Twisted Science: Pain Causes Arthritis

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Twisted Science: Pain Causes Arthritis

LiveScience Staff

LiveScience.com

As we all know, arthritis, the leading cause of disability among people over 55,

causes pain. But new research suggests that pain also causes arthritis.

Pain should no longer be thought of just as a symptom of arthritis,

according to the study in the October issue of the journal Arthritis and

Rheumatism. Pain signals originating in arthritic joints, and the biochemical

processing of those signals as they reach the spinal cord, worsen and expand

arthritis, the researchers say.

In addition, the researchers found that nerve pathways carrying pain signals

transfer inflammation from arthritic joints to the spine and back again, causing

disease at both ends.

Technically, pain is a patient's conscious realization of discomfort. Before

that can happen, however, information must be carried along nerve cell pathways

from, say, an injured knee to the pain processing centers in dorsal horns of the

spinal cord, a process called nociception. The current study provides strong

evidence

that two-way, nociceptive " crosstalk " may first enable joint arthritis to

transmit inflammation into the spinal cord and brain, and then to spread through

the central nervous system (CNS) from one joint to another.

Furthermore, if joint arthritis can cause neuro-inflammation, it could have a

role in conditions like Alzheimer's disease, dementia and multiple sclerosis.

Armed with the results, researchers have identified likely drug targets that

could interfere with key inflammatory receptors on sensory nerve cells as a

new way to treat osteoarthritis (OA), which destroys joint cartilage.

The most common form of arthritis, osteoarthritis eventually brings deformity

and severe pain as patients loose the protective cushion between bones in

weight-bearing joints like knees and hips.

About 27 million Americans have osteoarthritis and 1.3 million have rheumatoid

arthritis, according to the Arthritis Foundation.

" Until relatively recently, osteoarthritis was believed to be due solely to wear

and tear, and inevitable part of aging, " said Stephanos Kyrkanides, associate

professor of Dentistry at the University of Rochester Medical Center.

" Recent studies have revealed, however, that specific biochemical changes

contribute to the disease, changes that might be reversed by precision-designed

drugs, " he said. " Our study provides the first solid proof that some of those

changes are related to pain processing, and suggests the mechanisms behind

the effect, " said Kyrkanides, whose work on genetics in dentistry led to broader

applications.

The common ground between arthritis and dentistry: The jaw joint is a common

site of arthritic pain.

How the pain signal works

Past studies have shown that specific nerve pathways along which

pain signals travel repeatedly become more sensitive to pain signals with each

use. This may be a part of ancient survival skill (if that hurt once, don't do

it again).

Secondly, pain has long been associated with inflammation (swelling and fever).

In fact, past research has shown that the same chemicals that cause inflammation

also cause the sensation of pain and hyper-sensitivity to pain if injected.

Kyrkanides' work centers around one such pro-inflammatory, signaling chemical

called Interleukin 1-beta (IL-1beta), which helps to ramp up the body's attack

on an infection.

Specifically, Kyrkanides' team genetically engineered a mouse where they could

turn up on command the production of IL-1beta in the jaw joint, a common

site of arthritis.

Experiments showed for the first time that turning up IL-1beta in a peripheral

joint caused higher levels of IL-1beta to be produced in the dorsal horns

of the spinal cord as well.

Crosstalking signals

Using a second, even more elaborately engineered mouse model, the team also

demonstrated for the first time that creating higher levels of IL-1beta in cells

called astrocytes in the spinal cord caused more osteoarthritic symptoms in

joints.

Past studies had shown astrocytes, non-nerve cells (glia) in the central nervous

system that provide support for the spinal cord and brain, also serve as

the immune cells of CNS organs. Among other things, they release chemicals like

IL-1beta to fight disease when triggered. The same chemicals released from

CNS glia may also be released from neurons in joints, possibly explaining how

crosstalk carries pain, inflammation and hyper-sensitivity back and forth.

In both mouse models, experimental techniques that shut down IL-1beta signaling

reversed the crosstalk effects. Specifically, researchers used a molecule,

IL-1RA, known to inhibit the ability of IL-1beta to link up with its receptors

on nerve cells.

Existing drugs (e.g. anakinra, which is indicated for rheumatoid arthritis) act

like IL-1RA to block the ability IL-1beta to send a pain signal through

its specific nerve cell receptor, Kyrkanides said, and his group is exploring a

new use for the drugs as an osteoarthritis treatment.

The crosstalk compounds

The implications of this process go further, however, because the cells

surrounding sensory nerve cell pathways too can be affected by crosstalk. If 10

astrocytes secrete IL-1beta in response to a pain impulse, Kyrkanides said,

perhaps 1,000 adjacent cells will be affected, greatly expanding the field

of inflammation.

Spinal cord astrocytes are surrounded by sensory nerve cells that connect to

other areas of the periphery, further expanding the effect. According to

Kyrkanides' model, increased inflammation in the central nervous system can then

send signals back down the nerve pathways to the joints, causing the release of

inflammatory factors there.

Kyrkanides' colleagues for this research included M. Kerry O'Banion, Ross

Tallents, J. Puzas, Sabine M. Brouxhon, Paolo Fiorentino, all at the

University

of Rochester School of Medicine and Dentistry. This work was supported in part

by grants from the National Institutes of Health.

" Our study results confirm that joints can export inflammation in the form of

higher IL-1beta along sensory nerve pathways to the spinal cord, and that

higher IL-1beta inflammation in the spinal cord is sufficient in itself to

create osteoarthritis in peripheral joints, " Kyrkanides said. " We believe this

to be a vitally important process contributing to orthopaedic and neurological

diseases in which inflammation is a factor. "

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