Nov. 18, 1999 Discovery may be the key to preventing joint destruction in arthritis
(Toronto, November 18, 1999) - The role of T cells in the crippling bone and cartilage deterioration characteristic of many diseases including arthritis and other inflammatory diseases has been unraveled for the first time by a research team at Princess Margaret Hospital and the AMGEN Research Institute. Inflammation can trigger the body's T cells to inadvertently cannibalize its own bone, leading to severe bone degeneration and debilitating pain.
The finding paves the way for future research into preventing the onset and progression of bone erosion in arthritis and the prevention of osteoporosis associated with many different kinds of diseases. The findings are reported in the November 18, 1999 issue of the journal Nature. The research was funded by the AMGEN Research Institute.
"Stunned" by Findings
The research marks the first time in the world that a research team has clearly identified the molecular cause of the bone and cartilage deterioration characteristic of many inflammatory diseases. Lead author Dr. Josef Penninger, an immunologist at Princess Margaret Hospital and the AMGEN Institute, and a member of the Departments of Medical Biophysics and Immunology at the University of Toronto said, "When I realized what we had found, I was stunned. This could be the seminal paper for the prevention and treatment of bone loss in arthritis, and perhaps even for the treatment of bone loss in leukemia, hepatitis, HIV/AIDS, diabetes, multiple sclerosis, lupus and other diseases associated with inflammation and bone loss." The research was a collaborative effort between Dr. Penninger and his colleague Dr. Young-Yun Kong in Toronto, and Drs. Ulrich Feige and Bill Boyle at AMGEN in Thousand Oaks, California.
Earlier this year, Drs. Penninger, Kong and Boyle discovered OPGL, a gene that triggers the body's cells to cannibalize its own bone, leading to severe osteoporosis. They also discovered that the same gene regulates the development of lymph nodes and white blood cells, the body's protection against infection. "We were puzzled by our finding that certain white blood cells, called T cells, produce a substance that triggers bone loss," said Dr. Penninger. "We set out to find out why T cells make OPGL. What we uncovered is a molecular trigger for bone destruction in many diseases such as arthritis and even cancer."
Cells Become Cannibals
The infantry of the body's immune system, T cells spend most of their lives waiting to fight off offending disease. When the body is attacked by a virus or bacteria, T cells are "turned on" and begin producing OPGL, causing local or systemic bone loss.
Diseases which cause inflammation, such as arthritis, hepatitis, AIDS and many others attract T cells, which arrive at the sight of the inflammation ready to fight. When they head into battle, T cells produce OPGL. "The production of OPGL probably allows our T cells to activate the development of other blood cells required to fight off infection," said Dr. Penninger. "Unfortunately in chronic viral infections, autoimmune diseases and some cancers, T cells do not stop their attack, causing the OPGL-producing T cells to seek out and destroy the body's own bone and cartilage."
"Many patients who suffer from chronic viral infections, infectious diseases, allergic conditions, autoimmune disorders or various forms of cancer experience mild or severe bone and cartilage loss," said Dr. Kong. "Until now, we never knew why or what the connection was. Now we know that diseases, which cause inflammation in the body and activate the immune system initiate a T cell attack, also triggering an attack against the bones. Now that we know what is causing that bone loss, we can stop it."
Arthritis Blocker Possible
On the heels of successful experiments in rats, a natural blocker of OPGL is currently in phase I human clinical trials in the United States. If the trials are successful, testing of the OPGL blocker may begin in patients with osteoporosis, metastatic bone disease or rheumatoid arthritis. In human studies, Dr. Penninger and his research team found that, without exception, 100 percent of all osteoarthritis and rheumatoid arthritis patients they examined expressed OPGL in their joints, making the correlation absolute. "Arthritis patients suffer from severe destruction of the bone surrounding their joints, causing irreversible damage to the joints, pain and permanent physical disabilities," said Dr Penninger. "When arthritic rats are injected with the OPGL inhibitor or blocker at the first sign of inflammation, bone loss and cartilage destruction stops completely. OPGL inhibition may also be the future treatment of choice to block the crippling bone loss associated with cancer or hepatitis."
Arthritis exists in over 100 forms and is responsible for disabling over 600,000 Canadians and affecting more than four million people, including men, women and children. The USA alone spends over $50 billion a year to treat arthritis and related diseases. Forms of arthritis include tendinitis, bursitis, fibromyalgia, lupus, rheumatoid and osteoarthritis. The common denominator of all forms of the disease is joint and musculoskeletal pain and bone loss and ultimately life-long crippling as a result of inflammation of the joint lining.
Princess Margaret Hospital, a teaching hospital of the University of Toronto, has achieved an international reputation as a global leader in the fight against cancer and is considered one of the top comprehensive cancer research and treatment centres in the world. PMH is a member of the University Health Network, which also includes Toronto General Hospital and Toronto Western Hospital. The AMGEN Research Institute is an integral part of AMGEN, the world's largest biotechnology company and an innovative and pioneering world-wide organization dedicated to the research and development, manufacture and marketing of human proteins for therapeutic use, using recombinant DNA technology.
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