The Role of Exerkines in the Treatment of Knee Osteoarthritis: From Mechanisms to Exercise Strategies

Yuxiong Xu , Yizhuo Yang , Hanan Song , Ming Li , Weihao Shi , Tongwu Yu , Jianhao Lin , Yanli Yu

Orthopaedic Surgery ›› 2025, Vol. 17 ›› Issue (4) : 1021 -1035.

PDF
Orthopaedic Surgery ›› 2025, Vol. 17 ›› Issue (4) : 1021 -1035. DOI: 10.1111/os.14365
REVIEW ARTICLE

The Role of Exerkines in the Treatment of Knee Osteoarthritis: From Mechanisms to Exercise Strategies

Author information +
History +
PDF

Abstract

With the increasing prevalence of knee osteoarthritis (KOA), the limitations of traditional treatments, such as their limited efficacy in halting disease progression and their potential side effects, are becoming more evident. This situation has prompted scientists to seek more effective strategies. In recent years, exercise therapy has gained prominence in KOA treatment due to its safety, efficacy, and cost-effectiveness, which are underpinned by the molecular actions of exerkines. Unlike conventional therapies, exerkines offer specific advantages by targeting inflammatory responses, enhancing chondrocyte proliferation, and slowing cartilage degradation at the molecular level. This review explores the potential mechanisms involved in and application prospects of exerkines in KOA treatment and provides a comprehensive analysis of their role. Studies show that appropriate exercise not only promotes overall health, but also positively impacts KOA by stimulating exerkine production. The effectiveness of exerkines, however, is influenced by exercise modality, intensity, and duration of exercise, making the development of personalized exercise plans crucial for KOA patients. Based on these insights, this paper proposes targeted exercise strategies designed to maximize exerkine benefits, aiming to provide novel perspectives for KOA prevention and treatment.

Keywords

exercise intensity / exercise modality / exerkines / knee osteoarthritis

Cite this article

Download citation ▾
Yuxiong Xu, Yizhuo Yang, Hanan Song, Ming Li, Weihao Shi, Tongwu Yu, Jianhao Lin, Yanli Yu. The Role of Exerkines in the Treatment of Knee Osteoarthritis: From Mechanisms to Exercise Strategies. Orthopaedic Surgery, 2025, 17(4): 1021-1035 DOI:10.1111/os.14365

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

D. J. Hunter and S. Bierma-Zeinstra, “Osteoarthritis,” Lancet 393, no. 10182 (2019): 1745-1759.

[2]

J. G. Quicke, P. G. Conaghan, N. Corp, and G. Peat, “Osteoarthritis Year in Review 2021: Epidemiology & Therapy,” Osteoarthritis and Cartilage 30, no. 2 (2022): 196-206.

[3]

Q. Yao, X. Wu, C. Tao, et al., “Osteoarthritis: Pathogenic Signaling Pathways and Therapeutic Targets,” Signal Transduction and Targeted Therapy 8, no. 1 (2023): 56.

[4]

Y. J. Xiang and S. M. Dai, “Prevalence of Rheumatic Diseases and Disability in China,” Rheumatology International 29, no. 5 (2009): 481-490.

[5]

X. Tang, S. Wang, S. Zhan, et al., “The Prevalence of Symptomatic Knee Osteoarthritis in China: Results From the China Health and Retirement Longitudinal Study,” Arthritis & Rhematology 68, no. 3 (2016): 648-653.

[6]

E. Bandak, R. Christensen, A. Overgaard, et al., “Exercise and Education Versus Saline Injections for Knee Osteoarthritis: A Randomised Controlled Equivalence Trial,” Annals of the Rheumatic Diseases 81, no. 4 (2022): 537-543.

[7]

R. Geng, J. Li, C. Yu, et al., “Knee Osteoarthritis: Current Status and Research Progress in Treatment (Review),” Experimental and Therapeutic Medicine 26, no. 4 (2023): 481.

[8]

A. Safdar, A. Saleem, and M. A. Tarnopolsky, “The Potential of Endurance Exercise-Derived Exosomes to Treat Metabolic Diseases,” Nature Reviews. Endocrinology 12, no. 9 (2016): 504-517.

[9]

W. R. Thompson, R. Sallis, E. Joy, C. A. Jaworski, R. M. Stuhr, and J. L. Trilk, “Exercise Is Medicine,” American Journal of Lifestyle Medicine 14, no. 5 (2020): 511-523.

[10]

C. M. Tipton, “The History of "Exercise Is Medicine" in Ancient Civilizations,” Advances in Physiology Education 38, no. 2 (2014): 109-117.

[11]

R. J. Shephard and P. N. Shek, “Exercise, Aging and Immune Function,” International Journal of Sports Medicine 16, no. 1 (1995): 1-6.

[12]

M. S. Nash, “Exercise and Immunology,” Medicine and Science in Sports and Exercise 26, no. 2 (1994): 125-127.

[13]

R. Guthold, G. A. Stevens, L. M. Riley, and F. C. Bull, “Worldwide Trends in Insufficient Physical Activity From 2001 to 2016: A Pooled Analysis of 358 Population-Based Surveys With 1.9 Million Participants,” Lancet Global Health 6, no. 10 (2018): e1077-e1086.

[14]

H. Kong, X. Q. Wang, and X. A. Zhang, “Exercise for Osteoarthritis: A Literature Review of Pathology and Mechanism,” Frontiers in Aging Neuroscience 14 (2022): 854026.

[15]

G. N. Ruegsegger and F. W. Booth, “Health Benefits of Exercise,” Cold Spring Harbor Perspectives in Medicine 8, no. 7 (2018): a029694.

[16]

A. Steensberg, G. van Hall, T. Osada, M. Sacchetti, B. Saltin, and B. K. Pedersen, “Production of Interleukin-6 in Contracting Human Skeletal Muscles Can Account for the Exercise-Induced Increase in Plasma Interleukin-6,” Journal of Physiology 529, no. Pt 1 (2000): 237-242.

[17]

M. Singh, S. Valecha, R. Khinda, et al., “Multifactorial Landscape Parses to Reveal a Predictive Model for Knee Osteoarthritis,” International Journal of Environmental Research and Public Health 18, no. 11 (2021): 5933.

[18]

R. Starkie, S. R. Ostrowski, S. Jauffred, M. Febbraio, and B. K. Pedersen, “Exercise and IL-6 Infusion Inhibit Endotoxin-Induced TNF-Alpha Production in Humans,” FASEB Journal 17, no. 8 (2003): 884-886.

[19]

L. Busija, L. Bridgett, S. R. M. Williams, et al., “Osteoarthritis,” Best Practice & Research. Clinical Rheumatology 24, no. 6 (2010): 757-768.

[20]

J. W. Michael, K. U. Schlüter-Brust, and P. Eysel, “The Epidemiology, Etiology, Diagnosis, and Treatment of Osteoarthritis of the Knee,” Deutsches Ärzteblatt International 107, no. 9 (2010): 152-162.

[21]

R. P. Welsh, “Knee Joint Structure and Function,” Clinical Orthopaedics and Related Research 147 (1980): 7-14.

[22]

Y. Luo, D. Sinkeviciute, Y. He, et al., “The Minor Collagens in Articular Cartilage,” Protein & Cell 8, no. 8 (2017): 560-572.

[23]

A. D. Theocharis, S. S. Skandalis, C. Gialeli, and N. K. Karamanos, “Extracellular Matrix Structure,” Advanced Drug Delivery Reviews 97 (2016): 4-27.

[24]

C. J. Malemud, “Matrix Metalloproteinases and Synovial Joint Pathology,” Progress in Molecular Biology and Translational Science 148 (2017): 305-325.

[25]

M. Setayeshmehr, E. Esfandiari, M. Rafieinia, et al., “Hybrid and Composite Scaffolds Based on Extracellular Matrices for Cartilage Tissue Engineering,” Tissue Engineering. Part B, Reviews 25, no. 3 (2019): 202-224.

[26]

M. Kapoor, J. Martel-Pelletier, D. Lajeunesse, J. P. Pelletier, and H. Fahmi, “Role of Proinflammatory Cytokines in the Pathophysiology of Osteoarthritis,” Nature Reviews Rheumatology 7, no. 1 (2011): 33-42.

[27]

K. Sun, J. Luo, J. Guo, X. Yao, X. Jing, and F. Guo, “The PI3K/AKT/mTOR Signaling Pathway in Osteoarthritis: A Narrative Review,” Osteoarthritis and Cartilage 28, no. 4 (2020): 400-409.

[28]

G. Musumeci, C. Loreto, M. L. Carnazza, and G. Martinez, “Characterization of Apoptosis in Articular Cartilage Derived From the Knee Joints of Patients With Osteoarthritis,” Knee Surgery, Sports Traumatology, Arthroscopy 19, no. 2 (2011): 307-313.

[29]

J. Yang, S. Hu, Y. Bian, et al., “Targeting Cell Death: Pyroptosis, Ferroptosis, Apoptosis and Necroptosis in Osteoarthritis,” Frontiers in Cell and Development Biology 9 (2021): 789948.

[30]

C. M. Thomas, C. E. Whittles, C. J. Fuller, and M. Sharif, “Variations in Chondrocyte Apoptosis May Explain the Increased Prevalence of Osteoarthritis in Some Joints,” Rheumatology International 31, no. 10 (2011): 1341-1348.

[31]

D. C. Bauer, D. J. Hunter, S. B. Abramson, et al., “Classification of Osteoarthritis Biomarkers: A Proposed Approach,” Osteoarthritis and Cartilage 14, no. 8 (2006): 723-727.

[32]

J. Bondeson, A. B. Blom, S. Wainwright, C. Hughes, B. Caterson, and W. B. van den Berg, “The Role of Synovial Macrophages and Macrophage-Produced Mediators in Driving Inflammatory and Destructive Responses in Osteoarthritis,” Arthritis and Rheumatism 62, no. 3 (2010): 647-657.

[33]

J. E. Woodell-May and S. D. Sommerfeld, “Role of Inflammation and the Immune System in the Progression of Osteoarthritis,” Journal of Orthopaedic Research 38, no. 2 (2020): 253-257.

[34]

M. H. J. van den Bosch, “Inflammation in Osteoarthritis: Is It Time to Dampen the Alarm(in) in This Debilitating Disease?,” Clinical and Experimental Immunology 195, no. 2 (2019): 153-166.

[35]

R. Liu-Bryan, “Synovium and the Innate Inflammatory Network in Osteoarthritis Progression,” Current Rheumatology Reports 15, no. 5 (2013): 323.

[36]

M. S. D'Arcy, “Cell Death: A Review of the Major Forms of Apoptosis, Necrosis and Autophagy,” Cell Biology International 43, no. 6 (2019): 582-592.

[37]

P. Dalle Pezze, S. Ruf, A. G. Sonntag, et al., “A Systems Study Reveals Concurrent Activation of AMPK and mTOR by Amino Acids,” Nature Communications 7 (2016): 13254.

[38]

Y. Zhang, F. Vasheghani, Y. H. Li, et al., “Cartilage-Specific Deletion of mTOR Upregulates Autophagy and Protects Mice From Osteoarthritis,” Annals of the Rheumatic Diseases 74, no. 7 (2015): 1432-1440.

[39]

P. Peixoto, P. F. Cartron, A. A. Serandour, and E. Hervouet, “From 1957 to Nowadays: A Brief History of Epigenetics,” International Journal of Molecular Sciences 21, no. 20 (2020): 7571.

[40]

R. F. Pérez, J. R. Tejedor, A. F. Fernández, and M. F. Fraga, “Aging and Cancer Epigenetics: Where Do the Paths Fork?,” Aging Cell 21, no. 10 (2022): e13709.

[41]

M. Kato and R. Natarajan, “Epigenetics and Epigenomics in Diabetic Kidney Disease and Metabolic Memory,” Nature Reviews. Nephrology 15, no. 6 (2019): 327-345.

[42]

U. Styrkarsdottir, S. H. Lund, G. Thorleifsson, et al., “Meta-Analysis of Icelandic and UK Data Sets Identifies Missense Variants in SMO, IL11, COL11A1 and 13 More New Loci Associated With Osteoarthritis,” Nature Genetics 50, no. 12 (2018): 1681-1687.

[43]

M. D. Gallagher and A. S. Chen-Plotkin, “The Post-GWAS Era: From Association to Function,” American Journal of Human Genetics 102, no. 5 (2018): 717-730.

[44]

M. Yun, J. Wu, J. L. Workman, and B. Li, “Readers of Histone Modifications,” Cell Research 21, no. 4 (2011): 564-578.

[45]

N. Fujita, T. Matsushita, K. Ishida, et al., “Potential Involvement of SIRT1 in the Pathogenesis of Osteoarthritis Through the Modulation of Chondrocyte Gene Expressions,” Journal of Orthopaedic Research 29, no. 4 (2011): 511-515.

[46]

S. Panni, R. C. Lovering, P. Porras, and S. Orchard, “Non-Coding RNA Regulatory Networks,” Biochimica et Biophysica Acta, Gene Regulatory Mechanisms 1863, no. 6 (2020): 194417.

[47]

R. Coutinho de Almeida, Y. F. M. Ramos, A. Mahfouz, et al., “RNA Sequencing Data Integration Reveals an miRNA Interactome of Osteoarthritis Cartilage,” Annals of the Rheumatic Diseases 78, no. 2 (2019): 270-277.

[48]

E. Hong and A. H. Reddi, “MicroRNAs in Chondrogenesis, Articular Cartilage, and Osteoarthritis: Implications for Tissue Engineering,” Tissue Engineering. Part B, Reviews 18, no. 6 (2012): 445-453.

[49]

S. Tangyuenyong, P. Kongdang, N. Sirikaew, and S. Ongchai, “First Study on the Effect of Transforming Growth Factor Beta 1 and Insulin-Like Growth Factor 1 on the Chondrogenesis of Elephant Articular Chondrocytes in a Scaffold-Based 3D Culture Model,” Veterinary World 15, no. 7 (2022): 1869-1879.

[50]

F. S. Wang, C. W. Kuo, J. Y. Ko, et al., “Irisin Mitigates Oxidative Stress, Chondrocyte Dysfunction and Osteoarthritis Development Through Regulating Mitochondrial Integrity and Autophagy,” Antioxidants (Basel) 9, no. 9 (2020): 810.

[51]

G. Vadalà, G. di Giacomo, L. Ambrosio, et al., “Irisin Recovers Osteoarthritic Chondrocytes In Vitro,” Cells 9, no. 6 (2020): 1478.

[52]

S. A. Jones and B. J. Jenkins, “Recent Insights Into Targeting the IL-6 Cytokine Family in Inflammatory Diseases and Cancer,” Nature Reviews. Immunology 18, no. 12 (2018): 773-789.

[53]

S. Jia, Z. Yu, and L. Bai, “Exerkines and Osteoarthritis,” Frontiers in Physiology 14 (2023): 1302769.

[54]

F. Yang, S. Zhou, C. Wang, et al., “Epigenetic Modifications of Interleukin-6 in Synovial Fibroblasts From Osteoarthritis Patients,” Scientific Reports 7 (2017): 43592.

[55]

J. Bergmann, M. Müller, N. Baumann, et al., “IL-6 Trans-Signaling Is Essential for the Development of Hepatocellular Carcinoma in Mice,” Hepatology 65, no. 1 (2017): 89-103.

[56]

J. Scheller, A. Chalaris, D. Schmidt-Arras, and S. Rose-John, “The Pro- and Anti-Inflammatory Properties of the Cytokine Interleukin-6,” Biochimica et Biophysica Acta 1813, no. 5 (2011): 878-888.

[57]

A. I. Tsuchida, M. Beekhuizen, M. Rutgers, et al., “Interleukin-6 Is Elevated in Synovial Fluid of Patients With Focal Cartilage Defects and Stimulates Cartilage Matrix Production in an In Vitro Regeneration Model,” Arthritis Research & Therapy 14, no. 6 (2012): R262.

[58]

R. Wiegertjes, F. A. J. van de Loo, and E. N. Blaney Davidson, “A Roadmap to Target Interleukin-6 in Osteoarthritis,” Rheumatology (Oxford) 59, no. 10 (2020): 2681-2694.

[59]

M. Peters, S. Jacobs, M. Ehlers, et al., “The Function of the Soluble Interleukin 6 (IL-6) Receptor In Vivo: Sensitization of Human Soluble IL-6 Receptor Transgenic Mice Towards IL-6 and Prolongation of the Plasma Half-Life of IL-6,” Journal of Experimental Medicine 183, no. 4 (1996): 1399-1406.

[60]

R. Wiegertjes, N. G. M. Thielen, A. P. M. van Caam, et al., “Increased IL-6 Receptor Expression and Signaling in Ageing Cartilage Can Be Explained by Loss of TGF-β-Mediated IL-6 Receptor Suppression,” Osteoarthritis and Cartilage 29, no. 5 (2021): 773-782.

[61]

P. Tucker, B. Pfefferbaum, P. Nitiéma, Q. Khan, R. Aggarwal, and E. E. Walling, “Possible Link of Interleukin-6 and Interleukin-2 With Psychiatric Diagnosis, Ethnicity, Disaster or BMI,” Cytokine 96 (2017): 247-252.

[62]

J. H. Ryu, S. Yang, Y. Shin, J. Rhee, C. H. Chun, and J. S. Chun, “Interleukin-6 Plays an Essential Role in Hypoxia-Inducible Factor 2α-Induced Experimental Osteoarthritic Cartilage Destruction in Mice,” Arthritis and Rheumatism 63, no. 9 (2011): 2732-2743.

[63]

S. Liu, Z. Deng, K. Chen, et al., “Cartilage Tissue Engineering: From Proinflammatory and Anti-Inflammatory Cytokines to Osteoarthritis Treatments (Review),” Molecular Medicine Reports 25, no. 3 (2022): 12615.

[64]

J. M. Wilson, J. H. Yoon, C. J. Mun, et al., “The Association Between Changes in Clinical Pain Severity and IL-6 Reactivity Among Patients Undergoing Total Knee Arthroplasty: The Moderating Role of Change in Insomnia,” Brain, Behavior, and Immunity 120 (2024): 199-207.

[65]

E. Das Gupta, W. R. Ng, S. F. Wong, A. K. Bhurhanudeen, and S. S. Yeap, “Correlation of Serum Cartilage Oligomeric Matrix Protein (COMP) and Interleukin-16 (IL-16) Levels With Disease Severity in Primary Knee Osteoarthritis: A Pilot Study in a Malaysian Population,” PLoS One 12, no. 9 (2017): e0184802.

[66]

S. Nasi, A. So, C. Combes, M. Daudon, and N. Busso, “Interleukin-6 and Chondrocyte Mineralisation Act in Tandem to Promote Experimental Osteoarthritis,” Annals of the Rheumatic Diseases 75, no. 7 (2016): 1372-1379.

[67]

C. Keller, A. Steensberg, A. K. Hansen, C. P. Fischer, P. Plomgaard, and B. K. Pedersen, “Effect of Exercise, Training, and Glycogen Availability on IL-6 Receptor Expression in Human Skeletal Muscle,” Journal of Applied Physiology (1985) 99, no. 6 (2005): 2075-2079.

[68]

M. A. Szychlinska, P. Castrogiovanni, F. M. Trovato, et al., “Physical Activity and Mediterranean Diet Based on Olive Tree Phenolic Compounds From Two Different Geographical Areas Have Protective Effects on Early Osteoarthritis, Muscle Atrophy and Hepatic Steatosis,” European Journal of Nutrition 58, no. 2 (2019): 565-581.

[69]

C. E. Franciozi, V. A. F. Tarini, R. D. Reginato, et al., “Gradual Strenuous Running Regimen Predisposes to Osteoarthritis due to Cartilage Cell Death and Altered Levels of Glycosaminoglycans,” Osteoarthritis and Cartilage 21, no. 7 (2013): 965-972.

[70]

K. Ostrowski, T. Rohde, S. Asp, P. Schjerling, and B. K. Pedersen, “Pro- and Anti-Inflammatory Cytokine Balance in Strenuous Exercise in Humans,” Journal of Physiology 515, no. Pt 1 (1999): 287-291.

[71]

B. K. Pedersen, A. Steensberg, and P. Schjerling, “Exercise and Interleukin-6,” Current Opinion in Hematology 8, no. 3 (2001): 137-141.

[72]

M. Despeghel, T. Reichel, J. Zander, K. Krüger, and C. Weyh, “Effects of a 6 Week Low-Dose Combined Resistance and Endurance Training on T Cells and Systemic Inflammation in the Elderly,” Cells 10, no. 4 (2021): 843.

[73]

C. A. Libardi, G. V. De Souza, C. R. Cavaglieri, V. A. Madruga, and M. P. T. Chacon-Mikahil, “Effect of Resistance, Endurance, and Concurrent Training on TNF-α, IL-6, and CRP,” Medicine and Science in Sports and Exercise 44, no. 1 (2012): 50-56.

[74]

S. P. Messier, S. L. Mihalko, D. P. Beavers, et al., “Effect of High-Intensity Strength Training on Knee Pain and Knee Joint Compressive Forces Among Adults With Knee Osteoarthritis: The START Randomized Clinical Trial,” JAMA 325, no. 7 (2021): 646-657.

[75]

D. T. Holyoak, C. Chlebek, M. J. Kim, T. M. Wright, M. Otero, and M. C. H. van der Meulen, “Low-Level Cyclic Tibial Compression Attenuates Early Osteoarthritis Progression After Joint Injury in Mice,” Osteoarthritis and Cartilage 27, no. 10 (2019): 1526-1536.

[76]

J. Multanen, T. Rantalainen, H. Kautiainen, et al., “Effect of Progressive High-Impact Exercise on Femoral Neck Structural Strength in Postmenopausal Women With Mild Knee Osteoarthritis: A 12-Month RCT,” Osteoporosis International 28, no. 4 (2017): 1323-1333.

[77]

B. E. Forbes, A. J. Blyth, and J. M. Wit, “Disorders of IGFs and IGF-1R Signaling Pathways,” Molecular and Cellular Endocrinology 518 (2020): 111035.

[78]

D. Le Roith, “Seminars in Medicine of the Beth Israel Deaconess Medical Center. Insulin-Like Growth Factors,” New England Journal of Medicine 336, no. 9 (1997): 633-640.

[79]

B. C. Nindl, M. Santtila, J. Vaara, K. Hakkinen, and H. Kyrolainen, “Circulating IGF-I Is Associated With Fitness and Health Outcomes in a Population of 846 Young Healthy Men,” Growth Hormone & IGF Research 21, no. 3 (2011): 124-128.

[80]

J. Zhong, J. Zhang, Z. Zhou, et al., “Novel Insights Into the Effect of Deer IGF-1 on Chondrocyte Viability and IL-1β-Induced Inflammation Response,” Journal of Biochemical and Molecular Toxicology 37, no. 1 (2023): e23227.

[81]

M. Majorczyk and D. Smoląg, “Effect of Physical Activity on IGF-1 and IGFBP Levels in the Context of Civilization Diseases Prevention,” Roczniki Państwowego Zakładu Higieny 67, no. 2 (2016): 105-111.

[82]

L. Cai, F. W. Okumu, J. L. Cleland, et al., “A Slow Release Formulation of Insulin as a Treatment for Osteoarthritis,” Osteoarthritis and Cartilage 10, no. 9 (2002): 692-706.

[83]

T. E. McAlindon, J. D. Teale, and P. A. Dieppe, “Levels of Insulin Related Growth Factor 1 in Osteoarthritis of the Knee,” Annals of the Rheumatic Diseases 52, no. 3 (1993): 229-231.

[84]

M. Wiciński, D. Szwedowski, Ł. Wróbel, S. Jeka, and J. Zabrzyński, “The Influence of Body Mass Index on Growth Factor Composition in the Platelet-Rich Plasma in Patients With Knee Osteoarthritis,” International Journal of Environmental Research and Public Health 20, no. 1 (2022): 40.

[85]

R. F. Loeser, G. Shanker, C. S. Carlson, J. F. Gardin, B. J. Shelton, and W. E. Sonntag, “Reduction in the Chondrocyte Response to Insulin-Like Growth Factor 1 in Aging and Osteoarthritis: Studies in a Non-human Primate Model of Naturally Occurring Disease,” Arthritis and Rheumatism 43, no. 9 (2000): 2110-2120.

[86]

S. Hooshmand, S. Juma, D. A. Khalil, P. Shamloufard, and B. H. Arjmandi, “Women With Osteoarthritis Have Elevated Synovial Fluid Levels of Insulin-Like Growth Factor (IGF)-1 and IGF-Binding Protein-3,” Journal of Immunoassay & Immunochemistry 36, no. 3 (2015): 284-294.

[87]

K. J. Ekenstedt, W. E. Sonntag, R. F. Loeser, B. R. Lindgren, and C. S. Carlson, “Effects of Chronic Growth Hormone and Insulin-Like Growth Factor 1 Deficiency on Osteoarthritis Severity in Rat Knee Joints,” Arthritis and Rheumatism 54, no. 12 (2006): 3850-3858.

[88]

L. Feng, B. Li, Y. Xi, M. Cai, and Z. Tian, “Aerobic Exercise and Resistance Exercise Alleviate Skeletal Muscle Atrophy Through IGF-1/IGF-1R-PI3K/Akt Pathway in Mice With Myocardial Infarction,” American Journal of Physiology. Cell Physiology 322, no. 2 (2022): C164-c176.

[89]

T. Mushtaq, P. Bijman, S. F. Ahmed, and C. Farquharson, “Insulin-Like Growth Factor-I Augments Chondrocyte Hypertrophy and Reverses Glucocorticoid-Mediated Growth Retardation in Fetal Mice Metatarsal Cultures,” Endocrinology 145, no. 5 (2004): 2478-2486.

[90]

M. Koike, Y. Yamanaka, M. Inoue, H. Tanaka, R. Nishimura, and Y. Seino, “Insulin-Like Growth Factor-1 Rescues the Mutated FGF Receptor 3 (G380R) Expressing ATDC5 Cells From Apoptosis Through Phosphatidylinositol 3-Kinase and MAPK,” Journal of Bone and Mineral Research 18, no. 11 (2003): 2043-2051.

[91]

T. Yokota, H. Shimokawa, S. Shibata, et al., “Insulin-Like Growth Factor I Regulates Apoptosis in Condylar Cartilage,” Journal of Dental Research 87, no. 2 (2008): 159-163.

[92]

P. M. Cunha, J. P. Nunes, C. M. Tomeleri, et al., “Resistance Training Performed With Single and Multiple Sets Induces Similar Improvements in Muscular Strength, Muscle Mass, Muscle Quality, and IGF-1 in Older Women: A Randomized Controlled Trial,” Journal of Strength and Conditioning Research 34, no. 4 (2020): 1008-1016.

[93]

A. Grubb, S. Joanisse, D. R. Moore, et al., “IGF-1 Colocalizes With Muscle Satellite Cells Following Acute Exercise in Humans,” Applied Physiology, Nutrition, and Metabolism 39, no. 4 (2014): 514-518.

[94]

S. Rojas Vega, A. Knicker, W. Hollmann, W. Bloch, and H. K. Strüder, “Effect of Resistance Exercise on Serum Levels of Growth Factors in Humans,” Hormone and Metabolic Research 42, no. 13 (2010): 982-986.

[95]

H. Koistinen, R. Koistinen, L. Selenius, Q. Ylikorkala, and M. Seppala, “Effect of Marathon Run on Serum IGF-I and IGF-Binding Protein 1 and 3 Levels,” Journal of Applied Physiology (Bethesda, MD: 1985) 80, no. 3 (1996): 760-764.

[96]

Y. Chen, J. Wang, S. Li, and Y. Li, “Acute Effects of Low Load Resistance Training With Blood Flow Restriction on Serum Growth Hormone, Insulin-Like Growth Factor-1, and Testosterone in Patients With Mild to Moderate Unilateral Knee Osteoarthritis,” Heliyon 8, no. 10 (2022): e11051.

[97]

Q. Jiang, K. Lou, L. Hou, et al., “The Effect of Resistance Training on Serum Insulin-Like Growth Factor 1(IGF-1): A Systematic Review and Meta-Analysis,” Complementary Therapies in Medicine 50 (2020): 102360.

[98]

J. R. Pierce, B. J. Martin, K. R. Rarick, et al., “Growth Hormone and Insulin-Like Growth Factor-I Molecular Weight Isoform Responses to Resistance Exercise Are Sex-Dependent,” Frontiers in Endocrinology (Lausanne) 11 (2020): 571.

[99]

D. W. Kang, E. Bressel, and D. Y. Kim, “Effects of Aquatic Exercise on Insulin-Like Growth Factor-1, Brain-Derived Neurotrophic Factor, Vascular Endothelial Growth Factor, and Cognitive Function in Elderly Women,” Experimental Gerontology 132 (2020): 110842.

[100]

S. M. Gregory, B. A. Spiering, J. A. Alemany, et al., “Exercise-Induced Insulin-Like Growth Factor I System Concentrations After Training in Women,” Medicine and Science in Sports and Exercise 45, no. 3 (2013): 420-428.

[101]

G. McMahon, C. I. Morse, A. Burden, K. Winwood, and G. L. Onambélé, “Muscular Adaptations and Insulin-Like Growth Factor-1 Responses to Resistance Training Are Stretch-Mediated,” Muscle & Nerve 49, no. 1 (2014): 108-119.

[102]

Y. Zhang and J. Que, “BMP Signaling in Development, Stem Cells, and Diseases of the Gastrointestinal Tract,” Annual Review of Physiology 82 (2020): 251-273.

[103]

K. Janssens, P. ten Dijke, S. Janssens, and W. van Hul, “Transforming Growth Factor-beta1 to the Bone,” Endocrine Reviews 26, no. 6 (2005): 743-774.

[104]

M. G. Chambers, M. T. Bayliss, and R. M. Mason, “Chondrocyte Cytokine and Growth Factor Expression in Murine Osteoarthritis,” Osteoarthritis and Cartilage 5, no. 5 (1997): 301-308.

[105]

B. Halper, M. Hofmann, S. Oesen, et al., “Influence of Age and Physical Fitness on miRNA-21, TGF-β and Its Receptors in Leukocytes of Healthy Women,” Exercise Immunology Review 21 (2015): 154-163.

[106]

L. Ning, M. Ishijima, H. Kaneko, et al., “Correlations Between Both the Expression Levels of Inflammatory Mediators and Growth Factor in Medial Perimeniscal Synovial Tissue and the Severity of Medial Knee Osteoarthritis,” International Orthopaedics 35, no. 6 (2011): 831-838.

[107]

J. He, W. Cao, I. Azeem, Q. Zhao, and Z. Shao, “Transforming Growth Factor Beta1 Being Considered a Novel Biomarker in Knee Osteoarthritis,” Clinica Chimica Acta 472 (2017): 96-101.

[108]

H. Takahashi, C. R. R. Alves, K. I. Stanford, et al., “TGF-β2 Is an Exercise-Induced Adipokine That Regulates Glucose and Fatty Acid Metabolism,” Nature Metabolism 1, no. 2 (2019): 291-303.

[109]

Q. Zhang, S. Lai, X. Hou, W. Cao, Y. Zhang, and Z. Zhang, “Protective Effects of PI3K/Akt Signal Pathway Induced Cell Autophagy in Rat Knee Joint Cartilage Injury,” American Journal of Translational Research 10, no. 3 (2018): 762-770.

[110]

L. Zhong, X. Huang, M. Karperien, and J. Post, “The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes,” International Journal of Molecular Sciences 16, no. 8 (2015): 19225-19247.

[111]

R. D. Chavez, G. Coricor, J. Perez, H. S. Seo, and R. Serra, “SOX9 Protein Is Stabilized by TGF-β and Regulates PAPSS2 mRNA Expression in Chondrocytes,” Osteoarthritis and Cartilage 25, no. 2 (2017): 332-340.

[112]

A. Scharstuhl, H. M. van Beuningen, E. L. Vitters, P. M. van der Kraan, and W. B. van den Berg, “Loss of Transforming Growth Factor Counteraction on Interleukin 1 Mediated Effects in Cartilage of Old Mice,” Annals of the Rheumatic Diseases 61, no. 12 (2002): 1095-1098.

[113]

X. Ji, Z. Xu, D. Liu, and Y. Chen, “Effects of Exercise Training on Neurological Recovery, TGF-β1, HIF-1α, and Nogo-NgR Signaling Pathways After Spinal Cord Injury in Rats,” Clinics (São Paulo, Brazil) 78 (2023): 100236.

[114]

A. J. Han, L. C. Alexander, J. L. Huebner, A. B. Reed, and V. B. Kraus, “Increase in Free and Total Plasma TGF-β1 Following Physical Activity,” Cartilage 13, no. 1_suppl (2021): 1741s-1748s.

[115]

Y. Wang, L. Hong, J. Jiang, X. Zhang, J. Chen, and H. Diao, “Osteopontin May Improve Postinjury Muscle Repair via Matrix Metalloproteinases and Tgf-β Activation in Regular Exercise,” International Journal of Medical Sciences 20, no. 9 (2023): 1202-1211.

[116]

I. A. Eka Widiastuti, A. Arsyad, I. Idris, et al., “Exercise Adaptations and TGF-β1 Levels in Recreational Cyclists,” Annals of Medicine and Surgery 70 (2021): 102872.

[117]

H. Xiao, T. Zhang, C. Li, et al., “Mechanical Stimulation Promotes Enthesis Injury Repair by Mobilizing Prrx1(+) Cells via Ciliary TGF-β Signaling,” eLife 11 (2022): e73614.

[118]

R. Nikooie and S. Samaneh, “Exercise-Induced Lactate Accumulation Regulates Intramuscular Triglyceride Metabolism via Transforming Growth Factor-β1 Mediated Pathways,” Molecular and Cellular Endocrinology 419 (2016): 244-251.

[119]

P. Boström, J. Wu, M. P. Jedrychowski, et al., “A PGC1-α-Dependent Myokine That Drives Brown-Fat-Like Development of White Fat and Thermogenesis,” Nature 481, no. 7382 (2012): 463-468.

[120]

F. Roggio, L. Petrigna, B. Trovato, M. di Rosa, and G. Musumeci, “The Role of Lubricin, Irisin and Exercise in the Prevention and Treatment of Osteoarthritis,” International Journal of Molecular Sciences 24, no. 6 (2023): 5126.

[121]

L. Flori, L. Testai, and V. Calderone, “The ‘Irisin System’: From Biological Roles to Pharmacological and Nutraceutical Perspectives,” Life Sciences 267 (2021): 118954.

[122]

Q. Ruan, Y. Huang, L. Yang, et al., “The Effects of Both Age and Sex on Irisin Levels in Paired Plasma and Cerebrospinal Fluid in Healthy Humans,” Peptides 113 (2019): 41-51.

[123]

D. Almeida González, M. C. Rodríguez-Pérez, M. Fuentes Ferrer, F. J. Cuevas Fernández, I. Marcelino Rodríguez, and A. Cabrera de León, “Irisin, in Women and Men: Blood Pressure, Heart Rate, Obesity and Insulin Resistance,” Frontiers in Endocrinology (Lausanne) 14 (2023): 1193110.

[124]

B. Palacios-González, F. Vadillo-Ortega, E. Polo-Oteyza, et al., “Irisin Levels Before and After Physical Activity Among School-Age Children With Different BMI: A Direct Relation With Leptin,” Obesity (Silver Spring) 23, no. 4 (2015): 729-732.

[125]

Y. Mao, W. Xu, Z. Xie, and Q. Dong, “Association of Irisin and CRP Levels With the Radiographic Severity of Knee Osteoarthritis,” Genetic Testing and Molecular Biomarkers 20, no. 2 (2016): 86-89.

[126]

F. Oliviero and R. Ramonda, “Cartilage-Derived Biomarkers in Osteoarthritis,” Indian Journal of Medical Research 153, no. 4 (2021): 413-415.

[127]

X. Li, X. Zhu, H. Wu, et al., “Roles and Mechanisms of Irisin in Attenuating Pathological Features of Osteoarthritis,” Frontiers in Cell and Development Biology 9 (2021): 703670.

[128]

X. Li, Y. Liu, Q. Liu, S. Wang, Y. Ma, and Q. Jin, “Recombinant Human Irisin Regulated Collagen II, Matrix Metalloproteinase-13 and the Wnt/β-Catenin and NF-κB Signaling Pathways in Interleukin-1β-Induced Human SW1353 Cells,” Experimental and Therapeutic Medicine 19, no. 4 (2020): 2879-2886.

[129]

J. Zhang, P. Valverde, X. Zhu, et al., “Exercise-Induced Irisin in Bone and Systemic Irisin Administration Reveal New Regulatory Mechanisms of Bone Metabolism,” Bone Research 5 (2017): 16056.

[130]

M. T. Paris, K. E. Bell, and M. Mourtzakis, “Myokines and Adipokines in Sarcopenia: Understanding Cross-Talk Between Skeletal Muscle and Adipose Tissue and the Role of Exercise,” Current Opinion in Pharmacology 52 (2020): 61-66.

[131]

H. Kim, C. D. Wrann, M. Jedrychowski, et al., “Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors,” Cell 175, no. 7 (2018): 1756-1768.e17.

[132]

D. Löffler, U. Müller, K. Scheuermann, et al., “Serum Irisin Levels Are Regulated by Acute Strenuous Exercise,” Journal of Clinical Endocrinology and Metabolism 100, no. 4 (2015): 1289-1299.

[133]

Y. Tsuchiya, D. Ando, K. Takamatsu, and K. Goto, “Resistance Exercise Induces a Greater Irisin Response Than Endurance Exercise,” Metabolism 64, no. 9 (2015): 1042-1050.

[134]

Y. Liu, C. Guo, S. Liu, S. Zhang, Y. Mao, and L. Fang, “Eight Weeks of High-Intensity Interval Static Strength Training Improves Skeletal Muscle Atrophy and Motor Function in Aged Rats via the PGC-1α/FNDC5/UCP1 Pathway,” Clinical Interventions in Aging 16 (2021): 811-821.

[135]

Y. Tsuchiya, D. Ando, K. Goto, M. Kiuchi, M. Yamakita, and K. Koyama, “High-Intensity Exercise Causes Greater Irisin Response Compared With Low-Intensity Exercise Under Similar Energy Consumption,” Tohoku Journal of Experimental Medicine 233, no. 2 (2014): 135-140.

[136]

J. Park, J. Bae, and J. Lee, “Complex Exercise Improves Anti-Inflammatory and Anabolic Effects in Osteoarthritis-Induced Sarcopenia in Elderly Women,” Healthcare (Basel) 9, no. 6 (2021): 711.

[137]

E. Śliwicka, T. Cisoń, Z. Kasprzak, A. Nowak, and Ł. Pilaczyńska-Szcześniak, “Serum Irisin and Myostatin Levels After 2 Weeks of High-Altitude Climbing,” PLoS One 12, no. 7 (2017): e0181259.

[138]

A. G. Guazzarini, F. Mancinetti, P. Bastiani, et al., “Tai Chi, Irisin and Cognitive Performance: A Clinical and Biological Investigation in Older Adults,” Aging Clinical and Experimental Research 36, no. 1 (2024): 90.

[139]

G. A. Brooks, A. D. Osmond, J. A. Arevalo, et al., “Lactate as a Myokine and Exerkine: Drivers and Signals of Physiology and Metabolism,” Journal of Applied Physiology (Bethesda, MD: 1985) 134, no. 3 (2023): 529-548.

[140]

J. D. Covington, C. S. Tam, S. Bajpeyi, et al., “Myokine Expression in Muscle and Myotubes in Response to Exercise Stimulation,” Medicine and Science in Sports and Exercise 48, no. 3 (2016): 384-390.

[141]

Q. Li, H. Chen, Z. Li, F. Zhang, and L. Chen, “Glucocorticoid Caused Lactic Acid Accumulation and Damage in Human Chondrocytes via ROS-Mediated Inhibition of Monocarboxylate Transporter 4,” Bone 155 (2022): 116299.

[142]

C. Wang, Y. Gao, Z. Zhang, et al., “Ursolic Acid Protects Chondrocytes, Exhibits Anti-Inflammatory Properties via Regulation of the NF-κB/NLRP3 Inflammasome Pathway and Ameliorates Osteoarthritis,” Biomedicine & Pharmacotherapy 130 (2020): 110568.

[143]

N. Ratia, H. Lantto, E. Rotgers, et al., “Lactate and Ammonia Measurements During Cardiopulmonary Exercise Testing and Its Recovery Phase-Consideration of Age and Sex in Its Interpretation,” Clinical Physiology and Functional Imaging 43, no. 4 (2023): 278-290.

[144]

Y. F. Huang, G. Wang, L. Ding, et al., “Lactate-Upregulated NADPH-Dependent NOX4 Expression via HCAR1/PI3K Pathway Contributes to ROS-Induced Osteoarthritis Chondrocyte Damage,” Redox Biology 67 (2023): 102867.

[145]

X. Zhang, Y. Wu, Z. Pan, et al., “The Effects of Lactate and Acid on Articular Chondrocytes Function: Implications for Polymeric Cartilage Scaffold Design,” Acta Biomaterialia 42 (2016): 329-340.

[146]

Z. Zhu, Y. Chen, J. Zou, et al., “Lactate Mediates the Bone Anabolic Effect of High-Intensity Interval Training by Inducing Osteoblast Differentiation,” Journal of Bone and Joint Surgery. American Volume 105, no. 5 (2023): 369-379.

[147]

N. J. Chang, C. C. Lin, M. Y. Shie, et al., “Positive Effects of Cell-Free Porous PLGA Implants and Early Loading Exercise on Hyaline Cartilage Regeneration in Rabbits,” Acta Biomaterialia 28 (2015): 128-137.

[148]

J. Wu, M. Hu, H. Jiang, et al., “Endothelial Cell-Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis,” Advanced Science 10, no. 31 (2023): e2301300.

[149]

M. Samsom, Y. Iwabuchi, H. Sheardown, and T. A. Schmidt, “Proteoglycan 4 and Hyaluronan as Boundary Lubricants for Model Contact Lens Hydrogels,” Journal of Biomedical Materials Research. Part B, Applied Biomaterials 106, no. 3 (2018): 1329-1338.

[150]

H. Ye, M. Han, R. Huang, et al., “Interactions Between Lubricin and Hyaluronic Acid Synergistically Enhance Antiadhesive Properties,” ACS Applied Materials & Interfaces 11, no. 20 (2019): 18090-18102.

[151]

T. E. Ludwig, J. R. McAllister, V. Lun, J. P. Wiley, and T. A. Schmidt, “Diminished Cartilage-Lubricating Ability of Human Osteoarthritic Synovial Fluid Deficient in Proteoglycan 4: Restoration Through Proteoglycan 4 Supplementation,” Arthritis and Rheumatism 64, no. 12 (2012): 3963-3971.

[152]

H. Ogawa, K. Matsumoto, N. Terabayashi, K. Kawashima, K. Takeuchi, and H. Akiyama, “Association of Lubricin Concentration in Synovial Fluid and Clinical Status of Osteoarthritic Knee,” Modern Rheumatology 27, no. 3 (2017): 489-492.

[153]

L. Wei, B. C. Fleming, X. Sun, et al., “Comparison of Differential Biomarkers of Osteoarthritis With and Without Posttraumatic Injury in the Hartley Guinea Pig Model,” Journal of Orthopaedic Research 28, no. 7 (2010): 900-906.

[154]

G. E. Nugent, T. A. Schmidt, B. L. Schumacher, et al., “Static and Dynamic Compression Regulate Cartilage Metabolism of PRoteoGlycan 4 (PRG4),” Biorheology 43, no. 3,4 (2006): 191-200.

[155]

E. Teeple, K. A. Elsaid, B. C. Fleming, et al., “Coefficients of Friction, Lubricin, and Cartilage Damage in the Anterior Cruciate Ligament-Deficient Guinea Pig Knee,” Journal of Orthopaedic Research 26, no. 2 (2008): 231-237.

[156]

S. Y. Lee, T. Niikura, and A. H. Reddi, “Superficial Zone Protein (Lubricin) in the Different Tissue Compartments of the Knee Joint: Modulation by Transforming Growth Factor Beta 1 and Interleukin-1 Beta,” Tissue Engineering. Part A 14, no. 11 (2008): 1799-1808.

[157]

A. Y. Hui, W. J. McCarty, K. Masuda, G. S. Firestein, and R. L. Sah, “A Systems Biology Approach to Synovial Joint Lubrication in Health, Injury, and Disease,” Wiley Interdisciplinary Reviews. Systems Biology and Medicine 4, no. 1 (2012): 15-37.

[158]

A. E. M. Jørgensen, J. Agergaard, P. Schjerling, K. M. Heinemeier, G. van Hall, and M. Kjaer, “The Regional Turnover of Cartilage Collagen Matrix in Late-Stage Human Knee Osteoarthritis,” Osteoarthritis and Cartilage 30, no. 6 (2022): 886-895.

[159]

T. A. Schmidt, N. S. Gastelum, E. H. Han, G. E. Nugent-Derfus, B. L. Schumacher, and R. L. Sah, “Differential Regulation of Proteoglycan 4 Metabolism in Cartilage by IL-1alpha, IGF-I, and TGF-beta1,” Osteoarthritis and Cartilage 16, no. 1 (2008): 90-97.

[160]

P. Castrogiovanni, M. di Rosa, S. Ravalli, et al., “Moderate Physical Activity as a Prevention Method for Knee Osteoarthritis and the Role of Synoviocytes as Biological Key,” International Journal of Molecular Sciences 20, no. 3 (2019): 511.

[161]

S. Ravalli, F. Roggio, G. Lauretta, et al., “Exploiting Real-World Data to Monitor Physical Activity in Patients With Osteoarthritis: The Opportunity of Digital Epidemiology,” Heliyon 8, no. 2 (2022): e08991.

[162]

Y. L. Hsieh and C. C. Yang, “Early Intervention of Swimming Exercises Attenuate Articular Cartilage Destruction in a Rat Model of Anterior Cruciate Ligament and Meniscus Knee Injuries,” Life Sciences 212 (2018): 267-274.

[163]

H. M. Roberts, J. P. Moore, C. L. Griffith-McGeever, M. B. Fortes, and J. M. Thom, “The Effect of Vigorous Running and Cycling on Serum COMP, Lubricin, and Femoral Cartilage Thickness: A Pilot Study,” European Journal of Applied Physiology 116, no. 8 (2016): 1467-1477.

[164]

A. Matheson, S. C. Regmi, G. D. Jay, T. A. Schmidt, and W. M. Scott, “The Effect of Intense Exercise on Equine Serum Proteoglycan-4/Lubricin,” Frontiers in Veterinary Science 7 (2020): 599287.

[165]

G. X. Ni, L. Lei, and Y. Z. Zhou, “Intensity-Dependent Effect of Treadmill Running on Lubricin Metabolism of Rat Articular Cartilage,” Arthritis Research & Therapy 14, no. 6 (2012): R256.

[166]

K. L. Bennell, K. L. Paterson, B. R. Metcalf, et al., “Effect of Intra-Articular Platelet-Rich Plasma vs Placebo Injection on Pain and Medial Tibial Cartilage Volume in Patients With Knee Osteoarthritis: The RESTORE Randomized Clinical Trial,” JAMA 326, no. 20 (2021): 2021-2030.

[167]

L. Li, Z. Li, Y. Li, X. Hu, Y. Zhang, and P. Fan, “Profiling of Inflammatory Mediators in the Synovial Fluid Related to Pain in Knee Osteoarthritis,” BMC Musculoskeletal Disorders 21, no. 1 (2020): 99.

[168]

H. Yuan, L. L. E. Mears, Y. Wang, et al., “Lubricants for Osteoarthritis Treatment: From Natural to Bioinspired and Alternative Strategies,” Advances in Colloid and Interface Science 311 (2023): 102814.

[169]

Y. Li, Z. Yuan, H. Yang, H. Zhong, W. Peng, and R. Xie, “Recent Advances in Understanding the Role of Cartilage Lubrication in Osteoarthritis,” Molecules 26, no. 20 (2021): 6122.

RIGHTS & PERMISSIONS

2025 The Author(s). Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.

AI Summary AI Mindmap
PDF

15

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/