The role of the sirtuin family in cartilage and osteoarthritis: molecular mechanisms and therapeutic targets

Abstract

Osteoarthritis (OA) is mainly characterized by the progressive destruction of articular cartilage. Mounting studies have revealed that disruption of extracellular matrix (ECM) homeostasis, aberrant chondrocyte metabolism, an increase in the number of senescent chondrocytes and abnormal activation of cell death such as chondrocyte apoptosis and autophagy, are the crucial steps in OA development. Additionally, mitochondrial dysfunction also participates in the abovementioned processes and is the key element of OA pathogenesis. Sirtuin (SIRT) is a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that can actively participate and primarily regulate chondrocyte function in OA pathophysiological processes. Some members of the SIRT family located in mitochondria can regulate mitochondrial function and mediate mitochondrial homeostasis via deacetylation to protect chondrocytes. In addition, SIRT can maintain ECM homeostasis, regulate chondrocyte metabolism, inhibit chondrocyte apoptosis and autophagy, and prevent chondrocyte senescence in cartilage by exerting its deacetylation activity. However, the molecular mechanism of the SIRT family against the onset and development of OA remains poorly elucidated. In this review, we will discuss the potential protective role of SIRT in the progression of OA and summarize several sirtuin-activating molecules as well as their potential therapeutic applications for OA.

Oxidative stress as a key modulator of cell fate decision in osteoarthritis and osteoporosis: a narrative review

“…They are essential in terms of cellular anti-aging mechanisms, by being involved in DNA repair, antioxidative defense regulation, and immunomodulation. Therefore, sirtuins are considered to be important targets to counteract age-related diseases, including OA and OP [ 21 , 22 ]. Indeed, sirtuins have been found to maintain tissue anabolism, prevent apoptotic cell death, and attenuate senescence and inflammation in cartilage [ 23 – 27 ] as well as in bone [ 28 , 29 ].…”

“…Furthermore, recent studies demonstrated that Sirt1 and Sirt6 are downregulated in senescent chondrocytes. While Sirt1 suppresses the expression of SASP factors, Sirt6 presumably promotes DNA repair [ 219 ]. Accordingly, increased Sirt1 and Sirt6 expression attenuates OA progression by diminishing chondrocyte senescence [ 220 – 222 ].…”

Estradiol as the Trigger of Sirtuin-1-Dependent Cell Signaling with a Potential Utility in Anti-Aging Therapies

“…Although human chondrocytes from osteoarthritis cartilage samples, human knee articular chondrocytes [ 63 , 64 ], and chondrosarcoma HTB-94 cells express SIRT1 [ 64 ], their expression decreases with age, contributing to a higher risk of osteoarthritis development in humans and mice [ 64 , 65 ]; this is due to a shift in chondrocyte activity toward catabolic proteolysis, increasing the rate of apoptosis, together with lower chondrogenic action [ 64 ], decreasing autophagy, and accelerating chondrocyte senescence [ 66 ]. However, the exact mechanism of SIRT1 activation in chondrocytes and its role in age-associated osteoarthritis are poorly understood.…”

SKP2‐mediated ubiquitination and degradation of KLF11 promotes osteoarthritis via modulation of JMJD3/NOTCH1 pathway

“…It has been reported that OA affects about 12% of elderly individuals, 2 and its incidence is increasing around the world 3 . Abnormal chondrocyte apoptosis and defect in extracellular matrix (ECM) homeostasis have been recognized to participate in OA pathogenesis 4 . Currently, the therapeutic approaches for OA are conservative treatments, including pain relief and anti‐inflammatory drugs.…”

“…3 Abnormal chondrocyte apoptosis and defect in extracellular matrix (ECM) homeostasis have been recognized to participate in OA pathogenesis. 4 Currently, the therapeutic approaches for OA are conservative treatments, including pain relief and anti-inflammatory drugs. So far, there is still lack of disease-modifying treatments for OA.…”