Abstract
Ageing is the primary risk factor for osteoarthritis (OA). A decline in the ageing-associated process of autophagy is suggested as a potential contributor to OA development. Polyamines such as spermidine decrease during ageing, contributing to impaired autophagy and reduced cellular function. However, the role of polyamines and their effect on the regulatory mechanism governing autophagy in aged and arthritic cartilage tissue has not been established. Elucidating if polyamine regulation of autophagy is impaired during ageing and OA in chondrocytes may lead to improved treatment approaches to protect against cartilage degradation. Our results indicate that polyamine synthesis was decreased in aged and OA cartilage, along with reduced autophagy activity, evidenced by decreased autophagy-related gene and protein expression and autophagosome formation. Importantly, spermidine treatment increased the expression of the acetyltransferase EP300, which binds to crucial autophagy proteins, Beclin1 and LC3, and elevates chondrocyte autophagy. Our data indicate spermidine prevents the ageing- and OA-related decrease in autophagy and may protect against OA development.
Highlights
Osteoarthritis (OA) is the most common form of arthritis characterised by cartilage degradation, synovitis and pain[1]
Spermidine activates chondrocyte autophagy To determine whether stimulation with spermidine might activate autophagy in this system, protein and gene expression of critical autophagy-related molecules (ULK1, Fig. 1 Decreased autophagy and polyamine synthesis in aged and OA human and murine cartilage. a–c Autophagy gene expression in isolated chondrocytes from young (21–37 years), old (62–68 ) and OA (49–86 years) knee joints (n = 3). d Representative images (x20) of light chain 3B (LC3) protein expression in knee joints of WT mice at 2 months or 16 months of age. e Quantification of LC3 positive cells/total from murine knee joints (n = 4). f Representative EM images of chondrocytes from microdissected cartilage obtained from knee joints of WT young (2 months) or old (16 months) mice
Scale bars: 1 μm. g Quantification of autophagosomes in chondrocytes from murine knee joints (n = 18 cells per mouse. six mice used). h–k Real-time-quantitative polymerase chain reaction (RT-qPCR) analysis gene expression of key enzymes involved in polyamine synthesis from isolated chondrocytes from young healthy (21–37 years) or old (62–68 years) (n = 3). l–o RT-qPCR analysis gene expression of key enzymes involved in spermidine synthesis in microdissected cartilage obtained from knee joints of WT young (2 months) or old mice (16 months) (n = 3). p–s RT-qPCR analysis of gene expression of key enzymes involved in spermidine synthesis in non-OA and OA human chondrocytes (n = 3)
Summary
Osteoarthritis (OA) is the most common form of arthritis characterised by cartilage degradation, synovitis and pain[1]. Spermidine an organic polyamine, found in peas and whole grains, has previously been shown to enhance autophagy and protect against age-related pathologies[7]. The mechanistic regulation of autophagy by spermidine is not fully understood and the role of polyamines in OA is not established. The regulation of the epigenetic modifier and acetyltransferase EP300, has been linked to changes in autophagic flux, and where inhibition of EP300 by spermidine treatment may influence normal cell biology through post-translational modifications of essential autophagy-related protein complexes[8,9]. This study investigates the expression and autophagy-related protein interactions in ageing- and OA-cartilage and whether spermidine-induced EP300 regulation might provide a mechanism through which chondrocyte autophagy in aged cartilage and OA might be reactivated
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