Telomere shortening. A telomere is a region of repetitive DNA (TTAGGG repeats) at the end of a chromosome, which protects the end of the chromosome from deterioration. Each time cells divide, telomeres shorten, and there is a limit to the number of times a given cell can go on dividing, the socalled "Hayflick limit". When the length of the telomeres is too short cell division stops. 

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Context 1

... aging, or cell senescence, refers to the limited capacity of mitotic cells to further multiply in time (over 30-40 divisions). This limit is known as the "Hayflick limit" (Hayflick, 1984). This form of Age-related degeneration of articular cartilage is called "replicative senescence", also known as intrinsic senescence, which results from an arrest in cell-cycle progression. Some of the changes exhibited by cells, which have undergone replicative senescence can be found in cells in older adults, such as shortened telomeres, formation of senescence-associated (SA) heterochromatin (Muller, 2009) and changes of phenotype with an alteration in gene expression ( Bodnar et al., 1998). It has been hypothesized that the telomere length could be considered as a marker for replicative senescence. Telomeres cannot be completely replicated in primary cells and become shorter with each round of cell division. Telomeres are nucleoprotein structures (TTAGGG repeats) that cap the ends of the linear eukaryotic chromosomes and thereby protect their stability and integrity during replication by protecting chromosome ends against exonucleases (Fig. 1). Telomeres are replicated by a special reverse transcriptase called telomerase, in a complex mechanism that is coordinated with the genome's replication. Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences and comprises two essential components. One is the functional RNA component (in humans called hTERC), which serves as a template for telomeric DNA synthesis. The other is a catalytic protein (hTERT) with reverse transcriptase activity and the primary determinant for the enzyme activity ( Bryan and Cech, 1999;Kupiec, 2014). The level of telomerase in normal human somatic tissues is insufficient to prevent telomere shortening. Telomeres can be lengthened through increasing telomerase activity by exogenous expression of hTERT or hTR (the RNA template) (Greider, 1998). As proof of this concept the chondrocytes transduced with hTERT proved to be able to increase telomere length and therefore to prolong cell lifespan, increasing in this way the efficacy of cartilage repair (Martin and Buckwalter, 2003). Another type of senescence is "stress-induced senescence", also known as extrinsic senescence, which is independent of telomere length. In quiescent cells such as chondrocytes, this type of senescence may be more important than the replicative version, because progressive telomere shortening cannot completely explain senescence in these post-mitotic cells (Ben-Porath and Weinberg, 2005;Chen and Goligorsky, 2006). The various types of stress responsible for this kind of senescence include DNA damage, oxidative stress, oncogene activity, ultraviolet radiation and chronic inflammation ( Itahana et al., 2004;Campisi, 2005). Oxidative stress is thought to play a major role as a stressor. It results when the amount of reactive oxygen species (ROS) exceeds the anti-oxidant capacity of the cell. ROS are generated by intracellular enzymes such as nicotine amide adenine dinucleotide phosphate (NADPH) oxidase and 5- Age-related degeneration of articular cartilage lipoxygenase in response to activation of specific cell signaling pathways ( Kamata and Hirata, 1999;Finkel and Holbrook, 2000). A direct role for increased ROS levels in promoting cell senescence is a positive feedback activation of the ROS-protein kinase C delta (PKCδ) signaling pathway, which cooperates with the p16 INK4A -retinoblastoma protein (Rb) pathway, which plays an important role in the control of cell-cycle progression ( Takahashi et al., 2006). Telomere shortening is also observed in stress-induced senescence and it is due to oxidative damage to DNA caused by ROS. The ends of chromosomes are particularly sensitive to oxidative damage, which causes telomere erosion similar to that seen with replicative senescence ( Yudoh et al., 2005). Also, the ROS generated from excessive mechanical loading and stimulation of cytokines contribute to DNA damage, which subsequently results in telomere shortening ( Tomiyama et al., 2007;Davies et al., 2008). Cellular senescence, as well as apoptosis, can be viewed as a powerful tumor- suppressor mechanism that withdraws cells with irreparable DNA damage from the cell cycle (de Lange and Jacks, 1999;Artandi and DePinho, 2000;Puzzo et al., 2014) through the intrinsic or mitochondrial ( Loreto et al., 2011a;Caltabiano et al., 2013) and extrinsic apoptosis pathway ( Loreto et al., 2011b;Cardile et al., 2013). Several recent studies report that cartilage degeneration also coincides with increased apoptotic chondrocytes ( Musumeci et al., 2011a,b;Galanti et al., 2013). Therefore, the senescence signals, that is, a telomere-based one or a stress-based one, trigger a DNA damage response and this response shares a common signaling pathway that converges on either or both of the well-established two tumor-suppressor proteins, p53 (the p53-p21-pRb pathway) (Martin and Buckwalter, 2003;Herbig and Sedivy, 2006) and RB and pRb proteins (the p16-pRb pathway) ( Musumeci et al., 2010Musumeci et al., , 2011c). In the p53-p21-pRb pathway, senescence stimuli activate the p53, which then can induce senescence by activating pRb through p21, which is a transcriptional target of p53. This senescence can be reversed upon subsequent inactivation of p53. In the p16-pRb pathway, senescence stimuli induce p16, which activates pRb. Once the pRb pathway is engaged by p16, the senescence cannot be reversed by subsequent inactivation of p53, silencing of p16 or inactivation of pRb ( Beauséjour et al., 2003). The difference between these two pathways is that the p53-p21-pRb pathway mediates the senescence due to telomere shortening and the p16-pRB pathway is thought to mediate premature senescence ( Beauséjour et al., 2003). Once cells have entered senescence, they are arrested in the G1 phase of the cell cycle and display a characteristic morphology (vacuolated, flattened cells) and altered gene expression ( Cristofalo et al., 2004). The senescent cells exhibit the so-called "senescent secretory phenotype" (SSP), which Age-related degeneration of articular cartilage could be also correlated with the development of OA. It is interesting to note that the senescent cells, which are mitotically inactive, are biologically active (Campisi, 2005). These cells are able to increase the expression of genes that inhibit proliferation and to increase the secretion of several proteins, including inflammatory cytokines such as interleukin-6 (IL- Adda di Fagagna, 2007). Another important feature of senescent cells is represented by the epigenetic changes related to the formation of foci of heterochromatin, referred to as senescence-associated heterochromatin foci (SAHFs), which include histone variants such as the macro-H2A ( Zhang and Adams, ...

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... from older adults exhibit many changes, typical of cell senescence, when compared with cells isolated from young adults. The most evident change is represented by telomere shortening, characteristic of replicative senescence. This evidence is Age-related degeneration of articular cartilage controversial as adult articular chondrocytes rarely, if ever, divide in normal tissue in vivo. The lack of cell division in normal adult articular cartilage suggests that the chondrocytes present in the cartilage of an older adult are likely to be the same cells that were present decades earlier. This fact makes these cells more susceptible to the accumulation of changes from both aging and extrinsic stress. In fact, it is most likely that chondrocyte senescence is the extrinsic type, induced by different stressors. The telomere shortening in adult chondrocytes could be due to DNA damage from ROS as discussed further above (Mankin, 1963;Martin and Buckwalter, 2001b;Martin et al., 2004b). The increased ROS levels could be both age-related (Del Carlo and Loeser, 2003) and generated from excessive mechanical loading and/or stimulation by cytokines ( Kurz et al., 2005;Davies et al., 2008). There is also evidence for reduced levels of antioxidant enzymes in cartilage with aging and in OA that would contribute to chondrocyte senescence and oxidative damage. In human articular chondrocytes, decreased levels of mitochondrial superoxide dismutase were found both with aging and in OA cells (Finkel and Holbrook, 2000). Moreover, it has been hypothesized that joint injury accelerates chondrocyte senescence and that this acceleration plays a role in the joint degeneration responsible for post- traumatic OA. Indeed, excessive loading of articular surfaces due to acute joint trauma or post-traumatic joint instability, incongruity or mal-alignment increases release of ROS, and the increased oxidative stress on chondrocytes accelerates chondrocyte senescence ( James et al., 2004). Other important features of chondrocyte senescence are the exhibition of SSP, which has important implications in development and progression of OA and the decline in the proliferative and anabolic response to growth factors, as well as their reduction in cartilage. It has been noted that senescent chondrocytes lose the ability in response to: IGF-I, which is known to be an important autocrine survival factor that stimulates cartilage matrix synthesis (Martin et al., 1997); TGF-β, an important cartilage anabolic factor ( Scharstuhl et al., 2002) and to bone morphogenetic protein 6 (BMP-6), known to stimulate proteoglycan synthesis ( Bobacz et al., 2003). Chondrocyte senescence also contributes to the decline in the cell number within the cartilaginous tissue, due to increased cell death. Several studies demonstrated the loss of cellular density in cartilage with aging or/and in OA ( Vignon et al., 1976;Adams and Horton, 1998;Horton et al., 1998;Aigner et al., 2004a;Kuhn et al., 2004). These findings provide evidence to support the concept that chondrocyte senescence may be involved in the progression of cartilage degeneration, Age-related degeneration of articular cartilage Fig. 5. Stress-induced senescence and Osteoarthritis. The telomere shortening process in senescent chondrocytes is more probably due to the stress-induced type of senescence. Oxidative stress and excessive mechanical loading are thought to be the major stressors that induce the increased production of ROS, which are responsible for DNA damage and for the subsequent senescence of the cells. Once cells have entered senescence, they are arrested in the G1 phase of the cell cycle and they display a characteristic gene expression called "senescent secretory phenotype", which is strongly correlated with the development of ...

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... body is made up of an incredibly large number of cells, around 100 billion, some of them have a rather short life, others such as chondrocytes remain for a lifetime, but at a certain point, the mechanism slows down, cell duplication starts to fail and the cells are no longer replaced by other ones. The cells arrest their cell cycle progression. Each cell has a limited number of possible divisions, which is fixed between 50 and 70. The reason lies in the structure of chromosomes that are duplicated at each division in order to obtain one copy for itself and another for the daughter cell that will play the same role in the body. The division process, however, is not perfect, the cellular mechanism fails to copy the ends of chromosomes, the so-called telomeres (Fig. 1). After each cell division, the telomeres become shorter and shorter and are eventually completely worn out and parts of chromosomes that contain essential genetic information begin to erode. At this point the cell is at the end of its life and it approaches death ...