Regulation of senescence associated signaling mechanisms in chondrocytes for cartilage tissue regeneration

Abstract

Adult articular chondrocytes undergo slow senescence and dedifferentiation during in vitro expansion, restricting successful cartilage regeneration. A complete understanding of the molecular signaling pathways involved in the senescence and dedifferentiation of chondrocytes is essential in order to better characterize chondrocytes for cartilage tissue engineering applications. During expansion, cell fate is determined by the change in expression of various genes in response to aspects of the microenvironment, including oxidative stress, mechanical stress, and unsuitable culture conditions. Rapid senescence or dedifferentiation not only results in the loss of the chondrocytic phenotype but also enhances production of inflammatory mediators and matrix-degrading enzymes. This review focuses on the two groups of genes that play direct and indirect roles in the induction of senescence and dedifferentiation. Numerous degenerative signaling pathways associated with these genes have been reported. Upregulation of the genes interleukin 1 beta (IL-1β), p53, p16, p21, and p38 mitogen-activated protein kinase (MAPK) is responsible for the direct induction of senescence, whereas downregulation of the genes transforming growth factor-beta (TGF-β), bone morphogenetic protein-2 (BMP-2), SRY (sex determining region Y)-box 9 (SOX9), and insulin-like growth factor-1 (IGF-1), indirectly induces senescence. In senescent and dedifferentiated chondrocytes, it was found that TGF-β, BMP-2, SOX9, and IGF-1 are downregulated, while the levels of IL-1β, p53, p16, p21, and p38 MAPK are upregulated followed by inhibition of the normal molecular functioning of the chondrocytes. This review helps to elucidate the underlying mechanism in degenerative cartilage disease, which may help to improve cartilage tissue regeneration techniques.

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

“…The utility of p16 INK4a as a biomarker of molecular age in other cell types has been demonstrated by assessing the impact of lifestyle modifications such as smoking or exercise (Liu et al., 2009), predicting the risk for particular negative outcomes after chemotherapy (Demaria et al., 2017), and screening the quality of potential donor organs (Koppelstaetter et al., 2008). For chondrocytes, screening patients for low p16 INK4a expression may improve the outcomes of autologous chondrocyte implantation procedures, as the success of this procedure requires avoidance of senescence to ensure sufficient expansion and subsequent re‐differentiation of the chondrocytes (Ashraf et al., 2016). …”

Ageing and the pathogenesis of osteoarthritis

“…Although their competence for proliferation indicates that these chondrocytes are not senescent, cells that enter the cell cycle in the context of potentially damaging stimuli have an increased likelihood of entering senescence as opposed to returning to quiescence 53,54 . Observations that senescence occurs after monolayer expansion of chondrocytes (reviewed elsewhere 55 ) provide further evidence that contexts of increased proliferation correlate with emergence of the senescent phenotype.…”

Cellular senescence in aging and osteoarthritis

“…In addition, senescent cells show altered intracellular protein expression, altered responses to growth factors, and altered secretion profiles such as elevated levels of ROS and pro-inflammatory cytokine production, which contribute further to overall aging and progression of age-related diseases (Loeser 2009, Ashraf et al. 2016). …”