Osteoporosis: another reason
Age-related SIRT7 deficiency is the cause of osteoporosis
Osteoporosis is a disease manifested by high bone fragility due to a decrease in the mass and quality of bone tissue. One of the main causes of its development is aging and, according to experts, about 200 million people suffer from osteoporosis in the world. A fracture of the femoral neck connecting the femur and hip joint, or a vertebra, can deprive the patient of the ability to move independently, which increases the need for care, reduces the quality of life and increases mortality.
Bone is a living tissue that is continuously being destroyed (bone resorption) and recovering (bone formation) at a very low rate. In case of violation of this balance and its shift towards resorption, there is a decrease in bone density, which can lead to the development of osteoporosis. To date, several drugs are used to treat this disease, but there are much fewer means to enhance bone formation than there are means to suppress its resorption. Therefore, the development of drugs that promote bone tissue regeneration is an urgent task.
Sirtuins are a family of enzymes that play important roles in regulating the aging process, stress reactions, various aspects of metabolism and a number of other body functions. Several types of sirtuins are synthesized in the mammalian body, from SIRT1 to SIRT7. Despite the fact that there is data on the involvement of SIRT7 in the development of cancer and lipid metabolism, its participation in the formation of bone tissue and bone aging has not been known until now.
A study on mice recently conducted by Japanese scientists from Kumamoto University, working under the guidance of Dr. Tatsuya Yoshizawa, showed that the absence of the SIRT7 gene causes a decrease in bone mass. During bone morphometry, it was found that this was due to the suppression of the bone formation process and a decrease in the number of osteoblasts (bone-forming cells). Moreover, similar results were obtained in experiments on mice lacking SIRT7 only in osteoblasts.
A decrease in the activity of the bone formation process is characteristic of osteoporosis, and the underlying mechanism is not fully understood. To clarify this issue, the authors compared the expression of sirtuins (SIRT1, 6 and 7) on skeletal muscle cells of young and old mice and found that the level of SIRT7 expression decreases with age. They suggested that this decrease may be associated with the suppression of osteogenesis and cause the development of osteoporosis.
At the next stage of the study, the authors cultured osteoblasts with reduced SIRT7 expression. They demonstrated that the formation of a bone-like mass (calcified node) in this case was significantly worse than when cultivating normal osteoblasts. In addition, the expression of genes indicating osteoblast differentiation was also reduced. This observation indicates the regulatory role of SIRT7 in osteoblast differentiation.
In search of a mechanism by which SIRT7 expressed by osteoblasts positively regulates the differentiation of these cells, the researchers analyzed the activity of a transcription factor (also known as Osterix) that induces the differentiation of pre-osteoblasts into mature osteoblasts and osteocytes. As expected, it was significantly reduced in osteoblasts lacking the SIRT7 gene.
The authors also found that SIRT7 enhances the activity of the transcription factor SP7/Osterix by its chemical modification (deacetylation of the 368th lysine residue). Moreover, they were able to restore the ability of osteoblasts without SIRT7 to form a calcified node by inserting into cells of the mutant form of SP7/Osterix with a deacetylated 368th lysine residue.
The researchers are confident that in conditions of insufficient SIRT7 activity, for example, in an aging organism, the process of formation and differentiation of osteoblasts is disrupted due to the low activity of the transcription factor SP7/Osterix. They believe that such reduced osteogenesis is associated with osteoporosis, therefore the regulatory mechanism of SIRT7-SP7/Osterix is potentially a target for new therapeutic agents intended for the treatment of defective osteogenesis and osteoporosis.
Article by Fukuda, M. et al. SIRT7 has a critical role in bone formation by regulating lysine acylation of SP7/Osterix published in the journal Nature Communications.
Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Kumamoto University: Breaking osteoporosis: New mechanism activates bone-building cells.