Synergistic Effects of Natural Products and Mesenchymal Stem Cells in Osteoarthritis Treatment: A Narrative Review
Abstract
1. Introduction
Literature Search Methodology
2. Osteoarthritis and MSC Therapies
2.1. Overview of Osteoarthritis (OA)
2.2. Pathophysiology of Osteoarthritis
2.3. Inflammatory Pathways in Osteoarthritis
2.4. Mesenchymal Stem Cells (MSCs)
3. Natural Products
3.1. Natural Products in Enhancing MSC Therapies
3.2. Specific Natural Products and Their Effects on MSCs
3.2.1. Curcumin
3.2.2. Resveratrol
3.2.3. Quercetin
3.2.4. Epigallocatechin Gallate (EGCG)
4. Combination Therapies: MSCs and Natural Products
4.1. Synergistic Effects of MSCs and Natural Products
Category | Natural Product | Model Used | Outcomes | Author |
---|---|---|---|---|
Enhancement of MSC Survival and Differentiation | Curcumin Dosage regimens: General wellness: 500–1000 mg daily. Arthritis and joint pain: 1000–1500 mg daily, often divided into smaller doses. Heart health: 500–700 mg daily. Cognitive health: 500–1000 mg daily. Maximum safe limit: up to 8000 mg per day for short durations. | in vitro/ clinical studies | Decreased oxidative stress and inflammation improve MSC viability and differentiation potential. | [79,81,90] |
Resveratrol Dosage regimens: Anti-aging: 150–500 mg per day; up to 1000 mg daily for more pronounced effects. Heart health: 100–250 mg daily; higher doses of 250–500 mg per day for existing cardiovascular conditions. Anti-inflammatory: up to 1500 mg daily for up to 3 months; higher doses of 2000–3000 mg daily for 2–6 months. | in vitro | Promotes bone growth, reduces inflammation, and enhances regeneration. | [69,78,108] | |
Quercetin Dosage regimens: General wellness: 500 mg per day, often combined with vitamin C or bromelain to enhance absorption. Allergies or inflammation: 500–1000 mg per day, divided into multiple doses. | in vitro | Supports bone formation and decreases inflammation, especially in age-related bone loss. | [69,92,93] | |
Modulation of Inflammatory Microenvironment | Curcumin and resveratrol combination (no information) | in vitro/in vivo | Inhibits TNF-α-induced inflammation, suppresses NF-κB signaling, reduces vascular inflammation, and enhances MSC function in inflammatory conditions. | [95,96,109,110] |
Quercetin Dosage regimens: General wellness: 500 mg per day, often combined with vitamin C or bromelain to enhance absorption. Allergies or inflammation: 500–1000 mg per day, divided into multiple doses. | in vitro/in vivo | Enhances MSCs’ immunomodulatory capacity and modulates inflammatory signaling pathways. | [97,98] | |
Improvement of Bioavailability and Efficacy | Curcumin Dosage regimens: General wellness: 500–1000 mg daily. Arthritis and joint pain: 1000–1500 mg daily, often divided into smaller doses. Heart health: 500–700 mg daily. Cognitive health: 500–1000 mg daily. Maximum safe limit: up to 8000 mg per day for short durations | in vitro/in vivo | Improved efficacy through structural modifications or nano-delivery systems enhances solubility and absorption, maximizing the therapeutic potential of MSCs. | [99,100,101,102] |
Resveratrol and curcumin (no information) | in vitro/in vivo | Low concentrations of compounds work synergistically, improving the therapeutic outcomes of MSC-based therapies more effectively than when used individually. | [103,104,105,106] | |
Case Studies and Applications | Crocin (no information) | in vivo | Significant improvements in cell survival and reductions in oxidative stress highlight the potential of natural products to enhance MSC efficacy in lung injury models. | [1,107] |
Resveratrol Dosage regimens: Anti-aging: 150–500 mg per day; up to 1000 mg daily for more pronounced effects. Heart health: 100–250 mg daily; higher doses of 250–500 mg per day for existing cardiovascular conditions. Anti-inflammatory: up to 1500 mg daily for up to 3 months; higher doses of 2000–3000 mg daily for 2–6 months | in vivo | Ameliorates inflammation, promotes osteogenic differentiation in periodontal tissues, and demonstrates potential in dental applications of MSC therapy. | [108] |
4.2. Evidence from Preclinical Studies
4.3. Insights from Clinical Trials
4.4. Mechanisms Underlying Synergistic Effects
4.5. Challenges, Considerations and Future Direction
5. Mechanisms of Action
5.1. Modulation of Inflammatory Pathways
5.2. Reduction of Oxidative Stress
5.3. Promotion of Chondrogenic Differentiation
5.4. Enhanced Delivery via Biomaterials
5.5. Immune Modulation
5.6. Future Perspectives
5.7. Perspectives on Clinical Practice and Translation
6. Challenges and Considerations
6.1. Standardization and Quality Control
6.2. Bioavailability and Delivery
6.3. Safety and Potential Side Effects
6.4. Regulatory Hurdles
7. Challenges, Limitations, and Conflicting Evidence
7.1. Bioavailability and Stability Challenges
7.2. Variability in MSC Sources and Treatment Efficacy
7.3. Conflicting Clinical Data on MSC + Natural Product Therapies
7.4. Lack of Regulatory Guidelines and Standardized Protocols
7.5. Future Research Priorities
8. Conclusions and Future Directions
8.1. Research Priorities for Advancing MSC + Natural Product Therapies
8.2. Clinical Translation: Roadmap for the Next 5–10 Years
- Preclinical refinement (0–2 years): This phase focuses on optimizing bioavailability solutions, comparing MSC sources, and conducting high-throughput screening to identify the most effective MSC–natural product combinations.
- Small-scale clinical trials (2–5 years): During this period, phase I/II clinical trials will assess safety, dosing, and preliminary efficacy. Simultaneously, standardized MSC culture and expansion protocols will be developed, and collaboration with regulatory agencies will define safety standards for combined therapies.
- Large-scale clinical adoption (5–10 years): The final phase involves conducting multi-center phase III trials, establishing personalized treatment strategies based on patient biomarkers, and achieving regulatory approval and commercialization of MSC–natural product combination therapy for OA.
8.3. The Future of MSC + Natural Product Therapy for OA
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
NSAIDs | Nonsteroidal Anti-Inflammatory Drugs |
MSCs | Mesenchymal Stem Cells |
OA | Osteoarthritis |
PRP | Platelet-Rich Plasma |
EGCG | Epigallocatechin Gallate |
COMP | Cartilage Oligomeric Matrix Protein |
C2C | Collagen Type II Cleavage Products |
IL-1β | Interleukin-1β |
IL-6 | Interleukin-6 |
IL-17 | Interleukin-17 |
TNF-α | Tumor Necrosis Factor-Alpha |
miRNAs | MicroRNAs |
MMPs | Matrix Metalloproteinases |
NF-κB | Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells |
MAPK | Mitogen-Activated Protein Kinase |
ROS | Reactive Oxygen Species |
NO | Nitric Oxide |
Nrf2 | Nuclear Factor Erythroid 2-Related Factor 2 |
Wnt | Wingless-Related Integration Site |
Notch | Notch Gene |
TGF-β | Transforming Growth Factor-Beta |
TLR | Toll-Like Receptor |
PTOA | Post-Traumatic Osteoarthritis |
CaMKK2 | Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 |
SIRT1 | Sirtuin (Silent Mating Type Information Regulation 2 Homolog) 1 |
COX-2 | Cyclooxygenase-2 |
PI3K/AKT | Phosphatidylinositol 3-Kinase/Protein Kinase B (Also Known as Akt) |
ROCK1 | Rho-Associated, Coiled-Coil-Containing Protein Kinase 1 |
TLR9 | Toll-Like Receptor 9 |
mTOR | Mammalian Target of Rapamycin |
ADMSCs | Adipose-Derived MSCs |
sEV-CUR | Curcumin-Loaded Small Extracellular Vesicles |
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Treatment Category | Specific Treatments | Description | Effects |
---|---|---|---|
Non-Pharmacological | Regular physical activity | Promotes mobility and joint function | Aids weight reduction and overall health improvement |
Lifestyle modifications | Diet and other health-related changes | Critical for patients with obesity or poor nutrition | |
Weight management | Lifestyle changes, including diet and exercise | Reduces joint stress and improves overall health | |
Physical therapy | Exercises to improve joint mobility and muscle strength | Alleviates pain and enhances functional capacity | |
Pharmacological | Glucosamine and chondroitin | Supplements for cartilage health | Clinical results are inconsistent; generally not recommended |
Steroid injections | Corticosteroid injections for acute pain relief | Short-term pain relief and long-term use should be monitored | |
Duloxetine | Antidepressant approved for chronic pain in knee OA | Offers better relief in combination therapies compared to NSAIDs alone | |
Opioids/narcotics | Strong analgesics for severe cases | Effective but associated with addiction and adverse effects | |
Paracetamol | Analgesic for mild to moderate pain relief | Safe but less effective than NSAIDs | |
Nonsteroidal anti-inflammatory drugs | Cyclooxygenase inhibitors for pain relief | Effective pain relief but requires caution due to gastrointestinal side effects. | |
Viscosupplementation | Hyaluronic acid injection for joint lubrication | Offers potential chondroprotective benefits; effectiveness is debated | |
Surgical | Arthroscopy | Minor surgical adjustment within the joint | Less invasive, but the long-term effectiveness is debated |
Microfracture surgery | Stimulates growth of new cartilage | Standard due to low cost, it results in less-durable fibrocartilage | |
Total joint arthroplasty | Full joint replacement surgery | Practical in advanced cases; significant improvements in quality of life | |
Emerging Treatments | Platelet-rich plasma (PRP) | Concentrated platelets for tissue regeneration | Aids in inflammatory response modulation |
Gene therapy | Introducing therapeutic genes directly to the joint | Potential for long-term effects and slowing degenerative processes | |
Small molecule inhibitors | Target specific pathways of joint inflammation | Promising disease modification and symptomatic relief | |
Stem cell therapy | Mesenchymal stem cells for tissue regeneration | Potentially modulates inflammation and promotes regeneration |
Authors & Year | Study Type | Natural Product | MSC Source | Main Findings | Limitations |
---|---|---|---|---|---|
[67] | In vitro | Curcumin Dosage: 500–2000 mg/day; frequency: daily, divided doses | Bone marrow MSCs | Enhances chondrogenic differentiation and reduces oxidative stress | Lacks in vivo validation |
[68] | Animal (OA model) | ResveratrolDosage: 150–500 mg/day (up to 1000 mg); frequency: once daily or divided doses | Adipose-derived MSCs | Reduces cartilage degradation and inflammation | No human trial evidence |
[69] | Clinical trial | Resveratrol Dosage: 150–500 mg/day (up to 1000 mg); frequency: once daily or divided doses | Bone marrow MSCs | Improved pain and function in knee OA patients | Small sample size (n = 30) |
[70] | In vitro | Quercetin Dosage: 500–1000 mg/day; frequency: divided doses | Umbilical cord MSCs | Anti-inflammatory effects, reduces MMP expression | No long-term study |
[71] | In vivo (rat model) | EGCG Dosage: 400–800 mg/day; frequency: once or twice daily | Bone marrow MSCs | Protects cartilage from inflammatory damage | Bioavailability concerns |
[72] | In vivo (mouse model) | Resveratrol Dosage: 40 mg/kg/day; once daily, 4 weeks. s | Bone marroe MSCs | Enhances osteogenic differentiation by activating SIRT1 | No in vivo data |
[73] | In vitro | Quercetin Dosage: 500–1000 mg/day; frequency: divided doses | Bone marrow MSCs | Modulates macrophage polarization, reduces inflammatory cytokines | Needs validation in animal models |
[63] | In vivo (OA model) | EGCG Dosage: 400–800 mg/day; frequency: once or twice daily | Bone marrow MSCs | Protects MSCs from apoptosis and oxidative stress | No clinical translation yet |
[74] | In vitro and in vivo | Curcumin + resveratrol (no information) | Bone marrow MSCs | Synergistic effect in reducing TNF-α-induced inflammation | Dosage standardization needed |
[56] | In vitro | Quercetin + EGCG (no information) | Bone marrow MSCs | Enhances MSC survival under oxidative stress | No human trial conducted |
[52] | Animal (OA model) | Curcumin-loaded nanoparticles Dosage: 10.32% drug loading; frequency: sustained release over 10 days | Bone marrow MSCs | Improves MSC retention and differentiation in OA joints | Requires more safety studies for clinical use |
[75] | In vivo (OA model) | EGCG-loaded hydrogelsDosage: 10 mg/kg; frequency: sustained release | Adipose-derived MSCs | Increases MSC viability and cartilage regeneration | Lacks clinical trial data |
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Alfaqeh, H.H.; Idrus, R.B.H.; Saim, A.B.; Nordin, A. Synergistic Effects of Natural Products and Mesenchymal Stem Cells in Osteoarthritis Treatment: A Narrative Review. Curr. Issues Mol. Biol. 2025, 47, 445. https://doi.org/10.3390/cimb47060445
Alfaqeh HH, Idrus RBH, Saim AB, Nordin A. Synergistic Effects of Natural Products and Mesenchymal Stem Cells in Osteoarthritis Treatment: A Narrative Review. Current Issues in Molecular Biology. 2025; 47(6):445. https://doi.org/10.3390/cimb47060445
Chicago/Turabian StyleAlfaqeh, Hamoud H., Ruszymah Binti Hj Idrus, Aminuddin Bin Saim, and Abid Nordin. 2025. "Synergistic Effects of Natural Products and Mesenchymal Stem Cells in Osteoarthritis Treatment: A Narrative Review" Current Issues in Molecular Biology 47, no. 6: 445. https://doi.org/10.3390/cimb47060445
APA StyleAlfaqeh, H. H., Idrus, R. B. H., Saim, A. B., & Nordin, A. (2025). Synergistic Effects of Natural Products and Mesenchymal Stem Cells in Osteoarthritis Treatment: A Narrative Review. Current Issues in Molecular Biology, 47(6), 445. https://doi.org/10.3390/cimb47060445