SYSTEMATIC REVIEW article
Front. Med.
Sec. Gene and Cell Therapy
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1636181
This article is part of the Research TopicTranslation of Mesenchymal Stem Cells in vivo: Evidence from preclinical and clinical testing.View all 9 articles
Contextual Effects of Mesenchymal Stem Cell Injections for Knee Osteoarthritis: Systematic Review and Meta-analysis of Randomized Controlled Trials
Provisionally accepted
- 1Chengdu University of Chinese Medicine, Cheng Du, China
- 2orthopedics, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- 3Chengdu University of Traditional Chinese Medicine, Chengdu, China
- 4Chengdu Integrated TCM & Western Medicine Hospital, Chengdu, China
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Abstract Purpose To quantify the proportion of the overall clinical improvement produced by intra-articular mesenchymal stem cell (MSC) injections for knee osteoarthritis (KOA) that is attributable to contextual (placebo-related) effects. Methods This PRISMA-compliant systematic review and meta-analysis (PROSPERO CRD420251026818) searched five databases (CENTRAL, Embase, MEDLINE, Web of Science and Scopus) to 24 March 2025. Randomized controlled trials enrolling adults with KOA that compared MSC injections with inert placebo were included. Primary outcome was change in pain intensity (VAS or WOMAC-pain); physical function was analysed secondarily. Two reviewers independently extracted data and assessed risk of bias. The proportion of the treatment effect attributable to contextual factors (PCE) was calculated as described by Tsutsumi et al. Pain and function outcomes at 6 and 12 months were pooled with inverse-variance random-effects meta-analysis, and evidence certainty was appraised using GRADE. Results Eight RCTs (467 patients) met the inclusion criteria. At 6 months, contextual factors accounted for approximately 63 % of pain reduction and 61 % of functional improvement, with low heterogeneity (I² ≤ 8 %). At 12 months, contextual factors explained ~50 % of pain relief and ~66 % of functional gains, again with very low heterogeneity (I² = 0 %). Certainty of evidence was rated low for both time-points (GRADE). Conclusion Based on low-certainty evidence, this meta-analysis suggests that in knee osteoarthritis the majority of symptomatic improvement following intra-articular MSC injections is attributable to contextual (placebo) effects, whereas the MSCs themselves confer only a modest incremental benefit.
Keywords: Mesenchymal Stem Cells, knee osteoarthritis, contextual effects, Meta-analysis, Intra-articular injection
Received: 27 May 2025; Accepted: 30 Aug 2025.
Copyright: © 2025 Fengsheng, Zhang, Wu, Tong, Luo, Deng and Yan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yin Fengsheng, Chengdu University of Chinese Medicine, Cheng Du, China
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