The Study of the Effect of the Aerobic Training Together with Stem Cells on the Ievels of Some of the Apoptosis Indices of the Heart Tissue of the Male Wistar Rats of Osteoarthritis Model

Document Type : Original Article


1 department exercise physiology, School of Sport Sciences, Razi University, Kermanshah, Iran

2 Department of physical education and sport science, Kermanshah branch, Islamic Azad University, Kermanshah, Iran.

3 phd


Background and objective: Osteoarthritis is a common disease and painful arthritis with unknown etiology. In this study, the effects of mesenchymal stem cells and aerobic training on apoptosis biomarkers (BAX and BCL2) in the heart tissue of osteoarthritic rats was investigated.

Materials and methods: In this experimental study, 42 male Wistar rats (age range 6-8 weeks and body weight of 250-300 g) were divided into two groups: osteoarthritic group (n=35) and healthy control group (n=7). osteoarthritis was induced in rats by surgery. then osteoarthritic rats were divided into five subgroups of seven including control, saline, stem cell , aerobic training, and aerobic training+stem cell groups. aerobic training program was conducted for 8 weeks and 5 days a week. apoptosis biomarkers, including BAX and BCL2 proteins in the heart tissue of rats, were measured using ELISA kits. One-way ANOVA used to analyze the data.
Results: BAX concentration was significantly more in saline and unhealthy control groups compared to other groups and BCL2 concentration was significantly less in saline and unhealthy control groups compared to other groups (p<0.001). aerobic training and stem cell, whether used separately or together, caused a significant increase in BCL2 concentration and a significant decrease in BAX concentration (p<0.001).

Conclusion: Osteoarthritis caused an increase in heart cell apoptosis. Although stem sells have anti-apoptosis effects, they will be more effective in treatment if they are used with aerobic training.


1-Chahal  J , Gomez-Aristizabal  A, Shashank K, Chaboureau A , Fazio A and et al. Bone Marrow Mesenchymal Stromal Cell Treatment in Patients with Osteoarthritis Results in Overall Improvement in Pain and Symptoms and Reduces Synovial Inflammation. Stem Cells Transl Med. 2019 Aug; 8(8):746-757.
2-Hasandokht T, Salari A, Salari A, Fazeli A, Ashkan M. Evaluation of Relation between Cardiovascular Risk Factors and Osteoarthritis; Results of the Cross Sectional Study. Feyz, Journal of Kashan University of Medical Sciences, June, 2019; Vol. 23, No 2, Pages 209-215. [Persian]
3-Prior JA, Jordan KP, Kadam UT. Associations between cardiovascular disease severity, osteoarthritis co-morbidity and physical health: a population-based study. Rheumatology (Oxford). 2014 Oct; 53(10):1794-802.
4-Wang HBai JHe BHu XLiu D.Osteoarthritis and the risk of cardiovascular disease: a meta-analysis of observational studies. Sci Rep. 2016 Dec 22;6:39672.
5-Rahman MM, Kopec JA, Anis AH, Cibere J, Goldsmith CH. Risk of cardiovascular disease patients with osteoarthritis: a prospective in longitudinal study. Arthritis Care Res 2013; 65(12): 1951-8
6-Lee MY, Kim WJ, Kang YJ, Jung YM, Kang YM, Suk K, et al. Z39Ig is expressed on macrophages and may mediate inflammatory reactions in arthritis and atherosclerosis. J Leukoc Biol 2006; 80(4): 922-8.
7-Barnabe  C, Billie‐Jean Martin, William A. Ghali. Systematic review and meta‐analysis: Anti–tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2011 Apr; 63(4):522-9.
8-Montazeri F, Rahgozar S, Gaemi K. apoptosis and cytoplasmic organelles. Genetics In The 3rd Millennium 2011; 9(1): 2300-12. [Persian]
9-Wojdasiewicz, P., Poniatowski, Ł. A., & Szukiewicz, D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm. 2014;2014:561459.

10-Franz AJoseph LMayer CHarmsen JFSchrumpf HFröbel JOstapczuk MSKrauspe RZilkens C.The role of oxidative and nitrosative stress in the pathology of osteoarthritis: Novel candidate biomarkers for quantification of degenerative changes in the knee joint. Orthop Rev (Pavia). 2018 Jun 14; 10(2):7460.

11-Lu K, Wang L, Wang C, Yang Y, Hu D, Ding R. Effects of high-intensity interval versus continuous moderate intensity aerobic exercise on apoptosis, oxidative stress and metabolism of the infarcted myocardium in a rat model. Mol Med Rep 2015; 12(2): 2374-82.
12-Kourtis A, Adamopoulos PGPapalois AIliopoulos DCBabis GCScorilas A.  Quantitative analysis and study of the mRNA expression levels of apoptotic genes BCL2, BAX and BCL2L12 in the articular cartilage of an animal model of osteoarthritis. Ann Transl Med. 2018 Jun;6(12):243.

13-Asadi S, Farzanegi P, Azarbayjani M. Effect of exercise, ozone and mesenchymal stem cells therapies on the expression of IL-10 and TNF-α in the cartilage tissue of rats with knee osteoarthritis. Social Determinants of Health .vol 4, no 3(2018).

14-Lems WFden Uyl D. Exercise-induced changes in interleukin-10 in patients with knee osteoarthritis: new perspectives? Arthritis Res Ther. 2010;12(4):131.
15-Kwak HB.  Effects of aging and exercise training on apoptosis in the Heart. J Exerc Rehabil. 2013 Apr; 9(2): 212–219. 
16-Soleimani M, Nadri S, Izadpanah R. Isolation of mesenchymal stem cells from mouse bone marrow: frequent medium change method. Tehran Univ Med J. 2008; 66 (4):229-236. [Persian]
17-Ataie M, Solouk A, Bagheri F, Seyed Jafari E. Regeneration of musculoskeletal injuries using mesenchymal stem cells loaded scaffolds: review article. Tehran University Medical Journal, July 2017; Vol. 75, No. 4: 241-250. [Persian]
18-Gibbs N, Diamond R, Sekyere E, and  Thomas W .Management of knee osteoarthritis by combined stromal vascular fraction cell therapy, platelet-rich plasma, and musculoskeletal exercises: a case series. J Pain Res. 2015; 8: 799–806.
19-Bartels EM, Juhl CB, Christensen R, Hagen KB, Danneskiold-Samsoe B, Dagfinrud H, et al. Aquatic exercise for the treatment of knee and hip osteoarthritis. Cochrane Database Syst Rev. 2016; 3:Cd005523
20-Zhou J, Wang Y, Liu Y, Zeng H, Xu H, Lian F1.Adipose derived mesenchymal stem cells alleviated osteoarthritis and chondrocyte apoptosis through autophagy inducing.J Cell Biochem. 2018 Oct 13.
21-Zhang Y, Yuan M, Cheng L, Lin L, Du H and Chen R. Treadmill exercise enhances therapeutic potency of transplanted bone mesenchymal stem cells in cerebral ischemic rats via anti-apoptotic effects. Published online 2015 Sep 5. 2015; 16: 56.
22-Assis L, Milares L.P, Almeida T, Tim C, Magri A, FernandesC K.R,  Medalha and A.C. Muniz Renno. Aerobic exercise training and low-level laser therapy modulate inflammatory response and degenerative process in an experimental model of knee osteoarthritis in rats. Osteoarthritis Cartilage. 2016 Jan; 24(1):169-77.
23-Assis L, Tim C,  Martignago C,  Rodrigues  S, Ana Muniz Renno C. Effectiveness of photobiomodulation therapy and aerobic exercise training on articular cartilage in an experimental model of osteoarthritis in rats. 2018, San Francisco, California, United States.
24-akbari M, moradi L, alizadeh R, abbasi daloii A. Investigating the Effects of Endurance Training and Gallic Acid on Annexin-5 and caspase-3 of Cardiac Tissue in Male Wistar Rats Undergoing Boldenone. cmja. 2018; 8 (2):2279-2292. [Persian]
25-Sadraie M, Mehrabani D, Vahdati A. Comparison of  therapeutic effects of bone marrow mesenchymal stem cells and liquid culture environment(secreta) in the treatment of induced knee abrasion created in guinea pigs. Armaghane danesh. 2015, 20(8):651-665. [Persian]
26-Galois L, Etienne S, Grossin  L, Pinzano A, Henrionnet C, Loeuille D, Netter P, Mainard D and Gillet P.Dose–response relationship for exercise on severity of experimental osteoarthritis in rats: a pilot study Universite´ Nancy I, France. Department of Orthopaedic Surgery, Universitary Hospital of Nancy, France OsteoArthritis and Cartilage (2004) 12, 779e786.
27-Zhao Y, Liu B, Liu CJ. Establishment of a surgically-induced model in mice to investigate the protective role of progranulin in osteoarthritis. J Vis Exp. 2014; (84): 50924.
28-Emmanuel L. KuyinuGanesh NarayananLakshmi S. Nair, and Cato T. Laurencin.Animal models of osteoarthritis: classification, update, and measurement of outcomes. Journal of Orthopaedic Surgery and Research,volume 11, Article number: 19 (2016). 
29-Sharifi F, Roshan V, Mazaheri Z. Effect of Pretreatment of Aerobic Training on Doxorubicin-induced Left Ventricular Apoptosis Gene Expression in Aging Model Rats. MJMS. 2016; 19 (2):29-43. [Persian]
30-Safarzadeh Gargari S, Homai M, Mousavi Z. Effects of continues exercise on BAX and BCL-2 heart proteins following by different dos of H2O2 consumption in rat male. J Shahid Sadoughi Uni Med Sci 2018; 26(4): 363-73. [Persian]
31-Jonidi Shariatzadeh F, Gheydari K, Solouk A, Bonakdar S. Use of Stem Cells in Cartilage Tissue Regeneration and Engineering: A Review. MJMS. 2018; 21 (1):41-63. [Persian]
32-Sari-Sarraf V, Amirsasan R, Sheikholeslami-Vatani D, Faraji H. Effect of creatine supplementation on the factors involved in apoptosis-related process (Bax, Bcl-2) and their ratio (Bcl-2/Bax) during acute resistance exercise in middle-aged men. Scientific Journal of Kurdistan University of Medical Sciences. No.84/Oct-Nov 2016. [Persian]
33-Ranjbar K, Nazem F, Nazari A, Golami M. Effect of 10 Weeks Aerobic Exercise Training on Left Ventricular Systolic Function, Caspase-3 Level and Infarction Size in Myocardial Infarction Rat. Journal of Knowledge & Health 2015, Volume 10, Number 3 #M0093; Page(s) 16 To 24. [Persian]
34-Hughes EJ. Nutritional Protocol for Osteoarthrosis (Degenerative Joint Disease).  J Clin Nutr Diet. 2016, 2:4. doi:10.4172/2472-1921.100032.
35-Bhatti FUMehmood ALatief NZahra SCho HKhan SNRiazuddin S.Vitamin E protects rat mesenchymal stem cells against hydrogen peroxide-induced oxidative stress in vitro and improves their therapeutic potential in surgically-induced rat model of osteoarthritis. Osteoarthritis Cartilage. 2017 Feb;25(2):321-331
36-Fan MPSi MLi BJHu GHHou YYang WLiu LTang BNie L. Cell therapy of a knee osteoarthritis rat model using precartilaginous stem cells. Eur Rev Med Pharmacol Sci. 2018 Apr;22(7):2119-2125.
37-Centeno  C,  Sheinkop  M,  Stemper I,  Williams  C,  Hyzy  M,  Ichim  T &  Freeman  M. A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: a randomized controlled trial with 2 year follow-up.  J Transl Med. 2018 Dec 13; 16(1):355.
38-fallah mohammadi M, fallah mohammadi Z,mirkarimpour S. Exercise with and without glucosamine supplementation on rat׳s knee osteoarthritis.,journal of sports sciences. University of mazandaran. 10.22080/JAEP.2013.781. [Persian]
39-Franciozi CE1Tarini VAReginato RDGonçalves PRMedeiros VPFerretti MDreyfuss JLNader HBFaloppa F. Gradual strenuous running regimen predisposes to osteoarthritis due to cartilage cell death and  altered levels of glycosaminoglycans.Osteoarthritis Cartilage. 2013 Jul;21(7):965-72.
40-Zhang HJi LYang YWei YZhang XGang YLu JBai L. The Therapeutic Effects of Treadmill Exercise on Osteoarthritis in Rats by Inhibiting the HDAC3/NF-KappaB Pathway in vivo and in vitro. Front Physiol. 2019 Aug 20;10:1060.
41-Castrogiovanni PDi Rosa MRavalli SCastorina AGuglielmino CImbesi RVecchio MDrago FSzychlinska MAMusumeci G .Moderate Physical Activity as a Prevention Method for Knee Osteoarthritis and the Role of Synoviocytes as Biological Key. Int J Mol Sci. 2019 Jan 25;20(3). pii: E511.
42-Musumeci G, Loreto C, Leonardi R, Castorina S, Giunta S, Carnazza ML, Trovato FM, Pichler K, Weinberg AM. The effects of physical activity on apoptosis and lubricin expression in articular cartilage in rats with glucocorticoid-induced osteoporosis.J Bone Miner Metab. 2013 May; 31(3):274-84.
43-Rios J,  Boldt K,  William Mather J,  Seerattan R,  Arthur Hart D, and Walter Herzog. Quantifying the Effects of Different Treadmill Training Speeds and Durations on the Health of Rat Knee Joints.Sports Medicine – Openvolume 4, Article number: 15 (2018) 2018 Dec; 4: 15.
44-Cifuentes D, Rocha L, Silva L. Decrease in oxidative stress and histological changes induced by physical exercise calibrated in rats with osteoarthritis induced by monosodium iodoacetate. Osteoarthritis Cartilage. 2010 Aug; 18(8):1088-95
45-Milares L,  Assis L,  Siqueira A,  Claudino V. Effectiveness of an aquatic exercise program and low-level laser therapy on articular cartilage in an experimental model of osteoarthritis in rats. journal Connective Tissue Research,2016 Sep; 57(5):398-407.
46-Norouzi Kamareh M, Zolfaghari M, Ghaderi Pakdel F, Tolouei Azar J. Effect
of 12 weeks aerobic training and oral green tea extract on cardiac caspase-3  expression in aged male rats. A Journal of Faculty of Physical Education and Sport
Sciences University of Tehran. Article 6, Volume 10, Issue 2, Summer 2018, Page 221-235. [Persian]
47-Maulik N, Sasaki H, Addya S, Das DK. Regulation of cardiomyocyte apoptosis by redox‐sensitive transcription factors. FEBS letters. 2000; 485(1):7-12.
48-Rigoglou, S., & Papavassiliou, A. G. (2013). The NF-κB signalling pathway in osteoarthritis. The international journal of biochemistry& cell biology, 45(11),2580-2584.
49-Uusi-Rasi KPatil RKarinkanta STokola KKannus PSievänen H .Exercise Training in Treatment and Rehabilitation of Hip Osteoarthritis: A 12-Week Pilot Trial. J Osteoporos. 2017; Jan 1.2017:3905492.
50-Germanou EIChatzinikolaou AMalliou PBeneka AJamurtas AZBikos CTsoukas D. Oxidative stress and inflammatory responses following an acute bout of isokinetic exercise in obese women with knee osteoarthritis. Knee. 2013 Dec;20(6):581-90.
51-Knobloch TJMadhavan SNam JAgarwal S JrAgarwal S. Regulation of chondrocytic gene expression by biomechanical signals. Crit Rev Eukaryot Gene Expr. 2008;18(2):139-50.