Military funds research on how nicotine impairs bone healing

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Public release date: 18-Oct-2005

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University of Rochester Medical Center

Military funds research on how nicotine impairs bone healing

Goal to speed smokers' recovery from combat injuries

Researchers have received a grant from the U.S. Department of Defense

to study ways in which nicotine from cigarette smoke may interact

with stem cells to slow the healing of bone injuries.

Smoking has been shown to delay skeletal healing by as much as 60

percent following fractures. Slower healing means a greater chance of

re-injury and can lead to chronic pain and disability. The obvious

solution is for smokers to quit when they get hurt, but studies show

that just 15 percent can.

The military is interested in the issue because about 34 percent of

military personnel smoke, compared to 25 percent in the general

population, according to the Air Force Medical Support Agency. Long-

term health concerns aside, military experts say smoking reduces

soldiers' readiness to fight by impairing night vision, weakening the

immune system and lengthening healing time. The problem is especially

poignant now because more than 14,000 soldiers have been injured in

Iraq since 2003, with about 65 percent of the injuries including

orthopedic damage to extremities.

One goal of the research then is to determine, based on biochemical

evidence, the window of time during which healing has the greatest

chance of being delayed by cigarette smoke. Smokers could then be

advised to quit for a specific time period to afford them their best

chance of healing. Beyond the time window, researchers hope a better

understanding of the mechanisms involved will lead to treatments that

speed healing in persistent smokers and in all patients with bone

injuries.

" Smoking reduces the rate at which the two sides of a fracture come

together, " said Zuscik, Ph.D., assistant professor in the

Department of Orthopaedics at the University of Rochester Medical

Center, recipient of the $1.4 million DOD grant. " We believe this new

research will establish for the first time the mechanisms by which

nicotine interferes with the healing process, and identify ways to

prevent it. " Zuscik's work hinges on the theory that nicotine

prevents stem cells from maturing into replacement bone.

Healing Machinery

Acetylcholine is a neurotransmitter, a biochemical with the first

purpose of passing on nerve impulses that enable muscles to flex. The

neurotransmitter passes on its signal by attaching to nicotinic

acetylcholine receptors (nACHRs), proteins shaped specifically to

receive the neurotransmitter, like a lock receives a key, on the

surface of the nerve cell receiving the signal. As part of passing on

nerve messages carried by acetylcholine, nACHRs must transfer signals

from the outer surface of the cells they occur on to their inner

compartments. nACHRs can do this because they form gateways that pass

through the barrier that separates the outside and inside of cells.

nACHRs transfer nerve messages by allowing charged particles (e.g.

calcium ions) to flow through their gateways, which in turn sets off

actions inside the cell.

The DOD-funded research is based on the discovery that nACHR-enabled

calcium flow, along with helping to pass on nerve signals, also

regulates the behavior of certain genes. That the body has evolved to

use neurotransmitter receptors in this second way, to regulate genes,

may explain why the receptors appear on cells that have nothing to do

with passing on nerve signals. Central to the problem caused by

nicotine is that, although structurally different than acetylcholine,

it can bind to and activate the same receptor, nACHR. That may grant

nicotine the power to turn on and off genes without regard for the

delicate genetic controls that govern acetylcholine's ability to take

the same action.

Specifically, researchers plan to confirm that when nicotine binds to

nACHRs, it changes calcium flow, which in turn changes the action of

cyclic-AMP response element binding protein (CREB). Transcription

factors like CREB " turn on " certain sections of the genetic code at

the proper times. Medical Center researchers believe that nicotine

may cause CREB to distort gene function in the normal, two-step bone

healing process, where stem cells become cartilage and then cartilage

matures into bone.

They will test the idea that stem cells in the bone marrow

(mesenchymal stem cells), which differentiate to form replacement

bone after injury, have nACHRs on their surfaces. Activation by

nicotine of such receptors on stem cells could switch on genes that

delay the final transition of cartilage into new bone.

" Nicotine leaves the healing process in limbo, " Zuscik said. " In the

future, we hope to manipulate neurotransmitter receptors, much like

researchers have already done in neurology to create drugs for

depression, to accelerate bone healing. "