Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis

Abstract

Osteoarthritis (OA) is most prevalent in older individuals and exerts a heavy social and economic burden. However, an effective and noninvasive approach to OA treatment is currently not available. Chondrocyte senescence has recently been proposed as a key pathogenic mechanism in the etiology of OA. Furthermore, senescent chondrocytes (SnCCs) can release various proinflammatory cytokines, proteolytic enzymes, and other substances known as the senescence-associated secretory phenotype (SASP), allowing them to connect with surrounding cells and induce senesce. Studies have shown that the pharmacological elimination of SnCCs slows the progression of OA and promotes regeneration. Growth differentiation factor 15 (GDF15), a member of the tumor growth factor (TGF) superfamily, has recently been identified as a possible aging biomarker and has been linked to a variety of clinical conditions, including coronary artery disease, diabetes, and multiple cancer types. Thus, we obtained data from a publicly available single-cell sequencing RNA database and observed that GDF15, a critical protein in cellular senescence, is highly expressed in early OA. In addition, GDF15 is implicated in the senescence and modulation of MAPK14 in OA. Tissue and synovial fluid samples obtained from OA patients showed overexpression of GDF15. Next, we treated C20A4 cell lines with interleukin (IL)-1β with or without shGDF15 then removed the conditioned medium, and cultured C20A4 and HUVEC cell lines with the aforementioned media. We observed that C20A4 cells treated with IL-1β exhibited increased GDF15 secretion and that chondrocytes cultured with media derived from IL-1β–treated C20A4 exhibited senescence. HUVEC cell migration and tube formation were enhanced after culturing with IL-1β-treated chondrocyte media; however, decreased HUVEC cell migration and tube formation were noted in HUVEC cells cultured with GDF15-loss media. We tested the potential of inhibiting GDF15 by using a GDF15 neutralizing antibody, GDF15-nAb. GDF15-nAb exerted a similar effect, resulting in the molecular silencing of GDF15 in vivo and in vitro. Our results reveal that GDF15 is a driver of SnCCs and can contribute to OA progression by inducing angiogenesis.

Defining regorafenib as a senomorphic drug: therapeutic potential in the age-related lung disease emphysema

“…MAPK14 has also been reported as a specific target of regorafenib 46 . In this context, inhibition of the GDF15/MAPK14 pathway with a neutralizing anti-GDF15 antibody resulted in a senomorphic effect in senescent chondrocytes 47 . In addition, GDF15 expression is elevated in many pathological conditions, including COPD and idiopathic pulmonary fibrosis 48 .…”

Consensus cluster analysis of apoptosis-related genes in patients with osteoarthritis and their correlation with immune cell infiltration

“…Wen et al. ( 32 ) studied the role of the GDF15 /MAPK14 axis in the aging of chondrocytes in OA and found that GDF15 is a driving factor for chondrocyte aging and apoptosis and could promote the progression of OA by inducing angiogenesis. TLR7 is involved in immune responses in many inflammatory diseases.…”

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…Senescence and the associated SASP can affect cells within the tumor microenvironment (TME). The SASP was shown to promote tumorigenesis [ 66 ], EMT [ 67 , 68 , 69 ], cancer stemness [ 70 , 71 ], anticancer drug resistance [ 72 , 73 , 74 ], angiogenesis [ 75 , 76 , 77 , 78 ], immune suppression to promote tumorigenesis [ 79 , 80 ], and tumor suppression by the immune clearance of senescent cells [ 81 ]. Figure 4 shows the roles of the SASP, including tumor suppression and tumor promotion.…”

“…This suggests that senescence can also promote tumorigenesis. CM of IL-1β (a component of SASP)-treated chondrocytes enhanced migration and the tube-forming potential of human umbilical vein endothelial cells (HUVEC) in a growth differentiation factor 15 (GDF15)-dependent manner [ 78 ]. CDK4/6 inhibitors induced senescence and increased the production of pro-angiogenic SASP factors such as VEGF, basic FGF (bFGF), PDGF, as well as multiple MMPs, resulting in vascular remodeling in preclinical models of pancreatic ductal adenocarcinoma (PDAC) [ 82 ].…”