Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: A meta‑analysis

  • Authors:
    • Gang‑Hua Cui
    • Yang Yang Wang
    • Chang‑Jun Li
    • Chen‑Hui Shi
    • Wei‑Shan Wang
  • View Affiliations

  • Published online on: October 11, 2016     https://doi.org/10.3892/etm.2016.3791
  • Pages: 3390-3400
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Abstract

To assess the clinical efficacy and safety of mesenchymal stem cell (MSC) treatment for osteoarthritis of the knee (KOA), a systematic electronic literature search was performed on PubMed, EMBASE and Web of Science. Studies published in English from the earliest record to December 2014 were searched using the following keywords: Cartilage defect, cartilage repair, osteoarthritis, KOA, stem cells, MSCs, bone marrow concentrate (BMC), adipose‑derived mesenchymal stem cells, synovial‑derived mesenchymal stem cells and peripheral blood‑derived mesenchymal stem cells. The effect sizes of selected studies were determined by extracting pain scores from the visual analog scale and functional changes from International Knee Documentation Committee and Lysholm and Western Ontario and McMaster Universities Osteoarthritis Index before and after MSCs or reference treatments at 3, 6, 12, and 24 months. The factors were analyzed and the outcomes were modified after comparing the MSC group pooled values with the pretreatment baseline or between different treatment arms. A systematic search identified 18 clinical trials on this topic, including 10 single‑arm prospective studies, four quasi‑experimental studies and four randomized controlled trials that used BMCs to treat 565 patients with KOA in total. MSC treatment in patients with KOA showed continual efficacy for 24 months compared with their pretreatment condition. Effectiveness of MSCs was improved at 12 and 24 months post‑treatment, compared with at 3 and 6 months. No dose‑responsive association in the MSCs numbers was demonstrated. However, patients with arthroscopic debridement, activation agent or lower degrees of Kellgren‑Lawrence grade achieved improved outcomes. MSC application ameliorated the overall outcomes of patients with KOA, including pain relief and functional improvement from basal evaluations, particularly at 12 and 24 months after follow‑up.

Introduction

Osteoarthritis (OA) is a chronic, progressive and degenerative joint disease, involving single or multiple joints. OA of the knee (KOA) is the most common disabling disease, characterized by the degeneration and degradation of cartilage, subchondral bone remodeling, osteophyte formation and synovial inflammation, which affects the patient's quality of life and constitutes a heavy financial burden (13). With the exception of oral and intra-article injection medications that relieve the symptoms and improve joint function, there is no approved medical treatment that halts disease progression and joint destruction (1,4).

Various surgical methods, including microfracture (5,6) and subchondral drilling (7), have been proposed to regenerate articular cartilage. However, due to the complications and inferior quality of the regenerative fibrocartilage, risky and cost-effective joint replacement surgery is often ultimately required (8). Previous studies have investigated tissue engineering and cellular therapies for treating early stage OA, and autologous chondrocyte implantation has demonstrated positive clinical outcomes (9,10). Nevertheless, due to the poor self-renewal and regeneration potential of chondrocytes, it is a slow process that may lead to fibrocartilage rather than hyaline cartilage (11,12). Furthermore, this two-stage surgical procedure and is predominantly used to treat cartilage defects caused by injury rather than OA.

Therefore, research attention in this field has shifted to the more promising treatment of mesenchymal stem cells (MSCs). MSCs, which can be derived from blood, bone marrow, skeletal muscle, adipose, skin and synovial membrane (13), have the capacity to differentiate into osteocytes, adipocytes, chondrocytes, myoblasts, tenocytes (14,15), secrete bioactive molecules that stimulate angiogenesis and tissue repair, and reduce the response of T cells and inflammation (16,17). Previous clinical trials have reported that mild/moderate OA or advanced OA can be treated efficiently using autologous or allogenic MSCs through implantation, micro fracture or intra-articular injections (1820). However, so far, no meta-analytic research has evaluated the efficacy and safety of MSCs in treating patients with KOA.

Therefore, the present meta-analysis was conducted to analyze the clinical outcomes of MSC treatment on patients with KOA patients by analyzing pain and functional changes, compared with their pretreatment condition, or placebo controls.

Materials and methods

Search strategy and eligibility criteria

Electronic databases: including PubMed (ncbi.nlm.nih.gov/pubmed), EMBASE (embase.com) and Web of Science (webofknowledge.com), were used to comprehensively search for all relevant studies published in English from the earliest record to December 2014. The following keywords were used: ‘cartilage defect’, ‘cartilage repair’, ‘osteoarthritis’, ‘knee osteoarthritis’, ‘stem cells’, ‘mesenchymal stem cells’ (MSCs), ‘bone marrow concentrate’, ‘adipose-derived mesenchymal stem cells’ (ADMSCs), ‘synovial-derived mesenchymal stem cells’ and ‘peripheral blood-derived mesenchymal stem cells’, as medical subject headings or text words. In addition, Cochrane Systematic Reviews (cochrane.org/evidence) and ClinicalTrials.gov were manually searched for additional references. Articles were considered eligible if they met the following criteria: i) Patients were ≥18 years-old and had KOA symptom or diagnosed with KOA by clinical and imaging examination; ii) MSCs administered to at least one treatment group; iii) ≥3-month follow-up; iv) ≥1 valid outcome measurement before and after the administration of MSCs, such as the visual analogue scale (VAS), International Knee Documentation Committee (IKDC) Subjective Knee Form, Lysholm scale, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); and v) outcomes were presented as continuous data [mean ± standard deviation (SD)]. Studies that lacked an intervention plan or pain and functional measurements were excluded.

Data extraction and study quality assessment

Two independent reviewers searched the electronic databases and evaluated the eligibility of the searched articles and subsequently extracted data using a standardized form, including data on the study type, number of patients enrolled, patient characteristics, disease duration, dosage of MSCs, outcome measurements, follow-up time and adverse events. If additional data was necessary, the authors were contacted for further information. The Jadad scoring system was used to assess the methodological quality of the randomized controlled trials (RCTs) (21). The quality of the included RCTs ranged from 0–5 points, with a score of <3 indicating a low-quality study. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of other studies according to selection, comparability, exposure, and outcome, including single-arm prospective and quasi-experimental studies (22). NOS was scored out of 9 points, with total scores <4 points defined as low quality. Discrepancies between the two independent evaluations of potential articles were resolved by discussion and consensus.

Data synthesis and analysis

Data were extracted from four time points at or closest to the 3rd, 6th, 12th and 24th months after MSCs treatment. Effect size (ES) was calculated from knee joint pain and functional changes and the results were compared with the pretreatment baseline or between different treatment arms. VAS was extracted from the included articles. If >1 functional measurement was included in an article, only one functional scale in line with the order of IKDC, Lysholm and WOMAC was chosen. As multiple treatment groups wew included in some articles, each group was selected as a separate status set to analysis. Mean ± SD between the pretreatment baseline condition and functional scores after treatment was used to evaluate the effectiveness of MSCs therapy. Positive ES values demonstrated a pain or functional improvement, and vice versa. For studies in which the measurement score and SD was deficient, the value was calculated from the P-value of the corresponding hypothesis test. If the measurement scores and SD could not be extracted in some articles, a correlation of 0.5 was used to estimate the dispersion. A random effect model was used to pool the ESs with a 95% confidence interval (95%CI) on the basis of heterogeneity. A positive pooled ES with a 95%CI >0 indicated an advantage of MSCs compared with the pretreatment condition or reference treatments.

Assessment of heterogeneity and sensitivity

Statistical heterogeneity was assessed via the I-square and Cochran's Q tests. A P-value of <0.10 for χ2 test or an I-square >50% was indicative of the existence of substantial heterogeneity (21). Subgroup analysis was performed according to variables of the study design, different dosages, arthroscopic debridement (AD), activation agent, as well as the severity of Kellgren-Lawrence (K-L) grades. Sensitivity analysis was performed by excluding some articles with extreme ES values to assess whether the movement resulted in serious changes in the total result. Funnel plots were used to assess the potential publication bias. All analyses were conducted using Review Manager Version 5.2 (The Cochrane Collaboration, Oxford, UK).

Results

Study characteristics

A total of 152 studies were initially searched, of which 117 were removed after title and abstract screening. Of the 35 citations, 18 clinical studies which met the inclusion criteria were identified for eligibility (Fig. 1); five case studies (17,2226) were excluded and nine studies (24,2734) were removed due to difficulties in extracting the outcome measurements. Four systematic reviews (3538) were also excluded. An assessment of the remaining 18 studies revealed that 10 used a single-arm prospective design (1820,3945), four used quasi-experimental trials (4649) and four used RCT (5053) (Table I). A total of 565 participants (226 males and 339 females) were included from the 18 studies. The duration from the onset of knee pain to registration in each study was 3 months to ≥7 years. The follow-up period was 3–24 months. The majority of studies recruited patients with KOA with a severity grade of 1–4 on the K-L scale. K-L grade s 1–2, and grades 3–4 were defined as early OA and advanced OA, respectively (Table II).

Table I.

Summary of studies using MSCs to treat KOA patients.

Table I.

Summary of studies using MSCs to treat KOA patients.

Author, yearNumber of patientsMean age (year)BMIDisease durationDouble blindITTOutcome measureFollow-up time (month)Adverse eventsQuality assessmentRef.
Single-arm, prospective follow-up studies
  Buda et al, 201020 (12M, 8F)NMNM≥12 monthsNoYesIKDC6, 12, 24None4a(39)
  Gobbi et al, 201115 (10M, 5F)48 (32–58)24.5±2.53NMNoYesVAS, IKDC6, 12, 24None4a(40)
  Davatchi et al, 20114 (2M, 2F)57.7±5.030.25±4.86≥7 yearsNoYesVAS6None4a(18)
  Emadedin et al, 20126 (6F)53.8±8.931.6±4.2NMNoYesVAS, WOMAC2, 6, 12None4a(19)
  Koh et al, 201318 (6M, 12F)54.6±7.8NM≥6 monthsNoNoVAS, Lysholm24Marked pain in 1 patient4a(20)
  Turajane et al, 20135 (1M, 4F)57.2±1.9225.36±4.46≥3 monthsNoYesVAS, WOMAC1,6None4a(41)
  Orozco et al, 201312 (6M, 6F)49±17.3NM≥6 monthsNoYesVAS, WOMAC3, 6, 12, 24Local pain with discomfort in 6 patients4a(42)

Author, yearNumber of patientsAverage age (year)BMIDisease durationDouble blindITTOutcome measureFollow-up time (month)Adverse eventQuality assessmentRef.

  Kim et al, 201441 (17M, 24F)60.7 (53–80)<30≥12 monthsNoYesVAS, IKDC3, 6, 12Joint swelling in 69 knees, pain in 31 knees4a(43)
  Koh et al, 201330 (5M, 25F)70.3 (65–80)NM≥12 monthsNoYesVAS, Lysholm3, 12, 24Slight pain in 3 patients4a(44)
  Gobbi et al, 201425 (16M, 5F)46.5±8.5524.4±3.0≥3 yearsNoYesVAS, IKDC12, 24None4*(45)
Quasi-experimental studies
  Koh and Choi, 201250 (MSCs + PRP group: 8M, 17F; PRP group: 8M; 17F)MSC group: 54.2±9.3; placebo group: 54.4±11.3NM≥12 monthsNoYesVAS, Lysholm3, 12Marked pain with swelling in 1 patient5a(46)
  Koh et al, 201456 (Group 1: 8M, 13F; Group 2: 14M, 21F)Group 1: 55.3±4.1; Group 2: 57.4±5.7Group 1: 26.7±3.1; Group 2: 26.3±3.0≥12 monthsNoNoIKDS12, 24None5a(47)
  Jo et al, 201418 (LDG: 1M, 2F; MDG: 0M, 3F; HDG: 2M, 10F)LDG: 63±8.6 MDG: 65±6.6 HDG: 61±6.2LDG: 26±1.0 MDG: 28±2.1 HDG: 26±2.1≥4 monthsNoYesVAS, WOMAC3, 6Mild (LDG:3; MDG: 2; HDG:5)5a(48)
  Kim et al, 201454 (MSCs group: 14M, 23F; MSC + fibrin glue group: 8M, 9F)MSCs group: 57.5±5.9; MSC + fibrin glue group: 57.7±5.8MSCs group: 26.3±3.2; MSC + fibrin glue group: 27.3±2.9≥18 monthsNoNoIKDC12, 24None5a(49)
Randomized controlled trials
  Varma et al, 201050 (AD: 25; AD + MSC: 25)AD group: 48.20±5.13; AD + MSC: 50.67±5.38NMNMNoYesVAS3, 6None3b(50)
  Saw et al, 201350 (HAG: 7M, 17F; HA + PBSC group 10M, 15F)HAG: 42±5.91 HA + PBSC: 38±7.33HA: 24.83±4.04 HA + PBSC: 24.91±4.15≥12 monthsNoNoIKDS6, 12, 24None3b(51)
  Wong et al, 201356 (HTO + MSC: 15M, 13F HTO: 14M, 14F)HTO + MSC: 53 (36–54) HTO: 49 (24–54)HTO + MSC: 23.81±2.17 HTO: 23.89±3.20NMNoYesIKDS, Tegner, Lysholm6, 12, 24None3b(52)
  Vangsness et al, 201455 (LDG: 11M, 7F; HDG: 14M, 4F HAG: 13M, 6F)LDG: 44.6±9.82 HDG: 45.6±12.42 HAG: 47.8±8LDG: 29.86±7.94; HDG: 29.09±5.91; HAG: 26.89± 4.05NMYesNoVAS, Lysholm6, 12, 24Mild (LDG:18; HDG: 17; HAG: 17)5b(53)

{ label (or @symbol) needed for fn[@id='tfn1-etm-0-0-3791'] } MSC, mesenchymal stem cell; M, male; F, female; BMI, body mass index; ITT, intention-to-treat; HAG, hyaluronic acid group; PBSCs, peripheral blood stem cells; HTO, high tibial osteotomy; VAS, the visual analog scale; IKDC, International Knee Documentation Committee; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

a Quality scores derived from the Newcastle-Ottawa scale

b quality scores derived from the Jadad scale; NM, not mentioned; LDG, low-dose group; MDG, mid-dose group; HDG, high-dose group; AD, arthroscopic debridement.

Table II.

Summary of the preparations and injection details of MSCs in the retrieved trials.

Table II.

Summary of the preparations and injection details of MSCs in the retrieved trials.

Author, yearMSC originNumber of cellsDelivery systemMethod of implementationActivation agentK-L gradeComparisonRef.
Single-arm, prospective follow-up studies
  Buda et al, 2010Autologous BMACNMADImplantationHA, membrane scaffoldNMNone(39)
  Gobbi et al, 2011Autologous BMACNM Mini-arthrotomyImplantationCollagen matrixNMNone(40)
  Davatchi et al, 2011Autologous BMSCs 8–9×106NoneIntra-articular injectionNone3–4None(18)
  Emadedin et al, 2012Autologous BMSCs 2.0–2.4×107NoneIntra-articular injectionNone4None(19)
  Koh et al, 2013Autologous AMSCs 1.18×106AD, synovectomyIntra-articular injectionPRP3–4None(20)
  Turajane et al, 2013Autologous BSCNMMicrofractureIntra-articular injectionGFAP, HA2None(41)
  Orozco et al, 2013Autologous BMSCs 40×106NoneIntra-articular injectionNone2–4None(42)
  Kim et al, 2014Autologous BMSCs 2.4×105Microfracture and ADIntra-articular injectionAdipose tissues1–4None(43)
  Koh et al, 2013Autologous AMSCs 4.04×106Arthroscopic lavageIntra-articular injectionNone2–4None(44)
  Gobbi et al, 2014Autologous BMACNMADImplantationCollagen cell sheetsNMNone(45)
Quasi-experimental studies
  Koh and Choi, 2012Autologous AMSCs 1.89×106AD, synovectomyIntra-articular injectionPRP3MSCs + PRP vs. PRP(46)
  Koh et al, 2014Autologous AMSCs 3.8×106ADImplantationNone1–2None(47)
  Jo et al, 2014Autologous AMSCsLDG: 1×107 MDG: 5×107 HDG:10×107NoneIntra-articular injectionNone3–4None(48)
  Kim et al, 2014Autologous AMSCs 3.9×106ADImplantationFibrin glue1–2MSCs vs. MSCs + fibrin glue(49)
Randomized controlled trials
  Varma et al, 2010Buffy coatNot mentionedNoneIntra-articular injectionNone1–2None(50)

Author, yearNumber Origin of MSCsof cellsImplementation Delivery systemmethodActivation agentK-L gradeComparisonRef.

  Saw et al, 2013Autologous PBSCsNMMicrofracture injection Intra-articularNone HA + PBSC groupNMHA group vs.(51)
  Wang et al, 2013Autologous BMAC 1.46×107HTO injection Intra-articularHA vs. HTO groupNMHTO + MSCs group(52)
  Vangsness et al, 2014Allogenic BMSCs 5.0×107,15×107 meniscectomyPartial medialIntra-articular injectionNoneNMGroup A: LD MSCs + HA Group B: HD MSCs + HA; control group: HA(53)
Effects of MSCs

Compared with the pretreatment condition, a pooled ES of 0.80 (95%CI, 0.42–1.17) was determined at 3 months, 1.72 (95%CI, 1.13–2.31) at 6 months, 2.03 (95%CI, 1.30–2.76) at 12 months (Fig.2), and 1.81 (95%CI, 1.62–2.00) at 24 months (Fig. 3), which all favored the status after MSCs treatment. Following the exclusion of an outlier with an extremely high ES, the beneficial effects from MSCs treatment remained, with an ES of 0.77 (95%CI, 0.41–1.13) at 3 months, 1.49 (95%CI, 0.93–2.04) at 6 months, 1.63 (95%CI, 0.99–2.27) at 12 months, and 1.74 (95%CI, 1.55–1.93) at 24 months. A significant superiority of MSCs intervention was demonstrated by a high summed ES at 12 and 24 months without an overlap of the 95%CI of ES at 3 months, which indicated that the treatment effect of MSCs on KOA patients improved significantly over time. However, after excluding the data from quai-experimental and single-arm prospective studies and only using the data from RCTs, the treatment of MSCs did not demonstrate superiority. Relative to the baseline, patients improved in the pain and functional scale scores at all time points.

Stratified analysis

Participants receiving MSC treatment were stratified according to the study design, administration dosage, AD, activation agents and K-L grades. Point estimates of the pooled ES in the single-arm prospective studies and quasi-experimental trials were higher than those in the RCTs, and an uncertainty in the treatment effectiveness emerged regarding participants in the RCTs at 6, 12 and 24 months, since the 95%CI of the summed ES crossed the value of 0. Stratified analysis failed to demonstrate a dose-responsiveness association in the MSC numbers. However, the treatment effectiveness in the MSC groups with AD or activation agents was superior to the MSC groups without AD and activation agents, particularly at 12 months in the activation agents group (ES, 3.13; 95%CI, 1.55–4.71) compared with the group without activation agents (ES, 0.67; 95% CI, 0.01–1.34). And the early OA group exhibited a higher ES point estimate at all time points than the advanced OA group (Table III).

Table III.

Analysis of the effect sizes of MSC treatment stratified by the indicated subgroups.

Table III.

Analysis of the effect sizes of MSC treatment stratified by the indicated subgroups.

SubgroupPooled effect size at month 3Pooled effect size at month 6Pooled effect size at month 12Pooled effect size at month 24
Study design
  Single-arm follow-up study0.48 (0.18–0.77)1.48 (0.51–2.44)2.66 (1.69–3.62)2.87 (1.99–3.75)
  Quasi-experimental study0.75 (0.17–1.32)1.37 (0.59–2.14)2.53 (1.96–3.10)2.53 (2.18–2.89)
  Randomized controlled trial1.87 (1.19–2.54)1.09 (−0.35–2.53)0.14 (0.49–0.20)0.12 (0.24–0.48)
MSCs doses administered
  <5×1060.34 (−0.08–0.75)0.70 (0.46–0.93)1.60 (0.73–2.46)2.25 (1.54–2.97)
  5×106-5×1070.89 (0.36–1.42)1.39 (0.80–1.99)1.60 (0.55–2.65)−0.07 (−0.75–0.60)
  >1×1070.67 (0.09–1.26)1.91 (0.58–3.23)−0.01 (−0.67–0.64)0.12 (−0.53–0.78)
  Arthroscopic debridement
  Yes0.37 (0.01–0.74)0.45 (−0.16–1.06)2.20 (1.30–3.09)2.32 (1.61–3.03)
  No1.02 (0.58–1.47)1.48 (0.80–2.16)1.41 (0.83–2.00)1.56 (0.62–2.49)
Activation agent
  Yes0.37 (0.01–0.74)1.40 (0.26–2.54)3.13 (1.55–4.71)2.82 (2.07–3.56)
  No1.02 (0.58–1.47)1.29 (0.53–2.05)0.67 (0.01–1.34)0.84 (0.16–1.52)
Severity of degeneration
  Early OA1.55 (0.66–2.45)4.10 (3.16–5.04)2.53 (1.96–3.10)2.53 (2.18–2.89)
  Advanced OA0.78 (0.34–1.22)2.40 (1.34–3.46)1.99 (0.70–3.28)2.54 (1.64–3.44)

[i] Values are expressed by their point estimates with a 95% CI. 95% CI covered a zero value, which indicated an uncertainty of treatment effectiveness compared with the pretreatment baseline. MSC, mesenchymal stem cell; OA, osteoarthritis; CI, confidence interval.

Adverse effects and publication bias

Seven of the 18 trials reported adverse events after MSC treatment, in which the predominant symptoms were local swelling and transient regional pain. All of the adverse events reported by patients were self-limited or were remedied with therapeutic measures. None of the patients included in the present study were diagnosed with cancer that was associated with MSC therapy. Asymmetry was observed in the funnel plots based on the ESs of changes in the pain and functional scales from baseline (Fig. 4).

Discussion

The present meta-analysis comparing the conditions of patients with KOA before and after treatment with MSCs demonstrated a continual efficacy for at least 24 months. Following analysis of the pooled ESs at 12 and 24 months, these values were higher than the summed ESs at 3 months, which indicated that the treatment effect of MSCs did not decrease in a time-dependent manner. However, a dose-responsiveness association was not demonstrated in the MSC numbers. The treatment effectiveness in the MSC groups treated with AD or activation agents was superior to the MSCs groups alone. Notably, the early OA group exhibited a higher ES point estimate at all time points, as compared with the advanced OA group.

To the best of our knowledge, no previous meta-analytic research has quantified the effectiveness of MSC treatment and analyzed the factors and modified the outcomes. Several reviews of the literature (3538) have analyzed the role of MSCs therapy in KOA. Barry and Murphy (37) stressed that paracrine factor must be used as a measure to evaluate the potential treatment of MSCs in order to replace traditional measures based on differentiation and cell-surface markers. They also outlined that early-stage clinical trials are underway for test the method of intra-articular injection of MSCs into the knee. However, the optimal dose and vehicle have not been established. Filardo et al (38) reported that, due to the prevalence of low-quality preclinical studies and clinical trials, knowledge on the treatment of MSCs for cartilage regeneration remains preliminary, despite the growing interest in the biological approach. Rodriguez-Merchan (35) highlighted the efficacy of utilizing intra-articular injections of MSCs to treat KOA; however, the results of the treatment are simply encouraging. Kristjansson and Honsawek (36) discussed and assessed three ways in which MSCs may be used to treat OA patients by intra-articular injections and implantation as well as micro fracture. They reported that with higher numbers of MSCs injected superior results would be obtained. However, in order to facilitate the treatment, a single injection of MSCs alone or in combination of growth factors would be the ultimate solution.

The present meta-analysis suggested that MSC treatment significantly improved pain and functional status, relative to the basal evaluations in KOA, and the beneficial effect was maintained for two years after treatment. Furthermore, the treatment effectiveness did not reduce over time. Several factors mentioned by anecdotal research may modify the ESs of MSC treatment. In terms of the study design, the pooled ESs in single-arm and quasi-experimental studies were likely to be higher than those in RCTs. However, the results of these RCT studies suggested that MSCs also reduce pain and improve function in patients with KOA. Regarding the number of MSCs used in treatment, a dose-responsiveness relationship remained unclear. Jo et al (48) enrolled 18 patients who were injected with ADMSCs into the knee. The study consisted of three groups, the low-dose (1.0×107 cells), mid-dose (5.0×107), and high-dose (1.0×108) groups. However, a significant improvement in joint function and reduction in pain was observed in the low and mid-dose groups. Conversely, in previous studies, an increased number of cells yielded superior results. Therefore, the optimal dose and vehicle are yet to be established. One potential modifier is the AD. The present stratified analysis suggested that AD potentially contributed to an increase in treatment effectiveness. Another issue is the addition of activation agents, particularly at 12 months in the activation agents group (ES, 3.13; 95% CI, 1.55–4.71) compared with the group without activation agents (ES, 0.67; 95%CI, 0.01–1.34). The present subgroup analysis showed that the efficacy varied according to the degenerative severity, which was associated with the regenerative potential of damaged cartilage. These results are compatible with the findings of the majority of previous trials, and the early OA group exhibited a higher ES point estimated at all time points than the advanced OA group.

Acknowledgements

The study was supported by grants from the National Science Foundation of China (grant nos. 81160225, 81260453 and 81360451) and the Xinjiang Bingtuan Special Program of Medical Science (grant nos. 2014CC002, 2013BA020 and 2012BC002).

References

1 

Findlay DM: If good things come from above, do bad things come from below? Arthritis Res Ther. 12:1192010. View Article : Google Scholar : PubMed/NCBI

2 

Goldring MB and Goldring SR: Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann NY Acad Sci. 1192:230–237. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Gross JB, Guillaume C, Gégout-Pottie P, Mainard D and Presle N: Synovial fluid levels of adipokines in osteoarthritis: Association with local factors of inflammation and cartilage maintenance. Biomed Mater Eng. 24(Suppl 1): S17–S25. 2014.

4 

Hawker GA, Mian S, Bednis K and Stanaitis I: Osteoarthritis year 2010 in review: Non-pharmacologic therapy. Osteoarthritis Cartilage. 19:366–374. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Sakata K, Furumatsu T, Abe N, Miyazawa S, Sakoma Y and Ozaki T: Histological analysis of failed cartilage repair after marrow stimulation for the treatment of large cartilage defect in medial compartmental osteoarthritis of the knee. Acta Med Okayama. 67:65–74. 2013.PubMed/NCBI

6 

Lee GW, Son JH, Kim JD and Jung GH: Is platelet-rich plasma able to enhance the results of arthroscopic microfracture in early osteoarthritis and cartilage lesion over 40 years of age? Eur J Orthop Surg Traumatol. 23:581–587. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Eldracher M, Orth P, Cucchiarini M, Pape D and Madry H: Small subchondral drill holes improve marrow stimulation of articular cartilage defects. Am J Sports Med. 42:2741–2750. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Dowsey MM, Gunn J and Choong PF: Selecting those to refer for joint replacement: Who will likely benefit and who will not? Best Pract Res Clin Rheumatol. 28:157–171. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Knutsen G, Drogset JO, Engebretsen L, Grøntvedt T, Isaksen V, Ludvigsen TC, Roberts S, Solheim E, Strand T and Johansen O: A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am. 89:2105–2112. 2007. View Article : Google Scholar : PubMed/NCBI

10 

Lee CR, Grodzinsky AJ, Hsu HP, Martin SD and Spector M: Effects of harvest and selected cartilage repair procedures on the physical and biochemical properties of articular cartilage in the canine knee. J Orthop Res. 18:790–799. 2000. View Article : Google Scholar : PubMed/NCBI

11 

Vasiliadis HS and Wasiak J: Autologous chondrocyte implantation for full thickness articular cartilage defects of the knee. Cochrane Database Syst Rev. 10:CD0033232010.PubMed/NCBI

12 

Mandelbaum B, Browne JE, Fu F, Micheli LJ, Moseley JB Jr, Erggelet C and Anderson AF: Treatment outcomes of autologous chondrocyte implantation for full-thickness articular cartilage defects of the trochlea. Am J Sports Med. 35:915–921. 2007. View Article : Google Scholar : PubMed/NCBI

13 

Phinney DG and Prockop DJ: Concise review: Mesenchymal stem/multipotent stromal cells: The state of transdifferentiation and modes of tissue repair-current views. Stem cells. 25:2896–2902. 2007. View Article : Google Scholar : PubMed/NCBI

14 

Delorme B, Ringe J, Pontikoglou C, Gaillard J, Langonné A, Sensebé L, Noël D, Jorgensen C, Häupl T and Charbord P: Specific lineage-priming of bone marrow mesenchymal stem cells provides the molecular framework for their plasticity. Stem Cells. 27:1142–1151. 2009. View Article : Google Scholar : PubMed/NCBI

15 

Oreffo RO, Cooper C, Mason C and Clements M: Mesenchymal stem cells: Lineage, plasticity and skeletal therapeutic potential. Stem Cell Rev. 1:169–178. 2005. View Article : Google Scholar : PubMed/NCBI

16 

Robey PG and Bianco P: The use of adult stem cells in rebuilding the human face. J Am Dent Assoc. 137:961–972. 2006. View Article : Google Scholar : PubMed/NCBI

17 

Caplan AI: Why are MSCs therapeutic? New data: New insight. J Pathol. 217:318–324. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Davatchi F, Abdollahi B Sadeghi, Mohyeddin M and Nikbin B: Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int J Rheum Dis. 2015.

19 

Emadedin M, Aghdami N, Taghiyar L, Fazeli R, Moghadasali R, Jahangir S, Farjad R and Eslaminejad M Baghaban: Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch Iran Med. 15:422–428. 2012.PubMed/NCBI

20 

Koh YG, Jo SB, Kwon OR, Suh DS, Lee SW, Park SH and Choi YJ: Mesenchymal stem cell injections improve symptoms of knee osteoarthritis. Arthroscopy. 29:748–755. 2013. View Article : Google Scholar : PubMed/NCBI

21 

Higgins JP, Thompson SG, Deeks JJ and Altman DG: Measuring inconsistency in meta-analyses. BMJ. 327:557–560. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Kuroda R, Ishida K, Matsumoto T, Akisue T, Fujioka H, Mizuno K, Ohgushi H, Wakitani S and Kurosaka M: Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. Osteoarthritis Cartilage. 15:226–231. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Wakitani S, Nawata M, Tensho K, Okabe T, Machida H and Ohgushi H: Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: Three case reports involving nine defects in five knees. J Tissue Eng Regen Med. 1:74–79. 2007. View Article : Google Scholar : PubMed/NCBI

24 

Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M and Karli D: Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 11:343–353. 2008.PubMed/NCBI

25 

Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M and Karli D: Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Med Hypotheses. 71:900–908. 2008. View Article : Google Scholar : PubMed/NCBI

26 

Wakitani S, Mitsuoka T, Nakamura N, Toritsuka Y, Nakamura Y and Horibe S: Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: Two case reports. Cell Transplant. 13:595–600. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N and Yoneda M: Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage. 10:199–206. 2002. View Article : Google Scholar : PubMed/NCBI

28 

Nejadnik H, Hui JH, Choong EP Feng, Tai BC and Lee EH: Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: An observational cohort study. Am J Sports Med. 38:1110–1116. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Wakitani S, Okabe T, Horibe S, Mitsuoka T, Saito M, Koyama T, Nawata M, Tensho K, Kato H and Uematsu K: Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med. 5:146–150. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Saw KY, Anz A, Merican S, Tay YG, Ragavanaidu K, Jee CS and McGuire DA: Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic acid after arthroscopic subchondral drilling: A report of 5 cases with histology. Arthroscopy. 27:493–506. 2011. View Article : Google Scholar : PubMed/NCBI

31 

Hauser RA and Orlofsky A: Regenerative injection therapy with whole bone marrow aspirate for degenerative joint disease: A case series. Clin Med Insights Arthritis Musculoskelet Disord. 6:65–72. 2013.PubMed/NCBI

32 

Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, Sentís J, Sánchez A and García-Sancho J: Treatment of knee osteoarthritis with autologous mesenchymal stem cells: Two-year follow-up results. Transplantation. 97:e66–e68. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B and Hanson R: Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 6:368–378. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Centeno CJ, Schultz JR, Cheever M, Robinson B, Freeman M and Marasco W: Safety and complications reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 5:81–93. 2010. View Article : Google Scholar : PubMed/NCBI

35 

Rodriguez-Merchán EC: Intra-articular injections of mesenchymal stem cells for knee osteoarthritis. Am J Orthop (Belle Mead NJ). 43:E282–E291. 2014.PubMed/NCBI

36 

Kristjnsson B and Honsawek S: Current perspectives in mesenchymal stem cell therapies for osteoarthritis. Stem Cells Int. 2014:1943182014.PubMed/NCBI

37 

Barry F and Murphy M: Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol. 9:584–594. 2013. View Article : Google Scholar : PubMed/NCBI

38 

Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M and Kon E: Mesenchymal stem cells for the treatment of cartilage lesions: From preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. 21:1717–1729. 2013. View Article : Google Scholar : PubMed/NCBI

39 

Buda R, Vannini F, Cavallo M, Grigolo B, Cenacchi A and Giannini S: Osteochondral lesions of the knee: A new one-step repair technique with bone-marrow-derived cells. J Bone Joint Surg Am. 92(Suppl 2): S2–S11. 2010. View Article : Google Scholar

40 

Gobbi A, Karnatzikos G, Scotti C, Mahajan V, Mazzucco L and Grigolo B: One-step cartilage repair with bone marrow aspirate concentrated cells and collagen matrix in full-thickness knee cartilage lesions: Results at 2 year follow-up. Cartilage. 2:286–299. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Turajane T, Chaweewannakorn U, Larbpaiboonpong V, Aojanepong J, Thitiset T, Honsawek S, Fongsarun J and Papadopoulos KI: Combination of intra-articular autologous activated peripheral blood stem cells with growth factor addition/ preservation and hyaluronic acid in conjunction with arthroscopic microdrilling mesenchymal cell stimulation improves quality of life and regenerates articular cartilage in early osteoarthritic knee disease. J Med Assoc Thai. 96:580–588. 2013.PubMed/NCBI

42 

Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, Sentís J, Sánchez A and García-Sancho J: Treatment of knee osteoarthritis with autologous mesenchymal stem cells: A pilot study. Transplantation. 95:1535–1541. 2013. View Article : Google Scholar : PubMed/NCBI

43 

Kim JD, Lee GW, Jung GH, Kim CK, Kim T, Park JH, Cha SS and You YB: Clinical outcome of autologous bone marrow aspirates concentrate (BMAC) injection in degenerative arthritis of the knee. Eur J Orthop Surg Traumatol. 24:1505–1511. 2014. View Article : Google Scholar : PubMed/NCBI

44 

Koh YG, Choi YJ, Kwon SK, Kim YS and Yeo JE: Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 23:1308–1316. 2015. View Article : Google Scholar : PubMed/NCBI

45 

Gobbi A, Karnatzikos G and Sankineani SR: One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee. Am J Sports Med. 42:648–657. 2014. View Article : Google Scholar : PubMed/NCBI

46 

Koh YG and Choi YJ: Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee. 19:902–907. 2012. View Article : Google Scholar : PubMed/NCBI

47 

Koh YG, Choi YJ, Kwon OR and Kim YS: Second-look arthroscopic evaluation of cartilage lesions after mesenchymal stem cell implantation in osteoarthritic knees. Am J Sports Med. 42:1628–1637. 2014. View Article : Google Scholar : PubMed/NCBI

48 

Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, Kim JE, Shim H, Shin JS, Shin IS, et al: Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A proof-of-concept clinical trial. Stem Cells. 32:1254–1266. 2014. View Article : Google Scholar : PubMed/NCBI

49 

Kim YS, Choi YJ, Suh DS, Heo DB, Kim YI, Ryu JS and Koh YG: Mesenchymal stem cell implantation in osteoarthritic knees: Is fibrin glue effective as a scaffold? Am J Sports Med. 43:176–185. 2015. View Article : Google Scholar : PubMed/NCBI

50 

Varma HS, Dadarya B and Vidyarthi A: The new avenues in the management of osteo-arthritis of knee-stem cells. J Indian Med Assoc. 108:583–585. 2010.PubMed/NCBI

51 

Saw KY, Anz A, Siew-Yoke JC, Merican S, Ching-Soong Ng R, Roohi SA and Ragavanaidu K: Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: A randomized controlled trial. Arthroscopy. 29:684–694. 2013. View Article : Google Scholar : PubMed/NCBI

52 

Wong KL, Lee KB, Tai BC, Law P, Lee EH and Hui JH: Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: A prospective, randomized controlled clinical trial with 2 years' follow-up. Arthroscopy. 29:2020–2028. 2013. View Article : Google Scholar : PubMed/NCBI

53 

Vangsness CT Jr, Farr J II, Boyd J, Dellaero DT, Mills CR and LeRoux-Williams M: Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: A randomized, double-blind, controlled study. J Bone Joint Surg Am. 96:90–98. 2014. View Article : Google Scholar : PubMed/NCBI

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November 2016
Volume 12 Issue 5

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Online ISSN:1792-1015

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APA
Cui, G., Wang, Y.Y., Li, C., Shi, C., & Wang, W. (2016). Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: A meta‑analysis. Experimental and Therapeutic Medicine, 12, 3390-3400. https://doi.org/10.3892/etm.2016.3791
MLA
Cui, G., Wang, Y. Y., Li, C., Shi, C., Wang, W."Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: A meta‑analysis". Experimental and Therapeutic Medicine 12.5 (2016): 3390-3400.
Chicago
Cui, G., Wang, Y. Y., Li, C., Shi, C., Wang, W."Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: A meta‑analysis". Experimental and Therapeutic Medicine 12, no. 5 (2016): 3390-3400. https://doi.org/10.3892/etm.2016.3791