Aging Cell (2002) 1, pp57–65
Blackwell Science, Ltd
The role of chondrocyte senescence in osteoarthritis
骨关节炎中软骨细胞的衰老研究
——英国东安格利亚大学生命科学学院
Jo S. Price,* Jasmine G. Waters,* Clare Darrah, Caroline Pennington,* Dylan R. Edwards,* Simon T. Donell and Ian M. Clark*
*School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK Institute of Orthopaedics, Norfolk and Norwich University Hospital, Norwich
Introduction
Normal somatic cells do not divide indenitely; this leads to an eventual arrest of cell division by a process called replicative senescence (Hayick, 1965). Such cells remain viable, but often exhibit an altered phenotype. Senescence has been studied extensively in cultured cells, particularly broblasts, by allowing cells to grow until replication stops. Senescence is extremely stringent in human cells which rarely undergo spontaneous immortalization. A current hypothesis is that the 'counter' for replicative senescence is telomere length. Telomeres cannot be completely replicated in primary cells and hence become shorter with each round of cell division. When telomere length becomes critically short, genetic changes are triggered which stop cell division and the senescent cell changes phenotype with an alteration in gene expression (Bodnar et al., 1998). A signicant correlation between telomere length and donor age has been determined (Lindsey et al., 1991). Furthermore, in some cases, overexpression of the catalytic subunit of telomerase (the enzyme that maintains telomere length) can delay senescence; telomerase is not usually detectable in normal somatic cells, but is frequently expressed in tumours and immortalized cell lines (Yudoh et al., 2001) Cells cultured from old donors tend to senesce after fewer population doublings than cells from young donors (Campisi, 2000). Thus, cells in renewable tissues may deplete their replicative potential during aging. It is assumed that senescent cells accumulate in vivo, where their altered phenotype may contribute to age-related pathology, e.g. dermal thinning and collagen breakdown are hallmarks of aging skin that may be due to senescent broblasts which overexpress collagenase and underexpress collagenase inhibitors (Khorramizadeh et al., 1999); endothelial cells lining vessels may senesce in response to haemodynamic stress and this may initiate or exacerbate atherosclerosis (Okuda et al., 2000; Minamino et al., 2002). The most direct evidence for senescent cells in vivo comes from a modied histochemical marker for the enzyme β-galactosidase. When detected at pH 6, β-galactosidase is a biomarker of replicatively senescent cells. Dimri et al. (1995) used this marker to show an increase in senescent cells with donor age in skin sections from patients aged 20–90 years old. The SA-β-gal marker has also been used in vivo in other tissues, e.g. arteries (Minamino et al., 2002) and gastrointestinal tract (Going et al., 2002). Studies performed in human broblasts demonstrate that replicatively senescent, late passage cells display altered patterns of expression of MMPs and TIMPs compared to young, replication-competent cells. Aging broblasts express MMP-1 mRNA and secrete MMP-1 at elevated constitutive levels (Sottile et al., 1989; West et al., 1989; Edwards et al., 1996). This has also been shown for MMP-3, whereas steady-state levels of TIMP-1 were reduced compared to young broblasts (Millis et al., 1992).

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