The role of chondrocyte senescence in osteoarthritis

Abstract

SummaryReplicative 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 β β β β -galactosidase (SA-β β β β -gal) marker. Telomere length was assessed using Southern blot. MMP expression was measured at the mRNA level using Taqman® RT-PCR.No SA-β β β β -gal staining was observed in control cartilage regardless of patient age. In contrast, SA-β β β β -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-β β β β -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).

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

“…Chondrocyte proliferation can occur during the development of osteoarthritis (OA) in the form of cell clusters, but it is not known if this replicative response is regenerative, pathologic, or epiphenomenal (Lotz et al., 2010). Chondrocytes also display features of senescence with aging and OA, likely in response to macromolecular damage that accumulates in these long‐lived cells (Martin & Buckwalter, 2001; McCulloch, Litherland & Rai, 2017; Price et al., 2002; Rose et al., 2012). OA progression is driven by inflammatory cytokines that initiate a cascade of matrix degradation, and the prominent role for SASP factors such as matrix metalloproteinase 13 (MMP‐13) and interleukin 1 alpha (IL‐1α) implicates senescent cells in the joint as a source of these catabolic molecules (Loeser, Collins & Diekman, 2016).…”

Induction of bovine articular chondrocyte senescence with oxidized low‐density lipoprotein through lectin‐like oxidized low‐density lipoprotein receptor 1

“…SA ␤-gal activity has been recognized to be an important biologic marker of cell senescence (41), and it is higher in cloned chondrocytes in OA cartilage (23,32). Oxidized LDL increased the number of SA ␤-gal-positive BACs in a dosedependent manner, but native LDL had no effect.…”

“…Telomere shortening has been demonstrated in OA chondrocytes (23,31,32), and the lifespan of senescent chondrocytes retrieved from OA cartilage can be increased by the exogenous expression of telomerase (33), indicating an important relationship between chondrocyte senescence and telomerase activity. In addition to replicative senescence, stressinduced premature cell senescence (SIPS) also occurs; in SIPS, cells without discernible attrition of telomeres show a growth arrest (34,35).…”

“…The progressive degeneration of cartilage in the later phase of OA may be attributed to limited repair responses caused by cell senescence associated with reduced cell function and proliferative ability (22,40). Chondrocytes in OA cartilage show distinctive features of the senescent cell, including higher activity of SA ␤-gal, reduced matrix production and proliferative abilities, and telomere shortening, indicating a strong relationship between chondrocyte senescence and cartilage degeneration (22,23,32).…”

“…Both the endothelial cells in atherosclerotic lesions (20,21) and the chondrocytes in OA cartilage (22,23) show attributes of cell senescence, and cell senescence and aging of the tissue are strongly correlated in both diseases. The purpose of the present study was to investigate whether ox-LDL induces cell senescence of cultured BACs.…”