Abstract
IntroductionTelomere shortening is associated with a number of common age-related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. We addressed this role directly in vivo by using a newly developed assay, which measures specifically the load of ultra-short single telomeres (below 1,500 base pairs), that is, the telomere subpopulation believed to promote cellular senescence.MethodsSamples were obtained from human OA knees at two distances from the central lesion site. Each sample was split into three: one was used for quantification of ultra-short single telomeres through the Universal single telomere length assay (STELA), one for histological Mankin grading of OA, and one for mean telomere length measurement through quantitative fluorescence in situ hybridization (Q-FISH) as well as for assessment of senescence through quantification of senescence-associated heterochromatin foci (SAHF).ResultsThe load of ultra-short telomeres as well as mean telomere length was significantly associated with proximity to lesions, OA severity, and senescence level. The degree of significance was higher when assessed through load of ultra-short telomeres per cell compared with mean telomere length.ConclusionsThese in vivo data, especially the quantification of ultra-short telomeres, stress a role of telomere shortening in human OA.
Highlights
Telomere shortening is associated with a number of common age-related diseases
This 3-dimensional distribution pattern of ultra-short telomeres is shown in Figure 2, where their number is compared to mean telomere lengths, OA grades, and percentage of senescence-associated heterochromatin foci (SAHF) positive cells measured at the same positions
Development, we found that distance to the lesion was more closely related to the load of ultra-short telomeres measured by Universal single telomere length assay (STELA) than with mean telomere length evaluated by quantitative fluorescence in situ hybridization (Q-FISH)
Summary
Telomere shortening is associated with a number of common age-related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. There should be awareness that telomere shortening may occur by two superimposed processes [3]: (i) gradual linear shortening reflecting the number of cell divisions (that is, ‘replicative’ shortening); (ii) a more stochastic process, causing sudden extensive shortening of a single telomere, and induced by various stimuli, including oxidative damage (that is, ‘stressinduced’ shortening) The latter process deserves special attention with respect to cell senescence, because there are indications that it is the critical shortening of a few or even a single telomere, rather than a decrease in the mean length that leads to dysfunction and induces senescence [8,9,10]. If single critically short telomeres are the prevailing products of stress-induced telomere shortening and if they are responsible for induction of senescence, it appears essential to assess these fragments and not merely mean telomere length in chondrocytes
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