Volume 6,Issue 3
Mesenchymal stem cells (MSCs) have emerged as a cell type with great potential for cell-based articular cartilage repair in patients with knee osteoarthritis (OA). However, a meta-analysis of clinical trials of the MSC treatment revealed that current evidence about articular cartilage regeneration and objectively measured functional improvement in people with knee OA was inconclusive. Research for regenerative rehabilitation, a recently emerged interdisciplinary field, could contribute to establishing effective cell-based therapy that maximizes cartilage regeneration and functional improvement in people with knee OA. We herein summarize our cross-disciplinary approaches toward establishing effective regenerative rehabilitation in MSC-based treatment for people with knee OA. This review would serve as the foundation for future studies investigating the effects of rehabilitative approaches in regenerative medicine that lead to the clinical success of cell-based treatment.
1. Guccione AA, Felson DT, Anderson JJ, et al. The Effects of Specific Medical Conditions on the Functional Limitations of Elders in the Framingham Study. Am J Public Health. 1994;84(3):351–358. https://doi.org/10.2105/ajph.84.3.351
2. Keat G, McCarney R, Croft P. Knee Pain and Osteoarthritis in Older Adults: A Review of Community Burden and Current Use of Primary Health Care. Ann Rheum Dis. 2001;60(2):91–97. https://doi.org/10.1136/ard.60.2.91
3. McAlindon TE, Driban JB, Henrotin Y, et al. OARSI Clinical Trials Recommendations: Design, Conduct, and Reporting of Clinical Trials for Knee Osteoarthritis. Osteoarthritis Cartilage. 2015;23(5):747–760. https://doi.org/10.1015/j.joca.2015.03.005
4. Biswal S, Medhi B, Pandhi P. Longterm Efficacy of Topical Nonsteroidal Antiinflammatory Drugs in Knee Osteoarthritis: Metaanalysis of Randomized Placebo Controlled Clinical Trials. J Rheumatol. 2006;33(9):1841–1844.
5. Fransen M, McConnell S, Harmer AR, et al. Exercise for Osteoarthritis of the: A Cochrane Systematic Review. Br J Sports Med. 2015;49(24):1554–1557. https://doi.org/10.1136/bjsports-2015-095424
6. Galois L, Etienne S, Grossin L, et al. Dose-Response Relationship for Exercise on Severity of Experimental Osteoarthritis in Rats: A Pilot Study. Osteoarthritis Cartilage. 2004;12(10):779–786. https://doi.org/10.1016/j.joca.2004.06.008
7. Iijima H, Ito A, Nagai M, et al. Physiological Exercise Loading Suppresses Post-Traumatic Osteoarthritis Progression via an Increase in Bone Morphogenetic Proteins Expression in an Experimental Rat Knee Model. Osteoarthritis Cartilage. 2017;25(6):964–975. https://doi.org/10.1016/j.joca.2016.12.008
8. Nam J, Perera P, Liu J, et al. Transcriptome-Wide Gene Regulation by Gentle Treadmill Walking During the Progression of Monoiodoacetate Induced Arthritis. Arthritis Rheum. 2011;63(6):1613–1625. https://doi.org/10.1002/art.30311
9. Bricca A, Juhl CB, Steultjens M, et al. Impact of Exercise on Articular Cartilage in People at Risk of, or With Established, Knee Osteoarthritis: A Systematic Review of Randomised Controlled Trials. Br J Sports Med. 2019;53(15):940–947. https://doi.org/10.1136/bjsports-2017-098661
10. Bricca A, Struglics A, Larsson S, et al. Impact of Exercise Therapy on Molecular Biomarkers Related to Cartilage and Inflammation in Individuals at Risk of, or With Established, Knee Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Arthritis Care Res (Hoboken). 2019;71(11):1504–1515. https://doi.org/10.1002/acr.23786
11. Ambrosio F, Russell A. Regenerative Rehabilitation: A Call to Action. J Rehabil Res Dev. 2010;47(3):xi–xv. https://doi.org/10.1682/jrrd.2010.03.0021
12. Glatt V, Evans CH, Stoddart MJ. Regenerative Rehabilitation: The Role of Mechanotransduction in Orthopaedic Regenerative Medicine. J Orthop Res. 2019;37(6):1263–1269. https://doi.org/10.1002/jor.24205
13. Roos EM, Dahlberg L. Positive Effects of Moderate Exercise on Glycosaminoglycan Content in Knee Cartilage: A Four-Month, Randomized, Controlled Trial in Patients at Risk of Osteoarthritis. Arthritis Rheum. 2005;52(11):3507–3514. https://doi.org/10.1002/art.21415
14. Gabay O, Hall DJ, Berenbaum F, et al. Osteoarthritis and Obesity: Experimental Models. Joint Bone Spine. 2008;75(6):675–679. https://doi.org/10.1016/j.jbspin.2008.07.011
15. Dunn SL, Olmedo ML. Mechanotransduction: Relevance to Physical Therapist Practice-Understanding Our Ability to Affect Genetic Expression Through Mechanical Forces. Phys Ther. 2016;96(5):712–721. https://doi.org/10.2522/ptj.20150073
16. O’Conor CJ, Leddy HA, Benefield HC, et al. TRPV4-Mediated Mechanotransduction Regulates the Metabolic Response of Chondrocytes to Dynamic Loading. Proc Natl Acad Sci U S A. 2014;111(4):1316–1321. https://doi.org/10.1073/pnas.1319569111
17. Iijima H, Aoyama T, Ito A, et al. Destabilization of the Medial Meniscus Leads to Subchondral Bone Defects and Site-Specific Cartilage Degeneration in an Experimental Rat Model. Osteoarthritis Cartilage. 2014;22(7):1036–1043. https://doi.org/10.1016/j.joca.2014.05.009
18. Arunakul M, Tochigi Y, Goetz JE, et al. Replication of Chronic Abnormal Cartilage Loading by Medial Meniscus Destabilization for Modeling Osteoarthritis in the Rabbit Knee in vivo. J Orthop Res. 2013;31(10):1555–1560. https://doi.org/10.1002/jor.22393
19. Yamaguchi S, Aoyama T, Ito A, et al. Effects of Exercise Level on Biomarkers in a Rat Knee Model of Osteoarthritis. J Orthop Res. 2013;31(7):1026–1031. https://doi.org/10.1002/jor.22332
20. Li Y, Frank EH, Wang Y, et al. Moderate Dynamic Compression Inhibits Pro-Catabolic Response of Cartilage to Mechanical Injury, Tumor Necrosis Factor-α and Interleukin-6, but Accentuates Degradation Above a Strain Threshold. Osteoarthritis Cartilage. 2013;21(12):1933–1941. https://doi.org/10.1016/j.joca.2013.08.021
21. Madej W, Buna P, van der Kraan P. Inflammatory Conditions Partly Impair the Mechanically Mediated Activation of Smad2/3 Signaling in Articular Cartilage. Arthritis Res Ther. 2016;18:146. https://doi.org/10.1186/s13075-016-1038-6
22. Nam J, Aguda BS, Rath B, et al. Biomechanical Thresholds Regulate Inflammation Through the NF-kappaB Pathway: Experiments and Modeling. PLoS One. 2009;4(4):e5262. https://doi.org/10.1371/journal.pone.0005262
23. Nam J, Rath B, Knobloch TJ, et al. Novel Electrospun Scaffolds for the Molecular Analysis of Chondrocytes Under Dynamic Compression. Tissue Eng Part A. 2009;15(3):513–523. https://doi.org/10.1089/ten.tea.2007.0353
24. Findlay DM, Kuliwaba JS. Bone-Cartilage Crosstalk: A Conversation for Understanding Osteoarthritis. Bone Res. 2016;4:16028. https://doi.org/10.1038/boneres.2016.28
25. Iijima H, Aoyama T, Ito A, et al. Exercise Intervention Increases Expression of Bone Morphogenetic Proteins and Prevents the Progression of Cartilage-Subchondral Bone Lesions in a Post-Traumatic Rat Knee Model. Osteoarthritis Cartilage. 2016;24(6):1092–1102. https://doi.org/10.1016/j.joca.2016.01.006
26. Nam J, Perera P, Rath B, et al. Dynamic Regulation of Bone Morphogenetic Proteins in Engineered Osteochondral Constructs by Biomechanical Stimulation. Tissue Eng Part A. 2013;19(5–6):783–792. https://doi.org/10.1089/ten.tea.2012.0103
27. Majumdar MK, Askew R, Schelling S, et al. Double-Knockout of ADAMTS-4 and ADAMTS-5 in Mice Results in Physiologically Normal Animals and Prevents the Progression of Osteoarthritis. Arthritis Rheum. 2007;56(11):3670–3674. https://doi.org/10.1002/art.23027
28. Little CB, Barai A, Burkhardt D, et al. Matrix Metalloproteinase 13-Deficient Mice are Resistant to Osteoarthritic Cartilage Erosion but Not Chondrocyte Hypertrophy or Osteophyte Development. Arthritis Rheum. 2009;60(12):3723–3733. https://doi.org/10.1002/art.25002
29. Zhang M, Mani SB, He Y, et al. Induced Superficial Chondrocyte Death Reduces Catabolic Cartilage Damage in Murine Posttraumatic Osteoarthritis. J Clin Invest. 2016;126(8):2893–2902. https://doi.org/10.1172/JCI83676
30. Dolgin E. Cellular Rehab: Physical Therapy and Exercise are Critical to the Success of Cell Therapies Approaching the Clinic. The Scientist. 2015. https://www.the-scientist.com/features/cellular-rehab-34432
31. Rando TA, Ambrosio F. Regenerative Rehabilitation: Applied Biophysics Meets Stem Cell Therapeutics. Cell Stem Cell. 2018;22(3):306–309. https://doi.org/10.1016/j.stem.2018.02.003
32. Ito A. Rehabilitation in Regenerative Medicine – Regenerative Rehabilitation. Japanese Journal of Basic Physical Therapy. 2018;21:2–8.
33. Quarta M, Cromie M, Chacon R, et al. Bioengineered Constructs Combined with Exercise Enhance Stem Cell-Mediated Treatment of Volumetric Muscle Loss. Nat Commun. 2017;8:15613. https://doi.org/10.1038/ncomms15613
34. Distefano G, Ferrari RJ, Weiss C, et al. Neuromuscular Electrical Stimulation as a Method to Maximize the Beneficial Effects of Muscle Stem Cells Transplanted into Dystrophic Skeletal Muscle. PLoS One. 2013;8(3):e54922. https://doi.org/10.1371/journal.pone.0054922
35. Imura T, Matsumoto M, Fukazawa T, et al. Interactive Effects of Cell Therapy and Rehabilitation Realize the Full Potential of Neurogenesis in Brain Injury Model. Neurosci Lett. 2013;555:73–78. https://doi.org/10.1016/j.neulet.2013.09.009
36. Sasaki Y, Sasaki M, Kataoka-Sasaki Y, et al. Synergic Effects of Rehabilitation and Intravenous Infusion of Mesenchymal Stem Cells After Stroke in Rats. Phys Ther. 2013;96(11):1791–1798.
37. Tashiro S, Nishimura S, Iwai H, et al. Functional Recovery from Neural Stem/Progenitor Cell Transplantation Combined with Treadmill Training in Mice with Chronic Spinal Cord Injury. Sci Rep. 2016;3(6):30898. https://doi.org/10.1038/srep30898
38. Yamaguchi S, Aoyama T, Ito A, et al. The Effect of Exercise on the Early Stages of Mesenchymal Stromal Cell-Induced Cartilage Repair in a Rat Osteochondral Defect Model. PLoS One. 2016;11(3):e0151580. https://doi.org/10.1371/journal.pone.0151580
39. Yamaguchi S, Aoyama T, Ito A, et al. Effect of Low-Intensity Pulsed Ultrasound after Mesenchymal Stromal Cell Injection to Treat Osteochondral Defects: An in vivo Study. Ultrasound Med Biol. 2016;42(12):2903–2913. https://doi.org/10.1016/j.ultrasmedbio.2016.07.021
40. Ambrosio F, Rando TA. The Regenerative Rehabilitation Collection: A Forum for an Emerging Field. NPJ Regen Med. 2018;3:20. https://doi.org/10.1038/s41536-018-0058-z
41. Iijima H, Isho T, Kuroki H, et al. 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;3:15. https://doi.org/10.1038/s41536-018-0041-8
42. Fahy N, Alini M, Stoddart MJ. Mechanical Stimulation of Mesenchymal Stem Cells: Implications for Cartilage Tissue Engineering. J Orthop Res. 2018;36(1):52–63. https://doi.org/10.1002/jor.23670
43. Choi JR, Yong WY, Choi JY. Effects of Mechanical Loading on Human Mesenchymal Stem Cells for Cartilage Tissue Engineering. J Cell Physiol. 2018;233(3):1913–1928. https://doi.org/10.1002/jcp.26018
44. Baboolal TG, Mastbergen SC, Jones E, et al. Synovial Fluid Hyaluronan Mediates MSC Attachment to Cartilage, a Potential Novel Mechanism Contributing to Cartilage Repair in Osteoarthritis Using Knee Joint Distraction. Ann Rheum Dis. 2016;75(5):908–915. https://doi.org/10.1136/annrheumdis-2014-206847
45. Harada Y, Nakasa T, Mahmoud EE, et al. Combination Therapy With Intra-Articular Injection of Mesenchymal Stem Cells and Articulated Joint Distraction for Repair of a Chronic Osteochondral Defect in the Rabbit. J Orthop Res. 2015;33(10):1466–1473. https://doi.org/10.1002/jor.22922
46. Dobson F, Hinman RS, Roos EM, et al. OARSI Recommended Performance-Based Tests to Assess Physical Function in People Diagnosed with Hip or Knee Osteoarthritis. Osteoarthritis Cartilage. 2013;21(8):1042–1052. https://doi.org/10.1016/j.joca.2013.05.002
47. Mills K, Hunt Ma, Ferber R. Biomechanical Deviations During Level Walking Associated with Knee Osteoarthritis: A Systematic Review and Meta-Analysis. Arthritis Care Res (Hoboken). 2013;65(10):1643–1665. https://doi.org/10.1002/acr.22015
48. Iijima H, Shimoura K, Ono T, et al. Proximal Gait Adaptations in Individuals with Knee Osteoarthritis: A Systematic Review and Meta-Analysis. J Biomech. 2019;87:127–141. https://doi.org/10.1016/j.jbiomech.2019.02.027
49. Yorozu A, Moriguchi T, Takahashi M. Improved Leg Tracking Considering Gait Phase and Spline-Based Interpolation During Turning Motion in Walk Tests. Sensors (Basel). 2015;15(9):22451–22472. https://doi.org/10.3390/s150922451
50. Adachi D, Nishiguchi S, Fukutani N, et al. Generating Linear Regression Model to Predict Motor Functions by Use of Laser Range Finder During TUG. J Orthop Sci. 2017;22(3):549–553.
51. Iijima H, Yoroza A, Suzuki Y, et al. Specific Contribution of Hip Abductor Muscle Strength to Turning Movement in Individuals with Knee Osteoarthritis. Osteoarthritis Cartilage. 2018;26(S1):S388. https://doi.org/10.1016/j.joca.2018.02.756
52. Iijima H, Eguchi R, Aoyama T, et al. Trunk Movement Asymmetry Associated with Pain, Disability, and Quadriceps Strength Asymmetry in Individuals with Knee Osteoarthritis: A Cross-Sectional Study. Osteoarthritis Cartilage. 2019;27(2):248–256. https://doi.org/10.1016/j.joca.2018.10.012
53. Andriacchi TP, Andersson GB, Fermier RW, et al. A Study of Lower-Limb Mechanics During Stair-Climbing. J Bone Joint Surg Am. 1980;62(5):749–757.
54. Nadeau S, McFadyen BJ, Malouin F. Frontal and Sagittal Plane Analyses of the Stair Climbing Task in Healthy Adults Aged Over 40 Years: What are the Challenges Compared to Level Walking? Clin Biomech (Bristol, Avon). 2003;18(10):950–959. https://doi.org/10.1016/s0268-0033(03)00179-7
55. Iijima H, Shimoura K, Eguchi R, et al. Concurrent Validity and Measurement Error of Stair Climb Test in People With Pre-Radiographic to Mild Knee Osteoarthritis. Gait Posture. 2019;68:335–339. https://doi.org/10.1016/j.gaitpost.2018.12.014
56. Tolk JJ, Janssen RPA, Prinsen CAC, et al. The OARSI Core Set of Performance-Based Measures for Knee Osteoarthritis is Reliable but not Valid and Responsive. Knee Surg Sports Traumatol Arthrosc. 2019;27(9):2898–2909. https://doi.org/10.1007/s00167-017-4789-y
57. Iijima H, Shimoura K, Aoyama T, et al. Biomechanical Characteristics of Stair Ambulation in Patients with Knee OA: A Systematic Review with Meta-Analysis Toward a Better Definition of Clinical Hallmarks. Gait Posture. 2018;62:191–201. https://doi.org/10.1016/j.gaitpost.2018.03.002
58. Ogawa A, Mita A, Yorozu A, et al. Markerless Knee Joint Position Measurement Using Depth Data during Stair Walking. Sensors (Basel). 2017;17(11):2698. https://doi.org/10.3390/s17112698