On the road to developing new therapeutic drugs for osteoporosis and other bone degenerative diseases.
Osteoporosis is a disease that causes bones to fracture easily due to a reduction in both bone mass and quality. Aging is one of its leading causes, and it is estimated that around 200 million people are affected worldwide. Fractures of the femoral neck–the connection between the femur and the hip joint–or of vertebrae can leave a person bedridden which increases the need for care, reduces quality of life and systemic function, and increases mortality.
Bone is a living tissue that is repeatedly broken down (bone resorption) and remade (bone formation) little by little every day. If this balance collapses and bone resorption exceeds bone formation, bone density decreases and can lead to osteoporosis. Several medications are available to treat this disease, but the number of drugs that promote bone formation are far fewer compared to those that suppress bone resorption. The development of therapeutic agents that regenerate bones is highly desired.
Sirtuins are enzymes that play important roles in controlling aging, stress responses, various areas of the metabolism, and several other body functions. In mammals, there are seven types of sirtuins, SIRT1 to SIRT7. Although SIRT7 has been reported to be involved in cancer and lipid metabolism, its role in bone tissue and bone aging was unknown.
1. The effect of SIRT7 on bone formation
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 (bone-building cells) 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.
2. Expression of sirtuins in bone tissue of old mice
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.
3. The effect of SIRT7 on osteoblast differentiation
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.
4. Transcriptional activation of SP7/Osterix by SIRT7
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 realized 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 Dr. 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.”
The Latest on: Bone degenerative diseases
via Google News
The Latest on: Bone degenerative diseases
- Cerapedics receives PMA approval for peptide bone graft in ACDFon November 19, 2019 at 7:10 am
The FDA approved Cerapedics premarket approval supplement for i-Factor in anterior cervical discectomy and fusion procedures in patients with degenerative disc disease. Three things to know ...
- CMS Increases SI Fusion Payment 27%on November 18, 2019 at 7:30 am
Santa Clara, California-based SI-BONE was founded in 2008 and specializes in musculoskeletal disorders of the sacropelvic region ... conditions including sacroiliac joint dysfunction as a direct ...
- Cerapedics Announces FDA Approval of PMA Supplement Based on Two-Year Clinical Dataon November 18, 2019 at 6:34 am
The drug-device combination is based on synthetic small peptide (P-15) technology that accelerates new bone formation in patients with degenerative disc disease. It is in a new category of bone graft ...
- How to treat hip osteoarthritison November 15, 2019 at 11:07 pm
X-rays of the hips to look for signs of bone and cartilage deterioration. Blood tests to check for evidence of inflammation and rule out other forms of arthritis. Synovial fluid analysis that looks ...
- Bone loss and some other lesser known complications that accompany diabeteson November 15, 2019 at 5:41 am
It may also cause hardening of the internal auditory artery besides damaging the protective covering of the cochlear nerve, causing the degeneration of the spiral ... inflammation and increase the ...
- Navicular diseaseon November 13, 2019 at 2:49 am
The label navicular disease is used to describe a variety of conditions, including a progressive degenerative condition involving the navicular bone (which is located behind the pedal bone inside the ...
- Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromeson November 12, 2019 at 7:38 am
BCL2L10 positive cells in bone marrow are an independent prognostic factor of azacitidine outcome in myelodysplastic syndrome and acute myeloid leukemia. Oncotarget. 2017;8:47103–9. Jang KH, Do YJ, ...
- SI-BONE, Inc. Reports Third Quarter 2019 Financial Results and Updates Full-Year 2019 Revenue Guidanceon November 11, 2019 at 12:05 pm
Nov. 11, 2019 (GLOBE NEWSWIRE) -- SI-BONE, Inc. (NASDAQ:SIBN), a medical device company dedicated to solving musculoskeletal disorders of the sacropelvic anatomy ... joint dysfunction that is a direct ...
- Consider hip resurfacing instead of replacementon November 9, 2019 at 10:01 pm
Answer: Active adults suffering from hip pain due to degenerative hip disease, osteoarthritis and post traumatic arthritis do have an alternative to hip-replacement surgery — hip resurfacing. Unlike ...
via Bing News