The role of chondrocyte senescence in osteoarthritis.
Replicative senescence occurs when normal somatic cells stop dividing. Senescent cells remain viable, but show alterations in phenotype, e.g. altered expression of matrix metalloproteinases (MMPs); these enzymes are known to be involved in cartilage destruction. It is assumed that cells deplete their replicative potential during aging, and age is a major risk factor for osteoarthritis (OA). Therefore, we hypothesized that chondrocytes in aging or diseased cartilage become senescent with associated phenotypic changes contributing to development or progression of OA. Articular cartilage was obtained from OA patients undergoing arthroplasty, with 'normal' cartilage from trauma surgery for hip fracture. Senescent cells were identified using the senescence-associated beta-galactosidase (SA-beta-gal) marker. Telomere length was assessed using Southern blot. MMP expression was measured at the mRNA level using Taqman RT-PCR. No SA-beta-gal staining was observed in control cartilage regardless of patient age. In contrast, SA-beta-gal staining was observed in damaged OA cartilage adjacent to the lesion. Cultured chondrocytes isolated from sites near a lesion contained a greater percentage of SA-beta-gal positive cells than cultures isolated from distal sites or normal cartilage. Mean telomere length was shorter in cells near the lesion compared to distal sites in the same joint; thus the former population has undergone cell division. The expression of collagenases MMP-1, -8 and -13 and tissue inhibitor of metalloproteinases (TIMP)-1 was altered in OA cartilage, but no difference was detected between lesion and distal sites in the same joint (i.e. no correlation was found between senescent cells and proteinase/ inhibitor expression).
Price
Jo S
JS
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
Waters
Jasmine G
JG
Darrah
Clare
C
Pennington
Caroline
C
Edwards
Dylan R
DR
Donell
Simon T
ST
Clark
Ian M
IM
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002358:Cartilage, Articular / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D019902:Chondrocytes / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D010003:Osteoarthritis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D016615:Telomere / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D015415:Biomarkers; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D001616:beta-Galactosidase; D020782:Matrix Metalloproteinases