Inflammation, Osteoblastogenesis, Cardiovascular

Send Orders for Reprints to [email protected] Current Rheumatology Reviews, 2018, 14, 00-00

1

REVIEW ARTICLE

Metformin one in a Million Efficient Medicines for Rheumatoid Arthritis Complications: Inflammation, Osteoblastogenesis, Cardiovascular Disease, Malignancies Elham Rajaei1, Habib Haybar2 Karim Mowla1 and Zeinab D. Zayeri1,* 1

Golestan Hospital Clinical Research Development Unit, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 2Department of Cardiology, Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Abstract: Background: Rheumatoid arthritis is a widespread autoimmune disease and inflammation and bone destruction are two main issues in rheumatoid arthritis. Objective: To discussing metformin effects on rheumatoid arthritis complications.

ARTICLE HISTORY Received: April 17, 2018 Revised: June 15, 2018 Accepted: July 13, 2018 DOI: 10.2174/1573397114666180717145745

Methods: We conducted a narrative literature search including clinical trials, experimental studies on laboratory animals and cell lines. Our search covered Medline, PubMed and Google Scholar databases from 1999 until 2018. We used the terms” Metformin; Rheumatoid arthritis; Cardiovascular disease; Cancer; Osteoblastogenesis. Discussion: Inflammatory pro-cytokines such as Interlukin-6 play important roles in T. helper 17 cell lineage differentiation. Interlukin-6 and Tumor Necrosis Factor-α activate Janus kinase receptors signal through signaling transducer and activator of transcription signaling pathway which plays important role in inflammation, bone destruction and cancer in rheumatoid arthritis patients. Interlukin-6 and Tumor Necrosis Factor-α synergistically activate signaling transducer and activator of transcription and Nuclear Factor-kβ pathways and both cytokines increase the chance of cancer development in rheumatoid arthritis patients. Metformin is AMPK activators that can suppress mTOR, STAT3 and HIF-1 so AMPK activation plays important role in suppressing inflammation and osteoclastogenesis and decreasing cancer. Conclusion: Metformin effect on AMPK and mTOR pathways gives the capability to change Treg/Th17 balance and decrease Th17 differentiation and inflammation, osteoclastogenesis and cancers in RA patients. Metformin can be useful in protecting bones especially in first stages of RA and it can decrease inflammation, CVD and cancer in RA patients so Metformin beside DAMARs can be useful in increasing RA patients’ life quality with less harm and cost.

Keywords: Metformin, rheumatoid arthritis, cardiovascular disease, cancer, osteoblastogenesis. 1. INTRODUCTION Rheumatoid Arthritis (RA) is an autoimmune systemic inflammatory disease that leads to joint and bone destruction [1]. Approximately, 1% of people around the world are affected by RA however, there is no exact mechanism for its pathogenesis [2]. Etiologic studies investigate RA association with genetic back grounds and epigenetic factors [3]. Sunlight, vitamin D, smoking, sex hormones, viral and bacterial infections are important epigenetic factors in RA development [4]. Inflammation and osteoclastogenesis are two major issues in RA [5]. RA patients develop comorbid *Address correspondence to this author at the Golestan Hospital Clinical Research Development Unit, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Tel: +989167599983; E-mail: [email protected] 1573-3971/18 $58.00+.00

conditions such as cancer, solid malignancies, depression, asthma and cardiovascular events [6, 7]. Cardiovascular events risk is higher in RA population as a result of inflammatory mechanisms [8, 10]. Metformin is the first line antidiabetic drug [11], which decrease inflammation through several mechanisms such as activating 5’adenosin Monophosphate-Activated Protein Kinase (AMPK) pathway [12], and inhibition of inflammatory transcription factor NF-κB [13]. Furthermore Metformin increase osteoblast differentiation via inducing Runx-2 expression, activating AMPK/USF-1/SHP pathway [14, 15]. Metformin effect on AMPK pathway is a cross link pathway in inflammation and bone formation [16]. Metformin upregulates crucial tumor suppressor gene E-cadherin expression which decrease the risk of cancer [17]. Metformin can affect several signaling pathways and decrease cancer risk in patients [18]. Recent © 2018 Bentham Science Publishers

2 Current Rheumatology Reviews, 2018, Vol. 14, No. 0

Rajaei et al.

studies showed that Metformin attenuate the risk of cardiovascular disease (CVD) too [19]. Impressive safety profile and low cost of Metformin increased the development of Metformin use however several side effects such as uncomfortable gastrointestinal exist [20]. In this review, we discuss inflammatory mechanisms which develop several complications, such as inflammation, osteoclastogenesis, CVD and malignancies in RA patients then we will discuss the mechanism of effects of Metformin on these complications. The challenge of this review is to clarify Metformin possible benefits on these complications through several known and possible pathways and these effects of Metformin can make it a considerable medicine for RA patients.

6 induce matrix enzymes like MMPs production and also increase cartilage damage [37, 38]. IL-6 binding to its receptor activates Janus kinase (JAK)/Signaling transducer and activator of transcription (STAT) pathway. IL-6 increase has been proved in several bone diseases [39]. Anti-IL-6 can be effective in decreasing Th17 which can induce osteoclastogenesis in chronic phase of RA by inducing RANKL expression at osteoclast surface directly. IL-17 increases the differentiation of osteoclasts indirectly [40]. Tumor necrosis factor-α (TNF-α ) also induces RANKL expression but interestingly, TNF-α binds to osteoclasts through TNF-α receptor type 1 so TNF-α has dual function and it can be considerable in RA treatment [41].

2. INFLAMMATION, OSTEOCLASTOGENESIS, CARDIOVASCULAR DISEASE, MALIGNANCIES ASPECTS OF RHEUMATOID ARTHRITIS

2.3. Cardiovascular Disease

2.1. Inflammation Inflammation is a considerable aspect of RA. Inflammation develops as a result of several events such as increase in inflammatory cytokines level. Il-6 is an inflammatory cytokine which increases in RA [21]. IL-6 plays important role in Th17 lineage differentiation. Th17 produces IL-17 in inflammation [22]. IL-6 is one of the most important mediators which leads to extracellular matrix of bone and cartilage break down [23]. IL-6 plays important role in facilitating T cell differentiation to T effector [24]. IL-6 decrease AMPK activity and decrease Treg; Th17 ratio [25]. IL-6 activates STAT3 then STAT3 binds to IL-17 promoter directly [26, 27], so IL-17 transcription increases through STAT3 activation. On the other hand, increasing TGF-β level causes Treg cell development by inducing FOXP3 activation [28]. Although IL-6 promotes Th17 differentiation through RARrelated orphan protein γ (RORγ) pathway [29, 30], and Th17 increase the production of IL-17 which induces osteoclastogenesis in RA [31]. Th17 and IL-17 induce inflammation and inflammatory metabolites which lead to joint destruction.Th17 acts as a trigger for osteoclastogenesis in RA and its role is considerable. Th17 activates Tumor Necrosis Factor (TNF) independently so suppressing Th17 differentiation can be a candidate strategy in RA treatment [32, 33]. T effectors differentiate toTh17 and Treg differentiation would be inhibited by FOXP3 activation as a result of ROR γ impairment [34, 35]. In RA, Th17 plays an important role by secreting IL-17, which leads to pathogenesis processes such as inducing synovial fibroblasts, and osteoclasts differentiation [36]. 2.2. Osteoclastogenesis Studies investigated that inflammatory cytokines such as IL-6 and IL-17 increase in RA and these cytokines present inflammatory situation in RA patients. IL-6 and IL-17 increase receptor activator of NF-kB ligand (RANKL); (a member of TNF superfamily) expression and RANKL induce osteoclast differentiation [37]. RANKL binds to its receptor and mature osteoclasts induce Nuclear Factor-kB (NF-Κb) pathway which increase osteoclasts differentiation. IL-6 and TNF-α are also involved in pathogenesis of bone resorption in acute abdominal diseases, such as RA [38]. IL-

RA increases the mortality due to Cerebrovascular (CV) atherosclerosis which occurs earlier in RA population as compared to general population [42]. The prevalence of CV events in RA patients reveals that there are independent risk factors in addition to traditional CV risk factors. It means that additional mechanisms are responsible for CVD in RA [43]. Inflammation can lead to heart disease development in RA patients. Inflammatory cytokines and immune system play essential roles in the development of CVD in RA patients [44]. Studies suggest that controlling the inflammation and inflammatory cytokines can be a solution to decrease CVD in RA patients [45]. TNF-α may play several roles in atherosclerotic, as TNF-α increases Endothelial Cell (EC) surface adhesion increase. The increase in TNF-α- or IL-6 serum level can lead to thrombosis and plaque formation in RA patients [46]. However, the challenge is here; the ability of the body to protect itself from exogenous pathogens and repairing the damages in the tissue that might develop as a result of infection or trauma; is related to inflammatory response and cytokines balance and defect in inflammatory pathways and cytokines which can lead to chronic disease [47]. 2.4. Malignancies The risk of lung and lymphoma malignancies is higher in RA patients as compared to general population. Nonbiologic and biologic DMARD-users with RA history can show different prevalence and profile of malignancies [48]. Several studies showed that the risk of certain solid cancers is higher in RA patients [49]. Increase in IL-6 level leads to various results such as long term of inflammation which can increase the risk of cancer development [50]. Studies indicate that increase in IL-6 levels cause IL6Rα-gp130 receptor complexes to activate STAT3 which is hyper-activated in many cancers [51, 52]. IL-6 can activate JAK/STAT3 pathway. STAT3 can have an oncogenic role in linking inflammation and cancer and several studies showed that IL-6 elevates in several cancers such as lung cancer [53]. Several genes which increase the risk of RA are involved in NF-kB signaling pathway or JAK/STAT3 signaling pathway [54]. IL-6 and TNF-α synergistically activate STAT3 and NF-kB and both of these inflammatory cytokines increase the chance of cancer [55]. HLA region, and several polymorphisms of PTPN22 contribute to the risk of cancer development in Anti-Citrullinated Protein Antibodies (ACPA) posi-

Current Rheumatology Reviews, 2018, Vol. 18, No. 0

Metformin Effects on Rheumatoid Arthritis Complications

Table 1.

3

summary of the studies on metformin and RA complications.

Study on

Method

Result

Ref

CIA mice

Case control study, fed metformin three times a week for nine weeks Histological analysis of the joints were analyzed by immunohistochemistry and Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining

From day 7 metformin-treated CIA mice showed significantly reduced severity, serum immunoglobulin decrease, reciprocally regulated Th17/Treg axis reduced, the number of Th17 cells decreased and the number of Treg cells increased, gene expression and osteoclastogenic activity decreased in case and control

[59]

Breast cancer cell lines

Cancer stem cells compared with non-stem cancer cells in the same population, 0.1 mmol/L metformin were used

Metformin inhibits NF-κB and phosphorylation of STAT3 in cancer stem cells activation of the NF-κB, delays cellular transformation

[13]

Cohort study in Taiwan

968 OA and T2DM patients treated with COX-2 inhibitor and metformin therapy 1936 patients treated without metformin therapy, Cox proportional hazards analysis was used to compare the rate of receiving joint replacement surgery during 10 years

OA and T2DM patient treated with COX-2 inhibitors and metformin recived lower joint replacement surgery rates than those without, pro-inflammatory factors were lower in the metformin users group

[60]

ECs, SMCs

Metformin dose-dependently inhibited proinflammatory cytokines, To address the significance of the anti-inflammatory effects of a metformin was 20 mol/L

vascular anti-inflammatory effect of metformin via suppressing NFκB via blocking PI3K–Akt pathway, decreasing cardiovascular events through anti-inflammatory pathways

[61]

Meta-analysis

All trials containing the word ‘metformin’. Randomized trials with a duration ≥52 weeks were included

metformin on cardiovascular risk, suggesting a possible benefit

[62]

G-R, NSCLC and RA expression of sterol SREBP1were found in both G-R NSCLC cells and RASFs.

Treating malignancies and proliferative diseases via : Targeting ROS/AMPK/lipogenesis signaling pathway

[63]

DU145 human prostate tumor cell lines injected to one of ventral prostate lobes of Six-week old male BALB/c nude mice Control group received 150 µL saline injection, Metformin-treated group received metformin (120 mg/kg in 150 µL saline

Metformin prevents proliferation of prostate cancer by regulating IGF1R/PI3K/Akt signalling

[64]

G-R, NSCLC and RASFs Studying ROS/AMPK pathway activation

Mouse model

Abbreviations: Collagen-Induced Arthritis; CIA , Endothelial Cells; ECs , Human Vascular Smooth Muscle Cellsl; SMCs, Gefitinib-Resistant ;G-R, Nonsmall-Cell Lung Cancer; NSCLC, Sterol Regulatory Element-Binding Protein 1; SREBP1, Synovial Fibroblasts From RA Patients ;RASFs, Insulin-Like Growth Factor 1 Receptor ;IGF1R.

tive RA patients [56]. Studies showed that PTPN22 got pleiotropic effects in several autoimmune diseases such as RA [57]. Tumor biology showed that down-regulation of Human Leukocyte Antigen (HLA) expression and somatic mutation of HLA genes might be a significantly frequent process in several tumors [58]. Table 1 conducts a summary of the studies on metformin and RA complications.

69]. Metformin effects mTOR signaling through AMPK dependent and independent pathways [70]. mTOR activation proliferate fibroblasts in RA [71]. Metformin decreases Th17 cell differentiation. The effect of metformin on T-effector differentiation and reciprocal balance of Treg and Th17 change is another mechanism which decreases the inflammation [72].

3. METFORMIN PHARMACOLOGIC EFFECTS: ONE IN A MILLION EFFICIENT MEDICINES IN RHEUMATOID ARTHRITIS TREATMENT

3.2. Metformin Effect on Osteoblastogenesis

3.1. Metformin Effect on Inflammation Metformin is AMPK activator [65]. AMPK activation is associated to pleiotropic action of Metformin which restricts energy of the cell [66]. AMPK activation which occurs in low cellular energy, suppresses mTOR, STAT3 and HIF-1 so AMPK activation plays important role in suppressing inflammation and osteoclastogenesis by ruling mTOR activity [67]. On the other hand, metformin suppresses inflammatory cytokines production by suppressing NF-kB pathway [68,

Metformin increases osteoblastogenesis via inducing endothelial nitric oxide synthase (eNOS) directly [73], it also decreases osteoblasts apoptosis [74]. Metformin affects osteogenic genes, such as Alkaline Phosphatase (ALP), and Osteocalcin (OCN) [75], which are negatively related to glucose [76]. OCN is synthesized only by osteoblasts. Metformin also effects small heterodimer partner (SHP) [77]. AMPK/USF-1/SHP activation increases the osteoblastogenesis directly via increasing the expression of Runx-2 and IGF1 [78]. Inhibiting Runx-2 expression cause bone destruction [79] while increasing Runx-2 expression induces Osteoprotegrin (OPG) expression [5], and decreases RANKL expres-


sion, so OPG is osteoclastogenesis suppressor and RANKL is an OPG ligand [80]. Therefore, increase in OPG level and decrease in RANKL expression inhibit osteoclastogenesis [81] (Fig. 1). However, few studies claimed that metformin increases bone fraction, most of the observational studies showed no effect on bone fraction risk [81]. However, we think the failure in observational studies might be as a result of insufficient dosage of metformin so there might be an effective dosage in metformin used for ruling the balance of the osteoblasts and osteoclasts. Several studies showed that metformin can decrease osteoclastogenesis via inhibiting caMKK, TAK1 [15], and NF-kB expression [82]. The effect of metformin on AMPK activation inhibits STAT3, and STAT3 inhibition suppresses osteoclasts differentiation [59]. However, several studies showed that high concentration of metformin inhibits osteoblasts differentiation, it stimulates IGF-1 expression but it does not affect IGF-1 receptor (IGF1R), on the other hand, IGF-1 activates catalytic activity of IGF-1R in order to signal the nucleus and disturbs Runx-2 expression so IGF-1 and IGF-1R might be associated with osteoporosis [83]. Several studies showed no significant change in bone formation in metformin diabetic users [84], however, other studies showed that metformin can increase osteoblastogenesis in early progenitors of osteoblasts according to the OPG/RANKL ratio when evaluating bone formation [85]. Metformin effects the balance between osteoblast and osteoclast so this is a hopeful result for more observational studies to prove how much does metformin effect bone formation and the effective dose of metformin. These findings might be useful for decreasing RA bone and cartilage damages. 3.3. Metformin Effect on Cardiovascular Disease Studies showed that Metformin improves CVD risk [86]. Several Studies in this field showed Metformin decrease as anti-atherogenic effect in vascular endothelial through inhib-

Rajaei et al.

iting TNF–NF-κB-driven expression of proinflammatory cytokines through AMPK dependent mechanism and finally decrease CVD either as monotherapy or in combination with a sulfonylurea drug [87, 88]. The exact mechanisms of effect of metformin in CVD are not completely understood, however, several studies suggest that the use of Metformin improves myocardial preconditioning and reduces cardiomyocyte apoptosis. Several experiments investigated that Metformin reduces cardiac ischaemia and improves cardiac function [89]. The evidence in several studies showed that Metformin can be useful in the treatment of cardiovascular events associated with Type 2 Diabetes (T2D) and cause a state of cardioprotection, so metformin can potentially decrease myocardial problems through various molecular mechanisms, such as decreasing oxidative stress, apoptosis, and protein synthesis through AMPK-dependent and AMPKindependent pathways [90]. 3.4. Metformin Effect on Malagnancies Antineoplastic effect of metformin through inhibiting mTOR pathway disturbs protein synthesis and tumor cell proliferation which are very important pathways in cancer which decrease by metformin through AMPK dependent mechanism [91]. The inhibition of the PI3K/AKT/mTOR pathway can be used in the treatment of several cancers. This pathway plays important roles in cellular functions, such as protein synthesis, cell survival, and apoptosis and it is a highly mutated pathway in cancer [92]. PI3K/AKT/mTOR pathway inhibitors are categorized into four main groups: mTOR inhibitors, PI3K inhibitors, dual mTOR/PI3K inhibitors, and AKT inhibitors, and interestingly, Metformin can indirectly inhibit these pathways [93]. PI3K/AKT/mTOR pathway inhibitors can also be used in immune-mediated arthritis treatment, the overlap of this pathway in cancer and RA is attractive in decreasing cancers and solid tumors that occur in RA patients [94].

Fig. (1). Metformin activates AMPK. AMPK activation suppresses mTOR and inhibits STAT3 expression so metformin suppresses inflammatory cytokine production by suppressing NF-Kβ. Finally, these signals suppress Th17 differentiation. AMPK activation induces osteoblastogenesis by increasing eNOS and decrease osteoclastogenesis by increasing OPG and decreasing RANKL.


Metformin Effects on Rheumatoid Arthritis Complications

CONCLUSION AND FUTURE PERSPECTIVES RA is a complex disease with several complications such as inflammation, CVD, bone destruction and cancers. Two important pathway associated with RA, CVD, inflammation and cancer are AMPK and JAK/STAT3 pathways. Metformin has the potential to induce osteoblast differentiation through AMPK activation and affects osteogenic genes. Metformin has the capability of decreasing inflammation through AMPK activation mechanism; it also inhibits mTOR through AMPK dependent and independent pathways. mTOR changes Treg/Th17 balance and decrease Th17 differentiation and inflammation. PI3K/AKT/mTOR pathway plays important roles in cellular functions and according to the incident of cancer in RA patients Metformin can be a good and safe candidate to be used besides DAMARs for RA patient in order to decrease cancer incidence in them. Interesting point about metformin is that metformin decreases glucose which is the main nutrition in osteoblast differentiation so we suggest that metformin does not affect Runx-2 null osteoblasts so the effect of metformin might be limited on a numbers of osteoclasts. Finally, we suggest that Metformin can be useful in protecting bone especially in first stages of RA and it can decrease inflammation, CVD and cancer in RA patients can be useful in increasing RA patients’ life quality with the less harm and cost for RA patients. So we hypothesize that by adding Metformin besides DAMARs can have considerable effect in decreasing the complications of RA patients. More studies on the effects of metformin are considerable and finding the effective dose of metformin can be very precious in RA patients’ life.

CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2] [3] [4] [5]

[6]

[7]

SUMMARY One percent of people around the world are affected by RA. Several complications such as inflammation, bone destruction, CVD and cancer arise in RA patient as a result of inflammatory mechanisms. So finding ways to decrease these complications in RA patients is very precious and decrease the stress of thinking of these complications. AMPK, PI3K/AKT/mTOR and STAT pathways play important roles in cellular functions. Metformin is an anti-diabetic drug with several benefits. Metformin basically affects AMPK, PI3K/AKT/mTOR and STAT pathways so this drug can be effective in decreasing RA complications. However, more studies are needed to find the effective dose of metformin for activating these pathways.

[8]

LIST OF ABBREVIATION

[14]

AMPK

=

5’adenosin Monophosphate-Activated Protein Kinase

mTOR

=

mammalian Target of Rapamycin

STAT3

=

Signal Transducer and Activator of Transcription 3

NF-Kβ

=

Nuclear Factor-kβ

OPG

=

Osteoprotegrin, RANKL: Receptor Activator of NF-kb Ligand

eNOS

=

endothelial Nitric Oxide Synthase

5

[9] [10]

[11] [12] [13]

[15] [16] [17]

[18]

Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nature Reviews Immunology. 2017. Guo Y, Wu Q, Ni B, Mou Z, Jiang Q, Cao Y, et al. Tryptase is a candidate autoantigen in rheumatoid arthritis. Immunology. 2014;142(1):67-77. Frisell T, Saevarsdottir S, Askling J. Family history of rheumatoid arthritis: an old concept with new developments. Nature Reviews Rheumatology. 2016. Mowla K, Saki MA, Jalali MT, Zayeri ZD. How to manage rheumatoid arthritis according to classic biomarkers and polymorphisms? Frontiers in Biology. 2017:1-9. Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, et al. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. Journal of cellular biochemistry. 2011;112(10):2902-9. Dougados M, Soubrier M, Antunez A, Balint P, Balsa A, Buch M, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, crosssectional study (COMORA). Annals of the rheumatic diseases. 2013:annrheumdis-2013-204223. Dougados M, Soubrier M, Antunez A, Balint P, Balsa A, Buch MH, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, crosssectional study (COMORA). Annals of the rheumatic diseases. 2014;73(1):62-8. Liao KP. Cardiovascular disease in patients with rheumatoid arthritis. Trends Cardiovasc Med. 2017;27(2):136-40. Chimenti MS, Triggianese P, Conigliaro P, Candi E, Melino G, Perricone R. The interplay between inflammation and metabolism in rheumatoid arthritis. Cell Death Dis. 2015;6:e1887. Barra LJ, Pope JE, Hitchon C, Boire G, Schieir O, Lin D, et al. The effect of rheumatoid arthritis–associated autoantibodies on the incidence of cardiovascular events in a large inception cohort of early inflammatory arthritis. Rheumatology. 2017;56(5):768-76. Bailey CJ, Day C. Metformin: its botanical background. Practical diabetes. 2004;21(3):115-7. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. Journal of clinical investigation. 2001;108(8):1167. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proceedings of the National Academy of Sciences. 2013;110(3):972-7. Wang P, Ma T, Guo D, Hu K, Shu Y, Xu HH, et al. Metformin Induces Osteoblastic Differentiation of Human Induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells. Journal of Tissue Engineering and Regenerative Medicine. 2017. Mabilleau G, Chappard D, Flatt PR, Irwin N. Effects of antidiabetic drugs on bone metabolism. Expert Review of Endocrinology & Metabolism. 2015;10(6):663-75. Kim KH, Lee M-S. Autophagy [mdash] a key player in cellular and body metabolism. Nature Reviews Endocrinology. 2014;10(6):32237. Banerjee P, Surendran H, Chowdhury DR, Prabhakar K, Pal R. Metformin mediated reversal of epithelial to mesenchymal transition is triggered by epigenetic changes in E-cadherin promoter. Journal of molecular medicine. 2016;94(12):1397-409. Sahra IB, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, et al. The antidiabetic drug metformin exerts an


[19]

[20] [21] [22] [23] [24] [25] [26]

[27]

[28] [29] [30]

[31]

[32] [33] [34] [35] [36] [37] [38] [39]

[40]

[41] [42]

antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008;27(25):3576. Malin SK, Nightingale J, Choi SE, Chipkin SR, Braun B. Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose tolerant adults. Obesity. 2013;21(1):93-100. Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia. 2013;56(9):1898906. Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nature Reviews Rheumatology. 2014;10(12):720-7. Sharma J, Bhar S, C SD. A review on Interleukins: the key manipulators in Rheumatoid Arthritis. Mod Rheumatol. 2016:1-41. Deane KD, El-Gabalawy H. Pathogenesis and prevention of rheumatic disease: focus on preclinical RA and SLE. Nat Rev Rheumatol. 2014;10(4):212-28. Wei ST, Sun YH, Zong SH, Xiang YB. Serum Levels of IL-6 and TNF-alpha May Correlate with Activity and Severity of Rheumatoid Arthritis. Med Sci Monit. 2015;21:4030-8. Roy K, Kanwar RK, Kanwar JR. Molecular targets in arthritis and recent trends in nanotherapy. Int J Nanomedicine. 2015;10:540720. Alunno A, Manetti M, Caterbi S, Ibba-Manneschi L, Bistoni O, Bartoloni E, et al. Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proinflammatory Th17 cells and therapeutic implications. Mediators Inflamm. 2015;2015:751793. Tabarkiewicz J, Pogoda K, Karczmarczyk A, Pozarowski P, Giannopoulos K. The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases. Arch Immunol Ther Exp (Warsz). 2015;63(6):435-49. Huang G, Wang Y, Chi H. Regulation of TH17 cell differentiation by innate immune signals. Cell Mol Immunol. 2012;9(4):287-95. Barbi J, Pardoll D, Pan F. Metabolic control of the Treg/Th17 axis. Immunol Rev. 2013;252(1):52-77. Cook DN, Kang HS, Jetten AM. Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism. Nucl Receptor Res. 2015;2. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. The Journal of clinical investigation. 1999;103(9):1345-52. Yoshida Y, Tanaka T. Interleukin 6 and rheumatoid arthritis. Biomed Res Int. 2014;2014:698313. Abroun S, Saki N, Ahmadvand M, Asghari F, Salari F, Rahim F. STATs: An Old Story, Yet Mesmerizing. Cell J. 2015;17(3):395411. Bedoya SK, Lam B, Lau K, Larkin J, 3rd. Th17 cells in immunity and autoimmunity. Clin Dev Immunol. 2013;2013:986789. Park BV, Pan F. The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases. Cell Mol Immunol. 2015;12(5):533-42. McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. The Lancet. 2017;389(10086):2328-37. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429-42. Saki N, Abroun S, Salari F, Rahim F, Shahjahani M, Javad M-A. Molecular aspects of bone resorption in β-thalassemia major. Cell Journal (Yakhteh). 2015;17(2):193. Feng W, Liu H, Luo T, Liu D, Du J, Sun J, et al. Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKLinduced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways. Scientific Reports. 2017;7. Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda E, et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum. 2001;44(5):1003-12. Schett G. Cells of the synovium in rheumatoid arthritis. Osteoclasts. Arthritis research & therapy. 2007;9(1):203. Naranjo A, Sokka T, Descalzo MA, Calvo-Alén J, HørslevPetersen K, Luukkainen RK, et al. Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study. Arthritis research & therapy. 2008;10(2):R30.

Rajaei et al. [43]

[44] [45]

[46] [47] [48] [49]

[50] [51]

[52] [53] [54]

[55]

[56] [57]

[58]

[59]

[60]

[61]

[62]

[63]

Del Rincón I, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis & Rheumatology. 2001;44(12):2737-45. Crowson CS, Liao KP, Davis JM, Solomon DH, Matteson EL, Knutson KL, et al. Rheumatoid arthritis and cardiovascular disease. American heart journal. 2013;166(4):622-8. e1. Myasoedova E, Chandran A, Ilhan B, Major BT, Michet CJ, Matteson EL, et al. The role of rheumatoid arthritis (RA) flare and cumulative burden of RA severity in the risk of cardiovascular disease. Annals of the rheumatic diseases. 2016;75(3):560-5. Kahlenberg JM, Kaplan MJ. Mechanisms of premature atherosclerosis in rheumatoid arthritis and lupus. Annual review of medicine. 2013;64:249-63. Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science. 2013;339(6116):166-72. Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis research & therapy. 2015;17(1):212. Mercer LK, Lunt M, Low AL, Dixon WG, Watson KD, Symmons DP, et al. Risk of solid cancer in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Annals of the rheumatic diseases. 2014:annrheumdis-2013-204851. Mauer J, Denson JL, Brüning JC. Versatile functions for IL-6 in metabolism and cancer. Trends in immunology. 2015;36(2):92101. Sen M, Johnston PA, Pollock NI, DeGrave K, Joyce SC, Freilino ML, et al. Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines. Journal of Chemical Biology. 2017:1-13. Bromberg J, Wang TC. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer cell. 2009;15(2):79-80. Taniguchi K, Karin M, editors. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Seminars in immunology; 2014: Elsevier. Diogo D, Okada Y, Plenge RM. Genome-wide association studies to advance our understanding of critical cell types and pathways in rheumatoid arthritis: recent findings and challenges. Current opinion in rheumatology. 2014;26(1):85-92. De Simone V, Franze E, Ronchetti G, Colantoni A, Fantini M, Di Fusco D, et al. Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth. Oncogene. 2015;34(27):3493. Catrina AI, Joshua V, Klareskog L, Malmström V. Mechanisms involved in triggering rheumatoid arthritis. Immunological reviews. 2016;269(1):162-74. Zheng W, Rao S. Knowledge-based analysis of genetic associations of rheumatoid arthritis to inform studies searching for pleiotropic genes: a literature review and network analysis. Arthritis research & therapy. 2015;17(1):202. Shukla SA, Rooney MS, Rajasagi M, Tiao G, Dixon PM, Lawrence MS, et al. Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes. Nature biotechnology. 2015;33(11):1152. Son H-J, Lee J, Lee S-Y, Kim E-K, Park M-J, Kim K-W, et al. Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediators of inflammation. 2014;2014. Lu C-H, Chung C-H, Lee C-H, Hsieh C-H, Hung Y-J, Lin F-H, et al. Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan. PloS one. 2018;13(1):e0191242. Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, et al. Metformin inhibits proinflammatory responses and nuclear factor-κB in human vascular wall cells. Arteriosclerosis, thrombosis, and vascular biology. 2006;26(3):611-7. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes, Obesity and Metabolism. 2011;13(3):221-8. Fan X-X, Leung EL-H, Xie Y, Liu ZQ, Zheng YF, Yao XJ, et al. Suppression of Lipogenesis via Reactive Oxygen Species–AMPK Signaling for Treating Malignant and Proliferative Diseases. Antioxidants & redox signaling. 2018;28(5):339-57.


Metformin Effects on Rheumatoid Arthritis Complications [64] [65] [66]

[67] [68] [69]

[70] [71] [72] [73] [74] [75]

[76]

[77]

[78]

Jiang D, Bu Q, Zeng M, Qin S, Xia D, Peng Y. Metformin prevents proliferation of prostate cancer by regulating IGF1R/PI3K/Akt signalling in a mouse model. Biomedical Research. 2018;29. Grahame Hardie D. AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease. J Intern Med. 2014;276(6):543-59. Turban S, Stretton C, Drouin O, Green CJ, Watson ML, Gray A, et al. Defining the contribution of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) in regulation of glucose uptake by metformin in skeletal muscle cells. J Biol Chem. 2012;287(24):20088-99. Gaber T, Strehl C, Buttgereit F. Metabolic regulation of inflammation. Nature Reviews Rheumatology. 2017. Ramiscal RR, Parish IA, Lee-Young RS, Babon JJ, Blagih J, Pratama A, et al. Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation. Elife. 2015;4. Son HJ, Lee J, Lee SY, Kim EK, Park MJ, Kim KW, et al. Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediators Inflamm. 2014;2014:973986. Yan H, Zhou HF, Hu Y, Pham CT. Suppression of experimental arthritis through AMP-activated protein kinase activation and autophagy modulation. J Rheum Dis Treat. 2015;1(1):5. Perl A. Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat Rev Rheumatol. 2016;12(3):169-82. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253-70. Gu Q, Gu Y, Yang H, Shi Q. Metformin Enhances Osteogenesis and Suppresses Adipogenesis of Human Chorionic Villous Mesenchymal Stem Cells. Tohoku J Exp Med. 2017;241(1):13-9. Gilbert MP, Pratley RE. The impact of diabetes and diabetes medications on bone health. Endocrine reviews. 2015;36(2):194213. Iglesias P, Arrieta F, Pinera M, Botella-Carretero J, Balsa J, Zamarron I, et al. Serum concentrations of osteocalcin, procollagen type 1 N-terminal propeptide and beta-CrossLaps in obese subjects with varying degrees of glucose tolerance. Clinical endocrinology. 2011;75(2):184-8. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Kurioka S, Yano S, et al. Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. The Journal of Clinical Endocrinology & Metabolism. 2009;94(1):45-9. Jang WG, Kim EJ, Bae I-H, Lee K-N, Kim YD, Kim D-K, et al. Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone. 2011; 48(4): 885-93. Marycz K, Tomaszewski KA, Kornicka K, Henry BM, Wronski S, Tarasiuk J, et al. Metformin Decreases Reactive Oxygen Species, Enhances Osteogenic Properties of Adipose-Derived Multipotent Mesenchymal Stem Cells In Vitro, and Increases Bone Density In Vivo. Oxid Med Cell Longev. 2016; 2016: 9785890.

[79]

[80] [81] [82] [83] [84] [85] [86] [87]

[88]

[89] [90] [91] [92]

[93] [94]

7

Morimoto E, Li M, Khalid AB, Krum SA, Chimge NO, Frenkel B. Glucocorticoids hijack Runx2 to stimulate Wif1 for suppression of osteoblast growth and differentiation. Journal of cellular physiology. 2017;232(1):145-53. Bartl R. Control and Regulation of Bone Remodelling. Bone Disorders: Springer; 2017. p. 31-8. Meier C, Schwartz AV, Egger A, Lecka-Czernik B. Effects of diabetes drugs on the skeleton. Bone. 2016;82:93-100. Shao X, Cao X, Song G, Zhao Y, Shi B. Metformin rescues the MG63 osteoblasts against the effect of high glucose on proliferation. Journal of diabetes research. 2014;2014. Zhen D, Chen Y, Tang X. Metformin reverses the deleterious effects of high glucose on osteoblast function. Journal of Diabetes and its Complications. 2010;24(5):334-44. Hegazy SK. Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab. 2015;33(2):207-12. Shao X, Cao X, Song G, Zhao Y, Shi B. Metformin rescues the MG63 osteoblasts against the effect of high glucose on proliferation. J Diabetes Res. 2014;2014:453940. Association AD. Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program. Diabetes care. 2005;28(4):888-94. Abbasi F, Chu JW, McLaughlin T, Lamendola C, Leary ET, Reaven GM. Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus. Metabolism. 2004;53(2):159-64. Morgan CL, Mukherjee J, Jenkins-Jones S, Holden S, Currie C. Combination therapy with metformin plus sulphonylureas versus metformin plus DPP-4 inhibitors: association with major adverse cardiovascular events and all-cause mortality. Diabetes, Obesity and Metabolism. 2014;16(10):977-83. Viollet B, Guigas B, Garcia NS, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clinical science. 2012;122(6):253-70. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell metabolism. 2014;20(6):953-66. Pernicova I, Korbonits M. Metformin [mdash] mode of action and clinical implications for diabetes and cancer. Nature Reviews Endocrinology. 2014;10(3):143-56. Bertacchini J, Heidari N, Mediani L, Capitani S, Shahjahani M, Ahmadzadeh A, et al. Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cellular and molecular life sciences. 2015; 72(12): 2337-47. Mabuchi S, Kuroda H, Takahashi R, Sasano T. The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecologic Oncol 2015; 137(1): 173-9. Malemud CJ. The PI3K/Akt/PTEN/mTOR pathway: a fruitful target for inducing cell death in rheumatoid arthritis? Future medicinal chemistry. 2015;7(9):1137-47.

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.