthritis. Arthritis Care Res. 2008;59(9):1207–1213.
    1. Araujo I, Castro M, Daltro C, Matos M. Quality of life and functional independence in patients with osteoarthritis of the knee. Knee Surg Relat Res. 2016;28(3):219–224.
    1. Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthr Cartil. 2010;18(1):24–33. doi: 10.1016/j.joca.2009.08.010.
    1. Driban J, McAlindon T, Amin M, Price L, Eaton C, Davis J, et al. Risk factors can classify individuals who develop accelerated knee osteoarthritis: data from the osteoarthritis initiative. J Orthop Res. 2018;36(3):876–880.
    1. Silverwood V, Blagojevic-Bucknall M, Jinks C, Jordan JL, Protheroe J, Jordan KP. Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Osteoarthr Cartil. 2015;23(4):507–515.
    1. Ashkavand Z, Malekinejad H, Vishwanath B. The pathophysiology of osteoarthritis. J Pharm Res. 2013;7(1):132–138.
    1. Xing D, Wang B, Zhang W, Yang Z, Hou Y, Chen Y, et al. Intra-articular platelet-rich plasma injections for knee osteoarthritis: An overview of systematic reviews and risk of bias considerations. Int J Rheum Dis. 2017;20(11):1612–1630.
    1. Petecchia L, Viti F, Sbrana F, Vassalli M, Gavazzo P. A biophysical approach to quantify skeletal stem cells trans-differentiation as a model for the study of osteoporosis. Biophys Chem. 2017;229:84–92.
    1. Glyn-Jones S, Palmer AJR, Agricola R, Price AJ, Vincent TL, Weinans H, et al. Osteoarthritis. Lancet. 2015;386(9991):376–387.
    1. Tummala S, Bay-Jensen A-C, Karsdal MA, Dam EB. Diagnosis of osteoarthritis by cartilage surface smoothness quantified automatically from knee MRI. Cartilage. 2011;2(1):50–59.
    1. Guermazi A, Hayashi D, Roemer F, Felson DT, Wang K, Lynch J, et al. Severe radiographic knee osteoarthritis—does Kellgren and Lawrence grade 4 represent end stage disease?—the MOST study. Osteoarthr Cartil. 2015;23(9):1499–1505.
    1. McAlindon TE, LaValley MP, Harvey WF, Price LL, Driban JB, Zhang M, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis. JAMA. 2017;317(19):1967–1975.
    1. Rillo O, Riera H, Acosta C, Liendo V, Bolaños J, Monterola L, et al. PANLAR consensus recommendations for the management in osteoarthritis of hand, hip, and knee. JCR J Clin Rheumatol. 2016;22(7):345–354.
    1. Wise J. Steroid injections for knee osteoarthritis are not supported by study. BMJ. 2017;357:1–1.
    1. Shariatzadeh M, Song J, Wilson SL. The efficacy of different sources of mesenchymal stem cells for the treatment of knee osteoarthritis. Cell Tissue Res. 2019;378(3):339–410.
    1. O’Connell B, Wragg NM, Wilson SL. The use of PRP injections in the management of knee osteoarthritis. Cell Tissue Res. 2019;376(2):143–152.
    1. Chen F, Tuan R. Mesenchymal stem cells in arthritic diseases. Arthritis Res Ther. 2008;10(5):1–12.
    1. Chul-won D, Yong-beom Park M, Seong H, Kim H, Han-jun Lee D. Intra-articular mesenchymal stem cells in osteoarthritis of the knee: a systematic review of clinical outcomes and evidence of cartilage repair. Arthrosc J Arthrosc Relat Surg. 2019;35(1):277–288.
    1. Pastides P, Chimutengwende-Gordon M, Maffulli N, Khan W. Stem cell therapy for human cartilage defects: a systematic review. Osteoarthr Cartil. 2013;21(5):646–654.
    1. Ullah I, Subbarao R, Rho G. Human mesenchymal stem cells—current trends and future prospective. Biosci Rep. 2015;35(2):1–1962.
    1. Leuning DG, Beijer NRM, Du Fossé NA, Vermeulen S, Lievers E, Van Kooten C, et al. The cytokine secretion profile of mesenchymal stromal cells is determined by surface structure of the microenvironment. Sci Rep. 2018;8:1–26.
    1. Li H, Shen S, Fu H, Wang Z, Li X, Sui X, et al. Immunomodulatory functions of mesenchymal stem cells in tissue engineering. Stem Cells Int. 2019;2019:1–18.
    1. Chiang E-R, Ma H-L, Wang J-P, Liu C-L, Chen T-H, Hung S-C. Allogeneic mesenchymal stem cells in combination with hyaluronic acid for the treatment of osteoarthritis in rabbits. PLoS ONE. 2016;11(e0149835):1–15.
    1. Diekman B, Wu C-L, Louer C, Furman B, Huebner J, Kraus V, et al. Intra-articular delivery of purified mesenchymal stem cells from C57BL/6 or MRL/MpJ superhealer mice prevents posttraumatic arthritis. Cell Transplant. 2013;22(8):1395–1408.
    1. Al Faqeh H, Nor Hamdan BMY, Chen HC, Aminuddin BS, Ruszymah BHI. The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol. 2012;47(6):458–464.
    1. Gupta PK, Chullikana A, Rengasamy M, Shetty N, Pandey V, Agarwal V, et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther. 2016;18(1):1–18.
    1. Lee KBL, Hui JHP, Song IC, Ardany L, Lee EH. Injectable mesenchymal stem cell therapy for large cartilage defects—a porcine model. Stem Cells. 2007;25(11):2964–2971.
    1. Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheumatol. 2003;48(12):3464–3474.
    1. Suhaeb A, Naveen S, Mansor A, Kamarul T. Hyaluronic acid with or without bone marrow derived-mesenchymal stem cells imrpoves osteoarthritic knee changes in rat model: a preliminary report. Indian J Exp Biol. 2012;50(6):383–390.
    1. Al-Najar M, Khalil H, Al-Ajlouni J, Al-Antary E, Hamdan M, Rahmeh R, et al. Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study. J Orthop Surg Res. 2017;12(190):1–6.
    1. Centeno C, Busse D, Kisiday J, Keohan C, Freeman M. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells, platelet lysate and dexamethasone. Am J Case Rep. 2008;11(3):343–353.
    1. Davatchi F, Abdollahi BS, Mohyeddin M, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis. 2011;14(12):211–215.
    1. Davatchi F, Sadeghi Abdollahi B, Mohyeddin M, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int J Rheum Dis. 2016;19(3):219–225.
    1. Emadedin M, Aghdami N, Taghiyar L, Fazeli R, Moghadasali R, Jahangir S, et al. Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch Iran Med. 2012;15(7):422–428.
    1. Emadedin M, Hhorbani L, Fazeli R, Mohseni F, Moghadasali R, Mardpour S. Long-term follow-up of intra-articular injection of autologous mesenchymal stem cells in patients with knee, ankle, or hip osteoarthritis. Arch Iran Med. 2015;18(6):336–344.
    1. Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, et al. Treatment of knee osteoarthritis with autologous mesenchymal stem cells. Transplant J. 2013;95(12):1535–1541.
    1. Rich S, Munar A, Soler R, Peirau X, Huguet M, Alberca M, et al. Stem cell research and therapy treatment of knee osteoarthritis with autologous expanded bone marrow mesenchymal stem cells : 50 cases clinical and MRI results at one year follow-up. J Stem Cell Res Ther. 2015;95(12):1535–1541.
    1. Soler R, Orozco L, Munar A, Huguet M, López R, Vives J, et al. Final results of a phase I–II trial using ex vivo expanded autologous mesenchymal stromal cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration. Knee. 2016;23(4):647–654.
    1. Vangsness T, Farr J, Boyd J, Dellaero D, Mills R, LeRoux-Williams M. Adult human mesenchymal stem cells delivered via intra-articular injection of the knee following partial medial meniscectomy. J Bone Jt Surg. 2014;96(2):90–98.
    1. Vega A, Martín-Ferrero MA, Del Canto F, Alberca M, García V, Munar A, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells. Transplantation. 2015;99(8):1681–1690.
    1. Chahla J, Piuzzi NS, Mitchell JJ, Dean CS, Pascual-Garrido C, LaPrade RF, et al. Intra-articular cellular therapy for osteoarthritis and focal cartilage defects of the knee. J Bone Jt Surg. 2016;98(18):1511–1521.
    1. Cui G-H, Wang YY, Li C-J, Shi C-H, Wang W-S. Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: a meta-analysis. Exp Ther Med. 2016;12(5):3390–3400.
    1. Pas H, Winters M, Haisma H, Koenis M, Tol J, Moen M. Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br J Sports Med. 2017;51(15):1125–1133.
    1. Bolarinwa O. Principles and methods of validity and reliability testing of questionnaires used in social and health science researches. Niger Postgrad Med J. 2015;22(4):195–201.
    1. Lamo-Espinosa JM, Mora G, Blanco JF, Granero-Moltó F, Núñez-Córdoba JM, López-Elío S, et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II) J Transl Med BioMed Cent. 2016;16(1):1–9.
    1. Lopa S, Colombini A, Moretti M, de Girolamo L. Injective mesenchymal stem cell-based treatments for knee osteoarthritis: from mechanisms of action to current clinical evidences. Knee Surg Sport Tr A. 2019;27(6):2003–2020.
    1. Iijima H, Isho T, Kuroki H, Takahashi M, Aoyama T. Effectiveness of mesenchymal stem cells for treating patients with knee osteoarthritis: a meta-analysis toward the establishment of effective regenerative rehabilitation. NPJ Regen Med. 2018;3:1–15.
    1. Bosnakovski D, Mizuno M, Kim G, Takagi S, Okumura M, Fujinaga T. Chondrogenic differentiation of bovine bone marrow mesenchymal stem cells (MSCs) in different hydrogels: Influence of collagen type II extracellular matrix on MSC chondrogenesis. Biotechnol Bioeng. 2006;93(6):1152–1163.
    1. Gluud L. Bias in clinical intervention research. Am J Epidemiol. 2006;163(6):493–501.
    1. Ganguly P, El-Jawhari JJ, Giannoudis PV, Burska AN, Ponchel F, Jones EA. Age-related changes in bone marrow mesenchymal stromal cells. Cell Transplant. 2017;26(9):1520–1529.
    1. Lamo-Espinosa JM, Mora G, Blanco JF, Granero-Moltó F, Núñez-Córdoba JM, López-Elío S, et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II) J Transl Med. 2018;16(1):1–9.
    1. Bornes TD, Adesida AB, Jomha NM. Mesenchymal stem cells in the treatment of traumatic articular cartilage defects: a comprehensive review. Arthritis Res Ther. 2014;16(5):1–62.
    1. Brittberg M, Gomoll AH, Canseco JA, Far J, Lind M, Hui J. Cartilage repair in the degenerative ageing knee. Acta Orthop. 2016;87(sup 363):26–38.
    1. Sato M, Uchida K, Nakajima H, Miyazaki T, Guerrero A, Watanabe S, et al. Direct transplantation of mesenchymal stem cells into the knee joints of hartley strain guinea pigs with spontaneous osteoarthritis. Arthritis Res Ther. 2012;14(1):1–9.
    1. Shin Y, Yoon J, Kim H. Intra-articular injection of bone marrow-derived mesenchymal stem cells leading to better clinical outcomes without difference in MRI outcomes from baseline in patients with knee osteoarthritis. Knee Surg Relat Res. 2018;30(3):206–214.
    1. Glenn JD. Mesenchymal stem cells: emerging mechanisms of immunomodulation and therapy. World J Stem Cells. 2014;6(5):526–539.
    1. Shah K, Zhao A, Sumer H. New approaches to treat osteoarthritis with mesenchymal stem cells. Stem Cells Int. 2018;2018:1–9.
    1. De Bari C, Roelofs A. Stem cell-based therapeutic strategies for cartilage defects and osteoarthritis. Curr Opin Pharmacol. 2018;40:74–80.
    1. (2016) Mesenchymal stem cells (MSCs): overview, properties, functions and therapies.
    1. Adatia A, Rainsford K, Kean W. Osteoarthritis of the knee and hip. Part I: aetiology and pathogenesis as a basis for pharmacotherapy. J Pharm Pharmacol. 2012;64(5):617–625.
    1. Palmer K. Occupational activities and osteoarthritis of the knee. Br Med Bull. 2012;102:147–170.
    1. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317.
    1. Mehrabani D, Jaberi FM, Zakerinia M. The healing effect of bone marrow-derived stem cells in knee osteoarthritis: a case report. World J Plast Surg. 2016;5(2):168–174.

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