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Cellular aging towards osteoarthritis
Accepted Manuscript Title: Cellular aging towards osteoarthritis Author: Yu-Sheng Li Wen-feng Xiao Wei Luo PII: DOI: Reference:
S0047-6374(16)30281-0 http://dx.doi.org/doi:10.1016/j.mad.2016.12.012 MAD 10910
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Mechanisms of Ageing and Development
Received date: Revised date: Accepted date:
30-11-2016 22-12-2016 27-12-2016
Please cite this article as: Li, Yu-Sheng, Xiao, Wen-feng, Luo, Wei, Cellular aging towards osteoarthritis.Mechanisms of Ageing and Development http://dx.doi.org/10.1016/j.mad.2016.12.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cellular aging towards osteoarthritis
Yu-Sheng Li, Wen-feng Xiao, Wei Luo* Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha 410008, P.R.China *For correspondence: Dr. Wei Luo, Department of Orthopaedics, Xiangya Hospital of Central South University, No 87. Xiangya Road, Changsha 410008, Hunan Province, P.R. China; E-mail: [email protected], Tel: +86-0731-89753006
Highlights:
Osteoarthritis (OA) is age-related neurodegenerative disease.
Reactive oxygen species produced in cellular process play vital role in OA development
Antioxidants, histone deacetylase inhibitors, anti-miR34a agents might be beneficial for treating age related OA
Abstract Osteoarthritis (OA) is a common form of degenerative joint disease. Aging process is supposed to be a leading predictor for developing OA. In this review, we have discussed the potential roles of aging in OA, a better understanding of which might delay or stop the development and progression of OA. Different cellular signaling mechanisms are involved process of aging that induces age-related changes in chondrocytes. These changes influence the expression of catabolic factors resulting in increased production of matrix metalloproteinases and cytokines, reduced levels of collagen type II and aggrecan synthesis, and increased production of reactive oxygen species (ROS). ROS leads to mitochondrial dysfunction and chondrocyte death, which contributes to the development of OA. Antioxidant supplementation is probably the best way to prevent or delay the age-related OA. Some therapeutic agents like histone deacetylase inhibitors and anti-miR34a agents have been reported to be effective against age-related OA. However, further research is needed to demonstrate the efficacy of these alternative treatment strategies in clinical trials using controlled and prospective studies.
Keywords Osteoarthritis; Aging; Chondrocyte dysfunction; Antioxidants
Introduction Osteoarthritis (OA) is an age-related degenerative joint disease characterized by progressive degradation in articular cartilage, extensive remodeling of adjacent bone with new bone leading to synovitis as well as osteophyte formation (Bijlsma et al., 2011; Fang and Beier, 2014). OA is the most common form of arthritis resulting in substantial morbidity, physical disability, reduced quality of life and increased health costs. It is considered to be the fourth leading cause of disability due to the increasing life expectancy and aging populations (Freitag et al., 2016; Fransen et al., 2011). OA mainly affects the joints of knees, hips, hands and spine (cervical and lumbar); and the most common clinical manifestations of OA include pain, tenderness, stiffness, swelling and movement limitation (Jones, 2013; Pérez Martín, 2014). The exact cause of OA is mostly unclear. It is not a single disease condition, rather a complex disorder and is thought to be associated with a variety of risk factors including genetic factors, constitutional factors (such as age, sex, increased body weight and trauma) as well as several biochemical and biomechanical components (Brandt et al., 2009; Glyn-Jones et al., 2015). Currently, there is no satisfactory drug for effective OA treatment, and OA cannot be cured totally. Current medical treatment strategies only aim to control the symptoms and pain reduction (de Rezende et al., 2013). The initial management of OA includes patient education, exercise, lifestyle changes and pain medications such as the simple analgesics acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid injections, hyaluronic acid (HA) injections and glucosamine. In severe cases of OA, joint replacement surgery may be recommended (Vargas Negrín et al., 2014, Buttgereit et al., 2015). However, most of the conventional management options are not always satisfactory as these treatments are not readily available, highly expensive, can neither modify disease nor inhibit OA progression, and have some unwanted and hazardous side effects (Woolf and Pfleger, 2003; Cheng et al., 2014). To overcome these problems, alternative therapeutic strategies are urgently needed that can help to identify the more effective targets for the management and prevention of OA (Wyles et al., 2015). Aging is supposed to be the leading predictor for developing OA. However, the mechanisms by which aging contribute to the development of OA remain unclear (Loeser et al., 2016; Benderdour et al., 2015). In this study, we have reviewed the potential roles of aging in the development and progression of OA. A better understanding of the pathogenic mechanism of aging process may help to delay or stop the progression and development of OA.
Cell aging in different diseases Aging is a natural process characterized by a state of chronic, low-grade and sterile inflammation caused by a progressive loss of function and physiological integrity of the different organs and tissues. Aging induces homeostatic imbalance between inflammatory and anti-inflammatory pathways and risk of a number of age-related chronic disorders including atherosclerosis, type 2 diabetes, Alzheimer's disease, cancers, osteoarthritis and others. The incidence of all of these diseases increases rapidly with aging (Kirkwood, 2005; Zhu et al., 2014; MacNee et al., 2014). The exact etiology involved in aging process is unclear. Chronic inflammation and cytokine levels have been shown to be elevated in the aging process. Three main metabolic pathways have been identified that can influence the aging process separately. These are dietary restriction, insulin/IGF-1-like signaling pathway and the pathway involved in activity level of the mitochondrial electron transport chain. These pathways may play an important role in the prevention of aging and age-related diseases in humans and might be promising targets for future therapeutics (Taylor and Dillin, 2011; Wolff and Dillin 2006). The first is dietary restriction (DR, also referred to as calorie restriction) which leads to longer lifespan in various species. The amino-acid-sensing serine/threonine kinase, mammalian target of rapamycin (mTOR); and the NAD+ dependent deacetylase, SIRT1, are involved in DR signaling (Ghosh et al., 2010; Johnson et al., 2013). Dietary restriction reduces mTORC1 activity in some mammalian tissues and invertebrate organisms, which allows an increased level of autophagy. Inhibition of mTOR activity and induction of autophagy increase longevity by reducing the effects of reactive oxygen species on the body (Kenyon, 2010; Fontana et al., 2010; Stanfel et al., 2009). SIRT1 is a NAD+ dependent deacetylase that regulates caloric restriction mediated longevity in model organisms. SIRT1 negatively regulates mTOR signaling potentially through the TSC2, a component of the mTOR inhibitory-complex and contributes to longevity as well as health benefits as a result of dietary restriction (Tee et al., 2003, Niccoli and Partridge, 2012). Another pathway that mediates lifespan extension is the insulin/IGF-1-like signaling pathway (IIS). A decreased IIS pathway increases longevity by increasing insulin sensitivity and stress resistance as well as protection from carcinogenesis. Following ligand binding, the IIS receptor DAF-2 (abnormal DAuer Formation-2) recruits the insulin receptor substrate homolog IST-1 and AGE-1 through which the transcription factor DAF-16 is phosphorylated. Phosphorylation of DAF-16 in the cytosol represses raptor expression by activating a diverse transcriptional profile (such as SMK-1, HCF-1, HSF-1 and SIR-2) and promotes extension of
longevity (Taylor and Dillin, 2011; Johnson et al., 2013). The third pathway that enables extension of lifespan is the activity level of the mitochondrial electron transport chain (ETC). However, the mechanisms and signaling pathways involved in lifespan remain unknown. It has been reported that reduced expression of several mitochondrial genes including components of ETC complexes I, III, IV, and V by RNA interference (RNAi) can extend lifespan through reduced mitochondrial function (Feng et al., 2001; Dillin et al., 2002; Lee et al., 2003). Cell aging in osteoarthritis development Aging is an important contributing factor to the development of OA. However, the mechanism by which aging contributes to OA development is still not clearly understood. In OA, chondrocytes undergo premature aging due to several factors including an age-related inflammation that has been termed as "inflamm-aging." Inflamm-aging is a pro-inflammatory state that occurs during physiological aging and has been associated with decreased physical function and frailty. Inflamm-aging can contribute to OA through the degradation of articular cartilage and other joint tissues by inducing the production of pro-inflammatory mediators in the arthritic joint (Greene and Loeser, 2015; Loeser, 2011). OA can be the result of cellular senescence caused by a variety of stimuli and stresses, including genomic DNA damage, epigenetic changes, metabolic stresses and mitochondrial dysfunction (Portal-Núñez et al., 2016). Senescent cells accumulate with aging in joint tissues and display a senescence-associated secretory phenotype (SASP) associated with overproduction of cytokines (such as, interleukins 1 and 6) and growth factors (e.g., epidermal growth factor, transforming growth factor β), as well as matrix-degrading enzymes such as matrix metalloproteinases (MMPs) (e.g., MMP-3, MMP-13), all of which can contribute to the development and progression of OA (Loeser, 2009; Xu et al., 2016; Benderdour et al., 2015). Sirtuin is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase and is involved in controlling aging. In mammals, the sirtuin family contains seven genes (SIRT1- SIRT7) encoding sirtuin proteins that differ in tissue distribution, specificity and enzymatic activity. Among these, SIRT1 plays a crucial role in cartilage homeostasis, cell senescence, inflammation and apoptosis by deacetylating important transcriptional factors including p53, FOXO and p65 (Blander and Guarente, 2004; Imai and Guarente, 2010; Yan et al., 2016). Loss of SIRT1 enzymatic function or its inactivation attenuates the deacetylation of p53, leading to the up-regulation of Bax and down-regulation of Bcl-2. Enhanced acetylation of p53 contributes to OA severity by
reducing the levels of collagen type II and aggrecan in articular cartilage. SIRT6 is localized to the nucleus and plays an important role in transcriptional silencing, genome stability and the regulation of senescence of human chondrocytes. Depletion of SIRT6 in human chondrocytes caused increased MMP-1 and -13 mRNA level, DNA damage and telomere dysfunction, and subsequent premature senescence (Ailixiding et al., 2015; Wu et al., 2015). Autophagy is an essential homeostatic process that maintains cell homeostasis by adjusting cell metabolism to nutrient supply and removing damaged macromolecules and organelles. Recent studies indicated that autophagy declines with aging and during OA, leading to cell death and tissue damage. Aging-related loss of autophagy induced significant mitochondrial dysfunction in human chondrocytes that plays an important role in OA pathogenesis (López de Figueroa et al., 2015; Caramés et al., 2015). It has been suggested that HIF-2α plays a crucial role to suppress autophagy in chondrocytes. In OA cartilage, increased HIF-2α promotes expression of catabolic factors which contributes to the development of OA (Saito et al., 2010; Yang et al., 2010). The Sestrins (Sesn) promote chondrocyte survival under stress conditions and promote autophagy activation through modulating AMP-activated protein kinase (AMPK) and mTOR signaling. Sesn mRNA levels were significantly reduced in human OA cartilage. Sesn expression is suppressed in OA affected cartilage and contributes to deficiency in an important cellular homeostasis mechanism (Shen et al., 2016). Oxidative stress plays a key role in age-related cellular dysfunction and cartilage degeneration by inducing chronic production of endogenous reactive oxygen species (ROS) or “free radicals”. The mitochondria are an important source of ROS in cells and mitochondrial DNA damage in OA may be promoted by inflammatory mediators found to be increased in OA, including IL-1, IL-6, IL-8, TNF-α, and other cytokines, which can contribute to chondrocyte death (Shane Anderson and Loeser, 2010; Sacitharan and Vincent, 2016). Overproduction of mitochondrial superoxide can disrupt normal physiological signaling pathways (such as PI3K-Akt and ERK) by which it plays a pivotal role in the development and progression of OA (Toh et al., 2016; Koike et al., 2015). Figure 1 represents the schematic presentation of the pathogenic mechanism of aging in OA progression. Therapeutic strategies for age-related OA OA is a common joint disease and a global public health problem whose prevalence is rapidly growing with the increasing aging of the population. Age dependent changes in articular cartilage increase the risk of cartilage degeneration in OA. The conventional treatment of OA
is limited as the prescribed medications have higher risk of side effects (Martin et al., 2001; Vargas et al., 2014). Alternative strategies are necessary for the replacement of damaged tissue or to induce the cartilage regeneration in age-related OA. Identification of target molecules for gene therapy or biological or chemical reagent delivery to target sites could help prevent cartilage degeneration (Toh et al., 2016; Hügle et al., 2012) (Table 1). It has been demonstrated that age-related oxidative stress can disrupt normal physiological signaling and contribute to OA. The age-dependent changes were prevented in cultured human chondrocytes by adenoviral expression of catalase targeted to the mitochondria (MCAT) (Collins et al., 2016). Mesenchymal stem cells (MSC)-based therapy can also be a promising approach for the treatment of patients with OA. MSCs have been reported to protect chondrocytes from oxidative stress-induced apoptosis (Ruiz et al., 2016; Toh et al., 2016). Several studies have demonstrated the potent antioxidant and anti-inflammatory effects of plant-derived polyphenol resveratrol against IL-1-induced inflammation in human OA chondrocytes and in reducing progression of OA in a mouse model (Liu et al., 2014; Li et al., 2015). The anti-inflammatory activity of curcumin has established this spice molecule as a strong therapeutic candidate for OA treatment. Many clinical trials have been conducted to determine the effectiveness of curcumin in osteoarthritic patients, and OA patients showed improvement in pain, physical function, and quality of life after taking curcumin (Chin, 2016). Along with curcumin, some other antioxidant natural products like quercetin, pterostilbene and hydroxypterostilbene have also been regarded to have anti-inflammatory activities (Siard et al., 2016). The active ingredient from black seed, thymoquinone was found to inhibit IL-1β-induced inflammatory mediator production by inhibition of NF-κB and mitogen-activated protein kinases signaling pathways in osteoarthritis chondrocytes, and thus indicated as a potential agent in OA treatment (Wang et al., 2015). Chang et al. (2015) reported that ascorbic acid (AA) provides protection for human chondrocytes against OA by regulating multiple regulatory pathways. They treated chondrocytes with AA under conditions of oxidative stress and found that AA reduced apoptosis, inhibited differentiation of chondrocytes and markedly decreased H2O2-mediated senescence in cells by stimulating the expression levels of collagens and proteoglycans as well as decreased the activity of nrf2, NF-κB, AP1 and MMP-3. Cai et al. (2015) reported that nuclear factor (erythroid-derived 2)-like 2 (Nrf2) provides protection against oxidative stress and tissue damage in OA by regulating the expression of phase II antioxidant enzymes. They also suggested that the use of histone deacetylase inhibitors (HDACi) activated Nrf2
and showed chondroprotective effects in various animal models against OA. In their study, they administered a pan-HDACi, trichostatin A (TSA) into cartilage and found that TSA promoted the induction of Nrf2 downstream proteins in SW1353 chondrosarcoma cells and in mouse joint tissues. TSA also reduced the cartilage damage in OA models by reducing the expression of OA-associated proteins MMP1, MMP3, and MMP13 and pro-inflammatory cytokines TNF-α, IL-1β and IL-6 (Cai et al., 2015). MicroRNA-34a promotes apoptosis and inhibits proliferation pathway in primary human chondrocytes through direct regulation of the SIRT1/p53 signaling pathway and serves as a potential therapeutic target of OA. Down-regulation of miR-34a or targeted activation of SIRT1 in articular chondrocytes regulates energy balance and coordinates several housekeeping mechanisms to increase cell stress resistance and maintain quality control (Takayama et al., 2009; Yan et al., 2016). Yan et al. (2016) induced a rat model of OA through anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) and their study showed that silencing of miR-34a by intra-articular injection of lentiviral vector encoding anti-miR-34a sequence effectively increased ameliorated the progression of OA (Yan et al., 2016). Anti-miR-30b enhances autophagy and attenuates cartilage degradation and plays a protective role in TNF-α-induced apoptosis of chondrogenic ADTC5 cell line, and thus anti-miR-30b has therapeutic potential for osteoarthritis and inflammatory diseases (Chen et al., 2016). Additionally, Sirt6 can also suppress cartilage degradation by suppressing cellular senescence and inflammatory responses. In OA, sirt6 level was significantly decreased in the articular chondrocytes and over-expression or activation of Sirt6 can prevent the progression of OA (Wu et al., 2015; Piao et al., 2013). Wu et al. (2015) examined the protective effects of Sirt6 in IL-1β -treated chondrocytes and found that over-expression of Sirt6 can prevent chondrocytes replicative senescence and osteoarthritic changes induced by interleukin-1β (Wu et al., 2015). However, further research is still needed to demonstrate the efficacy of these alternative treatment strategies in clinical trials using controlled and prospective studies. Conclusion OA is a debilitating and degenerative disease which has become one of the major health and financial burdens of the world. Age is the most prominent risk factor for the development and progression of OA, however, little is known about the mechanisms by which aging contributes to OA. Understanding the aging-related mechanisms that promote OA could lead
to the discovery of new targets for therapies that aim to treat OA or to delay its development. More scientific investigations are needed to develop novel therapeutic targets to reduce pain, joint tissue destruction and disability in age-related OA in the future. Acknowledgement This work was supported by the National Natural Science Foundation of China (No. 81402224, 81401838), the Provincial Science Foundation of Hunan (No.2015JJ3139), the Science and Technology Office of Changsha City (K1203040-31), the Health and Family Planning Commission of Hunan Province (B2014-12, B2016105), the Administration of Traditional Chinese Medicine of Hunan Province (No.2015116). Conflict of interest None
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Figure 1: Pathogenic mechanism of aging in the development of OA. Many cellular signaling mechanisms have been implicated in the process of aging that induces age-related changes in chondrocytes (Sacitharan and Vincent, 2016). These changes influence the expression of catabolic factors resulting in increased production of MMPs and cytokines, reduced levels of collagen type II and aggrecan synthesis, and increased production of reactive oxygen species (ROS). The increase in ROS leads to mitochondrial dysfunction and chondrocyte death which contributes to the development of OA (Loeser, 2009; Wu et al., 2015).
Table 1: Potential treatment strategies for age-related osteoarthritis Therapeutic agents
Mode of action
References
MCAT
Activation of pro-survival Akt signaling and inhibition of pro-death p38 signaling
(Collins et al., 2016)
Resveratrol
Antioxidant, activation of SIRT1 and
(Li et al., 2015)
Inhibition of HIF-2α Curcumin
Antioxidant and anti-inflammatory activity
(Chin, 2016)
Ascorbic acid
Antoixidant, decreased the activity NF-κB, AP1 and MMP-3 that are stimulated by H2O2
(Chang et al., 2015)
Activation of nrf2, reduction of MMP (-1, -3, and -13) and proinflammatory cytokines TNF-α, IL-1β and IL-6
(Cai et al., 2015)
Anti-miR-34a agents
Activation of SIRT1
(Yan et al., 2016)
Anti-miR-30b agents
Enhances autophagy and attenuates cartilage degradation
(Chen et al., 2016)
Reduction of MMP-13, overproduction of colleagn II and suppression of NF-κB signaling
(Wu et al., 2015)
Histone deacetylase inhibitors
Lenti-Sirt6 intraarticular injection
Sirtuins
Autophagy
Cellular aging
Cellular senescence
Oxidative stress Biochemical stress
Catabolic factors Cytokines & MMPs collagen type II and aggrecan ROS Mitochondrial dysfunction Chondrocyte death Osteoarthritis development
S0047-6374(16)30281-0 http://dx.doi.org/doi:10.1016/j.mad.2016.12.012 MAD 10910
To appear in:
Mechanisms of Ageing and Development
Received date: Revised date: Accepted date:
30-11-2016 22-12-2016 27-12-2016
Please cite this article as: Li, Yu-Sheng, Xiao, Wen-feng, Luo, Wei, Cellular aging towards osteoarthritis.Mechanisms of Ageing and Development http://dx.doi.org/10.1016/j.mad.2016.12.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cellular aging towards osteoarthritis
Yu-Sheng Li, Wen-feng Xiao, Wei Luo* Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha 410008, P.R.China *For correspondence: Dr. Wei Luo, Department of Orthopaedics, Xiangya Hospital of Central South University, No 87. Xiangya Road, Changsha 410008, Hunan Province, P.R. China; E-mail: [email protected], Tel: +86-0731-89753006
Highlights:
Osteoarthritis (OA) is age-related neurodegenerative disease.
Reactive oxygen species produced in cellular process play vital role in OA development
Antioxidants, histone deacetylase inhibitors, anti-miR34a agents might be beneficial for treating age related OA
Abstract Osteoarthritis (OA) is a common form of degenerative joint disease. Aging process is supposed to be a leading predictor for developing OA. In this review, we have discussed the potential roles of aging in OA, a better understanding of which might delay or stop the development and progression of OA. Different cellular signaling mechanisms are involved process of aging that induces age-related changes in chondrocytes. These changes influence the expression of catabolic factors resulting in increased production of matrix metalloproteinases and cytokines, reduced levels of collagen type II and aggrecan synthesis, and increased production of reactive oxygen species (ROS). ROS leads to mitochondrial dysfunction and chondrocyte death, which contributes to the development of OA. Antioxidant supplementation is probably the best way to prevent or delay the age-related OA. Some therapeutic agents like histone deacetylase inhibitors and anti-miR34a agents have been reported to be effective against age-related OA. However, further research is needed to demonstrate the efficacy of these alternative treatment strategies in clinical trials using controlled and prospective studies.
Keywords Osteoarthritis; Aging; Chondrocyte dysfunction; Antioxidants
Introduction Osteoarthritis (OA) is an age-related degenerative joint disease characterized by progressive degradation in articular cartilage, extensive remodeling of adjacent bone with new bone leading to synovitis as well as osteophyte formation (Bijlsma et al., 2011; Fang and Beier, 2014). OA is the most common form of arthritis resulting in substantial morbidity, physical disability, reduced quality of life and increased health costs. It is considered to be the fourth leading cause of disability due to the increasing life expectancy and aging populations (Freitag et al., 2016; Fransen et al., 2011). OA mainly affects the joints of knees, hips, hands and spine (cervical and lumbar); and the most common clinical manifestations of OA include pain, tenderness, stiffness, swelling and movement limitation (Jones, 2013; Pérez Martín, 2014). The exact cause of OA is mostly unclear. It is not a single disease condition, rather a complex disorder and is thought to be associated with a variety of risk factors including genetic factors, constitutional factors (such as age, sex, increased body weight and trauma) as well as several biochemical and biomechanical components (Brandt et al., 2009; Glyn-Jones et al., 2015). Currently, there is no satisfactory drug for effective OA treatment, and OA cannot be cured totally. Current medical treatment strategies only aim to control the symptoms and pain reduction (de Rezende et al., 2013). The initial management of OA includes patient education, exercise, lifestyle changes and pain medications such as the simple analgesics acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid injections, hyaluronic acid (HA) injections and glucosamine. In severe cases of OA, joint replacement surgery may be recommended (Vargas Negrín et al., 2014, Buttgereit et al., 2015). However, most of the conventional management options are not always satisfactory as these treatments are not readily available, highly expensive, can neither modify disease nor inhibit OA progression, and have some unwanted and hazardous side effects (Woolf and Pfleger, 2003; Cheng et al., 2014). To overcome these problems, alternative therapeutic strategies are urgently needed that can help to identify the more effective targets for the management and prevention of OA (Wyles et al., 2015). Aging is supposed to be the leading predictor for developing OA. However, the mechanisms by which aging contribute to the development of OA remain unclear (Loeser et al., 2016; Benderdour et al., 2015). In this study, we have reviewed the potential roles of aging in the development and progression of OA. A better understanding of the pathogenic mechanism of aging process may help to delay or stop the progression and development of OA.
Cell aging in different diseases Aging is a natural process characterized by a state of chronic, low-grade and sterile inflammation caused by a progressive loss of function and physiological integrity of the different organs and tissues. Aging induces homeostatic imbalance between inflammatory and anti-inflammatory pathways and risk of a number of age-related chronic disorders including atherosclerosis, type 2 diabetes, Alzheimer's disease, cancers, osteoarthritis and others. The incidence of all of these diseases increases rapidly with aging (Kirkwood, 2005; Zhu et al., 2014; MacNee et al., 2014). The exact etiology involved in aging process is unclear. Chronic inflammation and cytokine levels have been shown to be elevated in the aging process. Three main metabolic pathways have been identified that can influence the aging process separately. These are dietary restriction, insulin/IGF-1-like signaling pathway and the pathway involved in activity level of the mitochondrial electron transport chain. These pathways may play an important role in the prevention of aging and age-related diseases in humans and might be promising targets for future therapeutics (Taylor and Dillin, 2011; Wolff and Dillin 2006). The first is dietary restriction (DR, also referred to as calorie restriction) which leads to longer lifespan in various species. The amino-acid-sensing serine/threonine kinase, mammalian target of rapamycin (mTOR); and the NAD+ dependent deacetylase, SIRT1, are involved in DR signaling (Ghosh et al., 2010; Johnson et al., 2013). Dietary restriction reduces mTORC1 activity in some mammalian tissues and invertebrate organisms, which allows an increased level of autophagy. Inhibition of mTOR activity and induction of autophagy increase longevity by reducing the effects of reactive oxygen species on the body (Kenyon, 2010; Fontana et al., 2010; Stanfel et al., 2009). SIRT1 is a NAD+ dependent deacetylase that regulates caloric restriction mediated longevity in model organisms. SIRT1 negatively regulates mTOR signaling potentially through the TSC2, a component of the mTOR inhibitory-complex and contributes to longevity as well as health benefits as a result of dietary restriction (Tee et al., 2003, Niccoli and Partridge, 2012). Another pathway that mediates lifespan extension is the insulin/IGF-1-like signaling pathway (IIS). A decreased IIS pathway increases longevity by increasing insulin sensitivity and stress resistance as well as protection from carcinogenesis. Following ligand binding, the IIS receptor DAF-2 (abnormal DAuer Formation-2) recruits the insulin receptor substrate homolog IST-1 and AGE-1 through which the transcription factor DAF-16 is phosphorylated. Phosphorylation of DAF-16 in the cytosol represses raptor expression by activating a diverse transcriptional profile (such as SMK-1, HCF-1, HSF-1 and SIR-2) and promotes extension of
longevity (Taylor and Dillin, 2011; Johnson et al., 2013). The third pathway that enables extension of lifespan is the activity level of the mitochondrial electron transport chain (ETC). However, the mechanisms and signaling pathways involved in lifespan remain unknown. It has been reported that reduced expression of several mitochondrial genes including components of ETC complexes I, III, IV, and V by RNA interference (RNAi) can extend lifespan through reduced mitochondrial function (Feng et al., 2001; Dillin et al., 2002; Lee et al., 2003). Cell aging in osteoarthritis development Aging is an important contributing factor to the development of OA. However, the mechanism by which aging contributes to OA development is still not clearly understood. In OA, chondrocytes undergo premature aging due to several factors including an age-related inflammation that has been termed as "inflamm-aging." Inflamm-aging is a pro-inflammatory state that occurs during physiological aging and has been associated with decreased physical function and frailty. Inflamm-aging can contribute to OA through the degradation of articular cartilage and other joint tissues by inducing the production of pro-inflammatory mediators in the arthritic joint (Greene and Loeser, 2015; Loeser, 2011). OA can be the result of cellular senescence caused by a variety of stimuli and stresses, including genomic DNA damage, epigenetic changes, metabolic stresses and mitochondrial dysfunction (Portal-Núñez et al., 2016). Senescent cells accumulate with aging in joint tissues and display a senescence-associated secretory phenotype (SASP) associated with overproduction of cytokines (such as, interleukins 1 and 6) and growth factors (e.g., epidermal growth factor, transforming growth factor β), as well as matrix-degrading enzymes such as matrix metalloproteinases (MMPs) (e.g., MMP-3, MMP-13), all of which can contribute to the development and progression of OA (Loeser, 2009; Xu et al., 2016; Benderdour et al., 2015). Sirtuin is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase and is involved in controlling aging. In mammals, the sirtuin family contains seven genes (SIRT1- SIRT7) encoding sirtuin proteins that differ in tissue distribution, specificity and enzymatic activity. Among these, SIRT1 plays a crucial role in cartilage homeostasis, cell senescence, inflammation and apoptosis by deacetylating important transcriptional factors including p53, FOXO and p65 (Blander and Guarente, 2004; Imai and Guarente, 2010; Yan et al., 2016). Loss of SIRT1 enzymatic function or its inactivation attenuates the deacetylation of p53, leading to the up-regulation of Bax and down-regulation of Bcl-2. Enhanced acetylation of p53 contributes to OA severity by
reducing the levels of collagen type II and aggrecan in articular cartilage. SIRT6 is localized to the nucleus and plays an important role in transcriptional silencing, genome stability and the regulation of senescence of human chondrocytes. Depletion of SIRT6 in human chondrocytes caused increased MMP-1 and -13 mRNA level, DNA damage and telomere dysfunction, and subsequent premature senescence (Ailixiding et al., 2015; Wu et al., 2015). Autophagy is an essential homeostatic process that maintains cell homeostasis by adjusting cell metabolism to nutrient supply and removing damaged macromolecules and organelles. Recent studies indicated that autophagy declines with aging and during OA, leading to cell death and tissue damage. Aging-related loss of autophagy induced significant mitochondrial dysfunction in human chondrocytes that plays an important role in OA pathogenesis (López de Figueroa et al., 2015; Caramés et al., 2015). It has been suggested that HIF-2α plays a crucial role to suppress autophagy in chondrocytes. In OA cartilage, increased HIF-2α promotes expression of catabolic factors which contributes to the development of OA (Saito et al., 2010; Yang et al., 2010). The Sestrins (Sesn) promote chondrocyte survival under stress conditions and promote autophagy activation through modulating AMP-activated protein kinase (AMPK) and mTOR signaling. Sesn mRNA levels were significantly reduced in human OA cartilage. Sesn expression is suppressed in OA affected cartilage and contributes to deficiency in an important cellular homeostasis mechanism (Shen et al., 2016). Oxidative stress plays a key role in age-related cellular dysfunction and cartilage degeneration by inducing chronic production of endogenous reactive oxygen species (ROS) or “free radicals”. The mitochondria are an important source of ROS in cells and mitochondrial DNA damage in OA may be promoted by inflammatory mediators found to be increased in OA, including IL-1, IL-6, IL-8, TNF-α, and other cytokines, which can contribute to chondrocyte death (Shane Anderson and Loeser, 2010; Sacitharan and Vincent, 2016). Overproduction of mitochondrial superoxide can disrupt normal physiological signaling pathways (such as PI3K-Akt and ERK) by which it plays a pivotal role in the development and progression of OA (Toh et al., 2016; Koike et al., 2015). Figure 1 represents the schematic presentation of the pathogenic mechanism of aging in OA progression. Therapeutic strategies for age-related OA OA is a common joint disease and a global public health problem whose prevalence is rapidly growing with the increasing aging of the population. Age dependent changes in articular cartilage increase the risk of cartilage degeneration in OA. The conventional treatment of OA
is limited as the prescribed medications have higher risk of side effects (Martin et al., 2001; Vargas et al., 2014). Alternative strategies are necessary for the replacement of damaged tissue or to induce the cartilage regeneration in age-related OA. Identification of target molecules for gene therapy or biological or chemical reagent delivery to target sites could help prevent cartilage degeneration (Toh et al., 2016; Hügle et al., 2012) (Table 1). It has been demonstrated that age-related oxidative stress can disrupt normal physiological signaling and contribute to OA. The age-dependent changes were prevented in cultured human chondrocytes by adenoviral expression of catalase targeted to the mitochondria (MCAT) (Collins et al., 2016). Mesenchymal stem cells (MSC)-based therapy can also be a promising approach for the treatment of patients with OA. MSCs have been reported to protect chondrocytes from oxidative stress-induced apoptosis (Ruiz et al., 2016; Toh et al., 2016). Several studies have demonstrated the potent antioxidant and anti-inflammatory effects of plant-derived polyphenol resveratrol against IL-1-induced inflammation in human OA chondrocytes and in reducing progression of OA in a mouse model (Liu et al., 2014; Li et al., 2015). The anti-inflammatory activity of curcumin has established this spice molecule as a strong therapeutic candidate for OA treatment. Many clinical trials have been conducted to determine the effectiveness of curcumin in osteoarthritic patients, and OA patients showed improvement in pain, physical function, and quality of life after taking curcumin (Chin, 2016). Along with curcumin, some other antioxidant natural products like quercetin, pterostilbene and hydroxypterostilbene have also been regarded to have anti-inflammatory activities (Siard et al., 2016). The active ingredient from black seed, thymoquinone was found to inhibit IL-1β-induced inflammatory mediator production by inhibition of NF-κB and mitogen-activated protein kinases signaling pathways in osteoarthritis chondrocytes, and thus indicated as a potential agent in OA treatment (Wang et al., 2015). Chang et al. (2015) reported that ascorbic acid (AA) provides protection for human chondrocytes against OA by regulating multiple regulatory pathways. They treated chondrocytes with AA under conditions of oxidative stress and found that AA reduced apoptosis, inhibited differentiation of chondrocytes and markedly decreased H2O2-mediated senescence in cells by stimulating the expression levels of collagens and proteoglycans as well as decreased the activity of nrf2, NF-κB, AP1 and MMP-3. Cai et al. (2015) reported that nuclear factor (erythroid-derived 2)-like 2 (Nrf2) provides protection against oxidative stress and tissue damage in OA by regulating the expression of phase II antioxidant enzymes. They also suggested that the use of histone deacetylase inhibitors (HDACi) activated Nrf2
and showed chondroprotective effects in various animal models against OA. In their study, they administered a pan-HDACi, trichostatin A (TSA) into cartilage and found that TSA promoted the induction of Nrf2 downstream proteins in SW1353 chondrosarcoma cells and in mouse joint tissues. TSA also reduced the cartilage damage in OA models by reducing the expression of OA-associated proteins MMP1, MMP3, and MMP13 and pro-inflammatory cytokines TNF-α, IL-1β and IL-6 (Cai et al., 2015). MicroRNA-34a promotes apoptosis and inhibits proliferation pathway in primary human chondrocytes through direct regulation of the SIRT1/p53 signaling pathway and serves as a potential therapeutic target of OA. Down-regulation of miR-34a or targeted activation of SIRT1 in articular chondrocytes regulates energy balance and coordinates several housekeeping mechanisms to increase cell stress resistance and maintain quality control (Takayama et al., 2009; Yan et al., 2016). Yan et al. (2016) induced a rat model of OA through anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) and their study showed that silencing of miR-34a by intra-articular injection of lentiviral vector encoding anti-miR-34a sequence effectively increased ameliorated the progression of OA (Yan et al., 2016). Anti-miR-30b enhances autophagy and attenuates cartilage degradation and plays a protective role in TNF-α-induced apoptosis of chondrogenic ADTC5 cell line, and thus anti-miR-30b has therapeutic potential for osteoarthritis and inflammatory diseases (Chen et al., 2016). Additionally, Sirt6 can also suppress cartilage degradation by suppressing cellular senescence and inflammatory responses. In OA, sirt6 level was significantly decreased in the articular chondrocytes and over-expression or activation of Sirt6 can prevent the progression of OA (Wu et al., 2015; Piao et al., 2013). Wu et al. (2015) examined the protective effects of Sirt6 in IL-1β -treated chondrocytes and found that over-expression of Sirt6 can prevent chondrocytes replicative senescence and osteoarthritic changes induced by interleukin-1β (Wu et al., 2015). However, further research is still needed to demonstrate the efficacy of these alternative treatment strategies in clinical trials using controlled and prospective studies. Conclusion OA is a debilitating and degenerative disease which has become one of the major health and financial burdens of the world. Age is the most prominent risk factor for the development and progression of OA, however, little is known about the mechanisms by which aging contributes to OA. Understanding the aging-related mechanisms that promote OA could lead
to the discovery of new targets for therapies that aim to treat OA or to delay its development. More scientific investigations are needed to develop novel therapeutic targets to reduce pain, joint tissue destruction and disability in age-related OA in the future. Acknowledgement This work was supported by the National Natural Science Foundation of China (No. 81402224, 81401838), the Provincial Science Foundation of Hunan (No.2015JJ3139), the Science and Technology Office of Changsha City (K1203040-31), the Health and Family Planning Commission of Hunan Province (B2014-12, B2016105), the Administration of Traditional Chinese Medicine of Hunan Province (No.2015116). Conflict of interest None
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Figure 1: Pathogenic mechanism of aging in the development of OA. Many cellular signaling mechanisms have been implicated in the process of aging that induces age-related changes in chondrocytes (Sacitharan and Vincent, 2016). These changes influence the expression of catabolic factors resulting in increased production of MMPs and cytokines, reduced levels of collagen type II and aggrecan synthesis, and increased production of reactive oxygen species (ROS). The increase in ROS leads to mitochondrial dysfunction and chondrocyte death which contributes to the development of OA (Loeser, 2009; Wu et al., 2015).
Table 1: Potential treatment strategies for age-related osteoarthritis Therapeutic agents
Mode of action
References
MCAT
Activation of pro-survival Akt signaling and inhibition of pro-death p38 signaling
(Collins et al., 2016)
Resveratrol
Antioxidant, activation of SIRT1 and
(Li et al., 2015)
Inhibition of HIF-2α Curcumin
Antioxidant and anti-inflammatory activity
(Chin, 2016)
Ascorbic acid
Antoixidant, decreased the activity NF-κB, AP1 and MMP-3 that are stimulated by H2O2
(Chang et al., 2015)
Activation of nrf2, reduction of MMP (-1, -3, and -13) and proinflammatory cytokines TNF-α, IL-1β and IL-6
(Cai et al., 2015)
Anti-miR-34a agents
Activation of SIRT1
(Yan et al., 2016)
Anti-miR-30b agents
Enhances autophagy and attenuates cartilage degradation
(Chen et al., 2016)
Reduction of MMP-13, overproduction of colleagn II and suppression of NF-κB signaling
(Wu et al., 2015)
Histone deacetylase inhibitors
Lenti-Sirt6 intraarticular injection
Sirtuins
Autophagy
Cellular aging
Cellular senescence
Oxidative stress Biochemical stress
Catabolic factors Cytokines & MMPs collagen type II and aggrecan ROS Mitochondrial dysfunction Chondrocyte death Osteoarthritis development