Reversing severe bone loss

February 05, 2018

A possible 'first-line' treatment for a rare bone loss disease has been identified by a research team led by Tohoku University in Japan. The research findings, published in the journal Molecular Cell, could also provide insight into treating age-related osteoporosis.

Hajdu-Cheney syndrome is a rare genetic disease that leads to severe osteoporosis and developmental defects, including the reabsorption of bones in the hands and feet. The disease is associated with mutations in a particular gene, called NOTCH2, which codes for proteins involved with bone maintenance. The NOTCH2 proteins usually help balance destruction and construction essential for bone maintenance and repair. Mutations associated with Hajdu-Cheney syndrome upset that balance, but the exact mechanisms causing bone resorption have not been well understood.

Now, through a series of detailed tests, molecular biologist Hiroyuki Inuzuka and his colleagues have worked out the specific molecular pathway that results in Hajdu-Cheney syndrome.

They found that this particular NOTCH2 mutation does not maintain normal NOTCH2 protein abundance, with the help of another protein, called FBW7. To discover this, the researchers knocked out the gene for Fbw7 in the bones of mice. Without the gene and resulting protein, the mice had severe osteoporosis, much like people with Hajdu-Cheney syndrome -- indicating that FBW7 is the primary regulator of this system.

They further determined that in humans with Hajdu-Cheney syndrome, the FBW7 protein was unable to bind to NOTCH2 proteins because the binding spot is missing in osteoclasts. This mutation allows the osteoclasts to over-operate, breaking down too much bone tissue.

The researchers were able to reverse bone loss in the knock-out mice with the elevated NOTCH2 by giving them a medication that blocks osteoclast formation. They tried several different treatments, including a chemical compound called DAPT that was particularly effective. DAPT has been shown to help with osteoarthritis by inhibiting function of NOTCH proteins in other studies. Using DAPT as well as Zoledronic acid, a common medication for osteoporosis, "may become a first-line treatment for Hadju-Cheney syndrome," the researchers conclude in their study.

"By clearly identifying the relationship between FBW7 and NOTCH2 proteins, we have identified potential therapeutic targets for patients with rare bone diseases as well as much more widespread age-related osteoporosis," said Inuzuka.
-end-


Tohoku University

Related Osteoporosis Articles from Brightsurf:

New opportunities for detecting osteoporosis
Osteoporosis can be detected through low dose computed tomography (LDCT) imaging tests performed for lung cancer screening or other purposes.

Oxytocin can help prevent osteoporosis
In a laboratory experiment with rats, Brazilian researchers succeeded in reversing natural processes associated with aging that lead to loss of bone density and strength.

New strategy against osteoporosis
An international research team has found a new approach that may be able to reduce bone loss in osteoporosis and maintain bone health.

New review on management of osteoporosis in premenopausal women
An IOF and ECTS Working Group have published an updated review of literature published after 2017 on premenopausal osteoporosis.

Cardiac CT can double as osteoporosis test
Cardiac CT exams performed to assess heart health also provide an effective way to screen for osteoporosis, potentially speeding treatment to the previously undiagnosed, according to a new study.

Osteoporosis treatment may also protect against pneumonia
A recent study published in the Journal of Bone and Mineral Research found that nitrogen-containing bisphosphonates (N-BPs) such as alendronate, which are widely used to treat postmenopausal osteoporosis, are linked with lower risks of pneumonia and of dying from pneumonia.

New pharmaceutical target reverses osteoporosis in mice
Biomedical engineers at Duke University have discovered that an adenosine receptor called A2B can be pharmaceutically activated to reverse bone degradation caused by osteoporosis in mouse models of the disease.

A link between mitochondrial damage and osteoporosis
In healthy people, a tightly controlled process balances out the activity of osteoblasts, which build bone, and osteoclasts, which break it down.

Many stroke patients not screened for osteoporosis, despite known risks
Many stroke survivors have an increased risk of osteoporosis, falls or breaks when compared to healthy people.

Many postmenopausal women do not receive treatment for osteoporosis
The benefits of treating osteoporosis in postmenopausal women outweigh the perceived risks, according to a Clinical Practice Guideline issued today by the Endocrine Society.

Read More: Osteoporosis News and Osteoporosis Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.