Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New Theory on Genesis of Osteoarthritis Comes with Successful Therapy in Mice

22.05.2013
In the future, joint replacement surgery might be avoidable
Scientists at Johns Hopkins have turned their view of osteoarthritis (OA) inside out. Literally. Instead of seeing the painful degenerative disease as a problem primarily of the cartilage that cushions joints, they now have evidence that the bone underneath the cartilage is also a key player and exacerbates the damage. In a proof-of-concept experiment, they found that blocking the action of a critical bone regulation protein in mice halts progression of the disease.

The prevailing theory on the development of OA focuses on joint cartilage, suggesting that unstable mechanical pressure on the joints leads to more and more harm to the cartilage—and pain to the patient—until the only treatment option left is total knee or hip replacement. The new theory, reported May 19 in Nature Medicine, suggests that initial harm to the cartilage causes the bone underneath it to behave improperly by building surplus bone. The extra bone stretches the cartilage above and speeds its decline.

“If there is something wrong with the leg of your chair and you try to fix it by replacing the cushion, you haven’t solved the problem,” says Xu Cao, Ph.D., director of the Center for Musculoskeletal Research in the Department of Orthopaedic Surgery at the Johns Hopkins University School of Medicine. “We think that the problem in OA is not just the cartilage ‘cushion,’ but the bone underneath,” he adds.

Joints are formed at the intersection of two bones. To prevent the grinding and wearing down of the ends of the bones, they are capped with a thin layer of cartilage, which not only provides a smooth surface for joint rotation but also absorbs some of the weight and mechanical strain placed on the joint. The degeneration of this protective layer causes extreme pain leading to limited mobility.

Gehua Zhen, Courtesy of Nature Medicine

When placed in the bone (green) beneath the cartilage (red) of a rat’s knee joint, antibodies against the protein TGF-beta1 can prevent the damage caused by osteoarthritis. Left, without treatment; right, with treatment.

Cao says degeneration is most frequently initiated by instability in the load-bearing joints of the knee and hip caused by injury or strain, so athletes, overweight people and people whose muscles are weakened by aging are at highest risk of developing OA. The prevalence of the disease is rapidly increasing; it currently affects 27 million Americans and may double by 2030. The only treatment available is pain management, or surgical replacement of the arthritic joint with a prosthetic one.

Cao says that the lack of effective drugs or a complete understanding of the underlying process that causes OA to progress led his group to search for a different underlying cause. “We began to think of cartilage and the bone underneath it, called subchondral bone, as functioning as a single unit,” says Cao. “That helped us to see the ways in which the bone was responding to changes in the cartilage and exacerbating the problem.”

Using mice with ACL (anterior cruciate ligament) tears, which are known to lead to OA of the knee, the researchers found that, as soon as one week after the injury, pockets of subchondral bone had been “chewed” away by cells called osteoclasts. This process activated high levels in the bone of a protein called TGF-beta1, which, in turn, recruited stem cells to the site so that they could create new bone to fill the holes. Cao calls these pockets of new bone formation “osteoid islets.”

But the bone building and the bone destruction processes were not coordinated in the mice, and the bone building prevailed, placing further strain on the cartilage cap. It is this extraneous bone formation that Cao and his colleagues believe to be at the heart of OA, as confirmed in a computer simulation of the human knee.

With this new hypothesis in hand, complete with a protein suspect, the team tried several methods to block the activity of TGF-beta1. When a TGF-beta1 inhibitor drug was given intravenously, the subchondral bone improved significantly, but the cartilage cap deteriorated further. However, when a different inhibitor of TGF-beta1, an antibody against it, was injected directly into the subchondral bone, the positive effects were seen in the bone without the negative effects on the cartilage. The same result was also seen when TGF-beta1 was genetically disrupted in the bone precursor cells alone.

“Our results are potentially really good news for patients with OA,” says Cao. “We are already working to develop a clinical trial to test the efficacy of locally applied TGF-beta1 antibodies in human patients at early stages of OA.” If successful, their nonsurgical treatment could make OA — and the pain and debilitation it causes — halt in its tracks, he says.
Other authors of the report include Gehua Zhen, Xiaofeng Jia, Janet Crane, Simon Mears, Frederic Askin, Frank Frassica, Weizhong Chang, John Carrino, Andrew Cosgarea, Dmitri Artemov, Lee Riley, Paul Sponseller and Mei Wan of the Johns Hopkins University School of Medicine; Chunyi Wen, Jie Yao and William Weijia Lu of the University of Hong Kong; and Yu Li, Qianming Chen, Zhihe Zhao and Xuedong Zhou of Sichuan University.

This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK057501, DK08098).

Catherine Kolf | Newswise
Further information:
http://www.jhmi.edu

More articles from Life Sciences:

nachricht Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Global study of world's beaches shows threat to protected areas

19.07.2018 | Earth Sciences

New creepy, crawly search and rescue robot developed at Ben-Gurion U

19.07.2018 | Power and Electrical Engineering

Metal too 'gummy' to cut? Draw on it with a Sharpie or glue stick, science says

19.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>