2020 年 66 巻 6 号 p. 478-479
Recently, much attention has been focused on the role of autophagy in osteoarthritis (OA), a disease associated with cartilage degeneration, since autophagy is reduced in chondrocytes of subjects with OA 1), and the chondrocyte-specific induction of autophagy improves the pathological change of OA in mice 2). Furthermore, it has been reported that sirtuin (SIRT) 1, known as a longevity gene, induces autophagy 3). Previously, we revealed that glucosamine, a functional food, which is widely used for the treatment of OA, enhances the expression of SIRT1 in human chondrocyte line 4). Based on these findings, we have hypothesized that glucosamine induces autophagy in chondrocytes via the expression of SIRT1 and may exhibit a chondroprotective action on OA 5).
When human chondrocytes (Hs819.T) were incubated with glucosamine, the expression of LC3-II, Beclin-1, ATG5 and ATG7 (autophagy markers) was increased, indicating that glucosamine induces autophagy in chondrocytes. Moreover, we confirmed that glucosamine induces the expression of SIRT1 in Hs819.T cells. Next, to examine the action of SIRT1 on the glucosamine-induced autophagy, Hs819.T cells were incubated with glucosamine in the presence of EX527, a SIRT1 inhibitor. The result indicated that EX527 inhibited the glucosamine-induced expression of LC3-II, suggesting that glucosamine induces autophagy in chondrocytes via the action of SIRT1.
SIRT1 functions as a deacetylase and regulates the action of target proteins by deacetylation 6). In this context, it has been reported that p53, a target protein of SIRT1, is negatively regulating autophagy 7), and when p53 is deacetylated (inactivated), autophagy is induced 8). Thus, the effect of glucosamine on the deacetylation of p53 was evaluated. The results indicated that in the presence of glucosamine p53 was deacetylated in Hs819.T cells, and the deacetylation was inhibited by EX527, a SIRT1 inhibitor, suggesting that glucosamine induces the expression of SIRT1, a deacetylase, and SIRT1 deacetylates (inactivates) p53, a negative regulator of autophagy.
Interestingly, it has been reported that when autophagy is induced in chondrocytes, the expression of cartilage matrix components such as type II collagen is increased 9), while the expression of matrix metalloproteinases (MMPs), cartilage matrix degrading enzymes, is suppressed 10).
It is unclear how glucosamine induces the expression of SIRT1 in chondrocytes. Interestingly, however, it has been reported that glucosamine alters glucose metabollism by reducing glucose transport/phpsophorylation and storage of glycogen in skeletal muscle cells 11), and lowers blood glucose level in mice 12). Importantly, SIRT1 is upregulated by fasting and caloric restriction 13). Thus, it is tempting to speculate that glusocomine induces the expression of SIRT1 via the action on glucose metabolism that may mimic the states of fasting and caloric restriction.
Together these observations suggest that glucosamine induces autophagy in chondrocytes via the expression of SIRT1, which deacetylates (inactivates) p53, a negative regulator of autophagy, and possibly exhibits a chondroprotective action on OA by increasing the expression of cartilage matrix components and suppressing the expression of cartilage matrix degrading enzymes (Figure-1).
