Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Experimental approach may reverse rheumatoid arthritis and osteoporosis

Researchers have identified a mechanism that may keep a well known signaling molecule from eroding bone and inflaming joints, according to an early study published online today in the Journal of Clinical Investigation.

Bone is continually recycled to maintain its strength through the competing action of osteoclasts, cells that break down aging bone, and osteoblasts, which build new bone. Osteoclasts also play a central role in common diseases that erode bone, where two signaling molecules, TNFá and RANKL, cause too much bone breakdown.

Both are known to turn on the nuclear factor kappa B complex (NF-êB), which turns on genes that cause the stem cell precursors of osteoclasts to mature and start eating bone. While both TNFá and RANKL encourage bone loss, the current study argues that TNFá and RANKL have different effects on levels of a key inhibitory protein within the NF-êB pathway called NF-êB p100, with important consequences for drug design.

The NF-êB pathway as a whole signals for more active osteoclasts, but NF-êB p100 (p100) interferes with the ability of that same pathway to pass on the bone loss signal. While both TNFá and RANKL activate NF-êB signaling, RANKL efficiently converts p100 into a form that no longer blocks NF-êB pathway signaling and that leads to bone loss. In contrast, the current study is the first to show that TNFá lets p100 build up. Thus, TNFá both causes bone loss through NF-êB signaling and limits it via p100 accumulation.

Experiments found further that mice genetically engineered to lack NF-êB2p100 suffered more severe joint erosion and inflammation than their normal littermates in the face of TNFá. TNFá, but not RANKL, also increased levels of a protein in osteoclast precursors called TNF receptor-associated factor 3 (TRAF 3), which may help NF-êB p100 block osteoclast formation and inflammation.

"While further studies will be required to confirm and detail this mechanism, our results argue strongly that increasing levels of either TRAF3 or NF-êB p100 could represent a powerful new way to limit bone destruction and inflammation-induced bone loss seen in osteoporosis and rheumatoid arthritis," said Brendan Boyce, M.D., professor within the Department of Pathology and Laboratory Medicine at the University of Rochester Medical Center, and the study's corresponding author. "NF-êB p100 levels may vary with each person's genes, making some more susceptible to TNFá-driven disease. Future solutions may be local delivery of p100 into diseased joints via gene therapy, or to target with a drug the enzyme, NIK, which otherwise limits the p100 supply."

At the Center of Bone Loss and Inflammation

Drugs that block the function of TNFá are blockbusters (e.g. Enbrel, Humira and Remicade) because they effectively prevent bone loss and inflammation in most patients with rheumatoid arthritis. They have also been shown to reduce bone loss in women early after menopause.

Other studies, however, have suggested that TNFá cannot cause precursor cells to become osteoclasts unless RANKL first "primes" them. The debate has been spirited because it goes to which molecule should be targeted in near-future attempts to design more precise drugs.

The current results show that TNFá can signal for bone loss without RANKL, providing NF-êB p100 is also absent. By engineering mice with neither RANKL nor NF-êB p100, Boyce and colleagues found that TNFá had greatly increased ability to signal for osteoclast maturation and bone loss in this scenario.

Another unexpected result was measured in changes in gene expression, the process by which information encoded in DNA chains is used to build proteins that make up the body's structures and carry it messages. The team found that mice engineered to over-express TNFá, but also to lack NF-êB p100, had significantly increased inflammation in their joints when compared to mice with high TNFá levels, but with p100 present to counter it.

Along with Boyce, the study was led by Zhenqiang Yao and Lianping Xing in the Department of Pathology and Laboratory Medicine at the University of Rochester Medical Center. The study was funded in part by the National Institutes of Health.

"We believe NF-êB p100 limits not only osteoclast maturation, but also the number of inflammatory cells attracted to the joints in response to TNFá," Boyce said. "If confirmed, it would mean that p100 has more than one role in more than one major bone disease, and thus would create new opportunities to reverse disease by manipulating p100 levels."

Greg Williams | EurekAlert!
Further information:

More articles from Health and Medicine:

nachricht Resolving the mystery of preeclampsia
21.10.2016 | Universitätsklinikum Magdeburg

nachricht New potential cancer treatment using microwaves to target deep tumors
12.10.2016 | University of Texas at Arlington

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>