Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Experimental approach may reverse rheumatoid arthritis and osteoporosis

24.09.2009
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:
http://www.urmc.rochester.edu

More articles from Health and Medicine:

nachricht Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University

nachricht Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München

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: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>