Toxins in cigarette smoke prevent stem cells from becoming cartilage

Medicine & Health / Research

A toxic pollutant spread by oil spills, forest fires and car exhaust is also present in cigarette smoke, and may represent a second way in which smoking delays bone healing, according to research presented today at the annual meeting of the Orthopaedic Research Society in San Francisco.

In 2005, researchers from the University of Rochester Medical Center identified one ingredient in smoke, nicotine, that delays bone growth by influencing gene expression in the two-step bone healing process: stem cells become cartilage; cartilage matures into bone. In the current study, some of the same researchers found that a second smoke ingredient, the polyaromatic hydrocarbon benzo(a)pyrene (BaP), also slows bone healing, but in a different way.

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.

“Our results provide the first evidence that BaP prevents stem cells from becoming cartilage cells as part of healing,” said Regis J. O'Keefe, M.D., Ph.D., chair of the Department of Orthopaedics and Rehabilitation at the Medical Center and a study investigator. “These findings extend our understanding of the impact of cigarette smoke on a process that is critical to fracture repair. Perhaps down the road we will be able to speed bone healing among smokers in more than one way.”

Gene expression is the process by which instructions encoded in genes are followed for the building of proteins, the workhorses that make up the body’s organs and carry its signals. In the current study, polymerase chain reaction (PCR), a technique that measures gene expression levels, revealed the genetic changes caused by exposure to BaP in mouse stem cells.

Among the many factors that influence gene expression are transcription factors, proteins designed to direct genes to create more or less of a protein. One such factor is Sex Determining Region Y-box 9 (SOX-9), required for the transition of stem cells into cartilage cells. The PCR results show that BaP in cigarette spoke interferes with SOX-9 expression in mesenchymal stem cells, blocking their conversion into cartilage cells. When this group of stem cells is free to differentiate, the newly formed cartilage cells immediately begin manufacturing collagen 2, the tough, fibrous protein framework for cartilage. Along with interfering with SOX-9, BaP was also found to reduce levels of type II collagen gene expression.

Past studies had shown that stem cells involved in cartilage formation contain proteins known to react with BaP called aryl hydrocarbon receptors. The current results suggest that BaP binding with these receptors may suppress SOX-9 activity, reducing the number of stem cells that turn into cartilage cells and the amount of collage produced. No one knows what such receptors are doing in these cells in the first place, but one theory has it that they signal cellular machinery to metabolize toxins.

The study compared the effect of BaP versus that of cigarette smoke extract, a substance representing all the ingredients in cigarette smoke. The hope was to confirm BaP as the specific cause of the observed effect on SOX-9. Results indeed suggest BaP alone may responsible for this specific mechanism of healing delay, since its effect was equal to the extract.

In addition measuring gene expression levels, researchers also conducted tests to show the effect of BaP visually. When newly differentiated cartilage cells begin to produce collagen in a culture dish, little mounds or nodules of collagen can be visualized using a stain. Staining experiments captured images showing BaP to “completely inhibit” collagen nodule deposition.

Along with O’Keefe, the Medical Center effort was led by Ming Kung, Donna Hoak, HsinChiu Ho, Edward Puzas and Michael Zuscik, all within the Department of Orthopaedics at the Medical Center.

"Smoking reduces the rate at which the two sides of a fracture come together," said Michael Zuscik, Ph.D., associate professor in the Department of Orthopaedics and Rehabilitation at the Medical Center. "We believe this new research will establish for the first time the mechanisms by which polyaromatic hydrocarbons interfere with the healing process.”

Source: University of Rochester

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Posted by CarolAST 03/09/08 09:05

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Except it just so happens that for benzo[a]pyrene, which is one of the common polycyclic hydrocarbons produced by combustion, "[T]he food chain is the dominant pathway of human exposure, accounting for about 97% of the total daily intake of BaP. Inhalation and consumption of contaminated water are only minor pathways of human exposure [2% from air, and 1% from water]. The long-term average daily intake of BaP by the general population is estimated to be 2.2 micrograms (ug) per day. Cigarette smoking and indoor activities do not substantially increase human exposure to BaP relative to background levels of BaP present in the environment." And, "[A]verage smokers (i.e., individuals who smoke 20 cigarettes a day) are taking in an additional 780 ng of BaP daily, which means that smokers get an additional 16% BaP from smoking" [based on pre-1979 cigarettes, which contained about twice the quantity of BaP as newer low-tar cigarettes]. Also, the exposure from cooked beef (0.2 -24.1 ug/kg) is less than the exposure from leafy vegetables (7.0 - 48 ug/kg). (Benzo-a-pyrene: Environmental partitioning and human exposure. H.A. Hattemer-Frey, C.C. Travis. Toxicology and Industrial Health 1991;7(3):141-157.)

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Posted by CarolAST 03/09/08 09:10

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Regis James O'Keefe M.D., Skull & Bones 1981, is just the latest in a long string of Skull & Bones conspirators going back for more than a century. Skull & Bones has played key roles on both sides of the anti-smoking movement. Taking over the tobacco industry was the first thing they did.
=> William Collins Whitney, Skull & Bones 1863, was one of the business partners of tobacco financier Thomas Fortune Ryan when he first came to New York City in the 1870s
=> Irving Fisher, Skull & Bones 1888, founded the Life Extension Institute in the boardroom of the Guaranty Trust
=> Thomas Cochran, Skull & Bones 1894, was a founder of the Tobacco Products Corporation, a predecessor of Philip Morris, in 1912
=> Harold Stanley, Skull & Bones 1908, was a director of the Tobacco Products Corporation in 1923
=> Joseph Taylor Foster, Skull & Bones 1908 - director of Tobacco and Allied Stocks, which held the largest share of Philip Morris stock
=> Stanhope Bayne-Jones, Skull & Bones 1910, overseer of the 1965 Surgeon General Report
=> The New England Institute for Medical Research & Prescott S. Bush, S&B 1917 - the Bones Link to the Microbiological Associates Mouse Inhalation Study
=> Artemus Lamb Gates, S&B 1918, raised funds for American Cancer Society's predecessor, and was a member of the first American Heart Association governing board to include laymen
=> Charles Phelps Taft, S&B 1918, headed "Republicans for Progress," whose cronies created the Evironmental Protection Agency and lobbied for it to proclaim that secondhand smoke causes cancer
=> Charles Dewey Hilles Jr., Skull & Bones 1924 - the direct personal link between the American Cancer Society and the Nazis
=> Amory Howe Bradford, Skull & Bones 1934, was on the staff of the 1971 Ash Council which created the EPA.
=> Frederick Peter Haas, Skull & Bones 1935 - General Counsel of Liggett & Myers, 1965-76
=> The EPA's corrupt and fraudulent report on secondhand smoke was released during the final days of the Administration of President George H.W. Bush, Skull & Bones 1948 - and a crony of his and his son George W. Bush, Skull & Bones 1968, was on the board of directors of the crooked EPA contracting firm.
=> William H. Donaldson, Skull & Bones 1953 - director of Philip Morris, 1979-99
=> John Mercer Pinney, Skull & Bones 1965, was in charge of Surgeon General Reports 1977-81 and continues as a professional anti-smoker
=>Alan W. Cross, Skull & Bones 1966 - a third generation Bonesman - member of the US DHHS Secretary's Council on Health Promotion and Disease Prevention
=> Robert Davis McCallum Jr., Skull & Bones 1968, crony of President Bush since Yale, U.S. Associate Attorney General, was in charge of the federal tobacco lawsuit
=> Christopher Taylor Buckley, Skull & Bones 1975 - Author of the novel, "Thank You For Smoking" (1994), disinformation which purveys health fascist pseudoscience and anti-smoker stereotypes about tobacco industry lobbyists.

http://www.smoker...rder.htm