Osteoarthritis (OA) is an age-related degenerative disease of the joint which is characterized by progressive degradation of cartilage along with joint pain and stiffness. Millions of individuals across the world suffer from this condition that causes poorer quality of life and increased health costs.
In the end of 2015 a team of researchers from prominent Chinese universities published the results of an investigation whether SIRT6 plays a role in the development of osteoarthritis (OA). As they noted the role of inflammation and aging in OA have been established but the underlying mechanisms are not completely clarified yet. Therefore, studies on the mechanisms of aging and inflammation may help point to new therapeutic targets for OA. SIRT6 is a member of a family of deacetylases whose activities are dependent on availability of nicotinamide adenine dinucleotide (NAD+) and has been implicated in aging, inflammatory and metabolic pathways.
The researchers hypothesized that over-expression or activation of Sirt6 can prevent the progression of osteoarthritis. To test this hypothesis, they analyzed in vitro the protective effects of Sirt6 in human chondrocytes. The chondrocytes are the only cells located in cartilage, they produce and maintain the cartilage matrix which consists mainly of collagen and proteoglycans. The mechanistic pathway of Sirt6 involvement in chondrocytes denegeration was also investigated in vitro. In addition the role of Sirt6 in OA development in vivo was studied in a mouse model for OA knee joints.
Normal human articular cartilage was obtained from 4 donors. The OA human articular cartilage was obtained form 6 patients undergoing total knee arthroplasty. Here it was identified that the expression of Sirt6 was reduced in OA human cartilage compared to normal. In the in-vitro cellular study, IL-1β was used to mimic the development of OA. Transfection of the chondrocytes with special lentiviruses was used to trigger SIRT6 overexpression. Testing confirmed that the overexpression of Sirt6 in chondrocytes by lentivirus could significantly decrease the levels of MMP13 and preserve the expression of type II collagen.
Next the researchers investigated the in-vivo potential of sirt6 Lentivirus to protect articular cartilage when injected into mice OA knee joints. It was observed that the overexpression of Sirt6 could effectively ameliorate cartilage degradation in mature mice both in-vivo and in-vitro. The mechanism for the anti-degenerative effect of Sirt6 depends on its function of suppressing nuclear factor-κB signaling.
In conclusion, the study indicates that Sirt6 acts as a crucial mediator of OA development. Overexpression of Sirt6 can prevent chondrocytes replicative senescence and osteoarthritic changes. Developing specific activators of Sirt6 may therefore be beneficial for the prevention or therapeutic treatment of osteoarthritis.
Even if not mentioned in the publication it is worth to note that the NAD+ pool, which enables sirtuin and SIRT6 activity can be enlarged by supplementation with for example Nicotinamide Riboside.