The number of osteoporosis medications that promote bone-building cells are few compared to those that suppress bone resorption.
A research group led by Kumamoto University scientists has discovered that the gene SIRT7 is important for bone formation, and have succeeded in finding a new mechanism to activate gene functions essential for bone formation. The researchers expect that the ‘SIRT7-regulated osteoblastogenesis pathway’ will be a new therapeutic drug target to treat decreased osteogenesis and osteoporosis.
Recent experiments performed by a research group led by scientists from Kumamoto University, Japan, showed that mice lacking the SIRT7 gene had reduced bone mass. A bone morphometry analysis showed that bone formation and the number of osteoblasts had been reduced. Furthermore, the researchers obtained similar results using osteoblast-specific SIRT7 deficient mice, thereby showing that (osteoblast-specific) SIRT7 is important for bone formation.
Reduced bone formation is common in people with osteoporosis, and the mechanism for this reduction is not well known. To clarify the mechanism, the researchers compared sirtuin (SIRT1, 6, and 7) expression in the skeletal tissue of young and old mice, and found that SIRT7 decreased with age. They then considered that this decrease in SIRT7 in the older specimens may be associated with decreased osteogenesis, and may even be a cause of osteoporosis.
When the researchers cultured osteoblasts (in vitro) with decreased SIRT7 expression in their next experiment, the formation of a bone-like mass (calcified nodule) was markedly suppressed compared to cultures of normal osteoblasts. Additionally, the expression of genes indicating osteoblast differentiation was also decreased, thereby revealing that SIRT7 controls the differentiation of osteoblasts.
To clarify the mechanism by which osteoblastic SIRT7 positively regulates the differentiation of osteoblasts, researchers investigated the transcription activity of the gene expression regulatory factor essential for osteoblast differentiation. They found that the transcription activity of SP7 (also known as Osterix), a protein known to induce differentiation of pre-osteoblasts into mature osteoblasts and osteocytes, was markedly decreased in osteoblasts that lacked the SIRT7 gene.
They also realised that to get high transcription activation of SP7/Osterix, it is important for SIRT7 to deacylate the 368th lysine residue of the SP7/Osterix protein. In other words, SIRT7 enhances the transcriptional activity of SP7/Osterix by chemically modifying it (deacylating the 368th lysine residue). Furthermore, the researchers were able to recover osteoblast functionality in the calcified nodule formation by introducing a mutant SP7/Osterix, which deacylated the 368th lysine of SP7/Osterix, into the osteoblasts that had reduced SIRT7 expression.
The research group is confident that their results show a new mechanism for SIRT7 as a deacylating enzyme important for transcriptional activation of the gene expression regulator SP7/Osterix and is essential for osteoblast differentiation.
“In situations where SIRT7 does not work sufficiently, such as in an older individual, osteoblast formation is impaired due to low SP7/Osterix transcriptional activity. We believe that this decreased osteogenesis is associated with osteoporosis,” said study leader Tatsuya Yoshizawa of Kumamoto University.
“Our results, show that the regulatory pathway of SIRT7 – SP7 /Osterix is a promising target for new therapeutic agents to treat decreased osteogenesis and osteoporosis.”
Source: Kumamoto University
Reference: Masatoshi Fukuda, and others. SIRT7 has a critical role in bone formation by regulating lysine acylation of SP7/Osterix. Nature Communications, 2018; 9 (1) DOI: 10.1038/s41467-018-05187-4