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Spotlight on Research 2010
December 2010 (historical)
Change in B Cell Protein Production Drives Bone Loss in HIV
Researchers supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute of Allergy and Infectious Diseases (NIAID) have discovered how the HIV virus causes bone loss in rats by altering the balance of key proteins that affect the bone renewal process. Their findings were published in a recent issue of the Proceedings of the National Academy of Sciences.
Bone is constantly rejuvenated in response to everyday stresses and damage in a cycle where old, damaged bone is removed, or resorbed, and new bone forms in its place. During the resorption part of this cycle, bone cells called osteoclasts break down damaged bone and clear it away.
In healthy adults, formation and resorption are synchronized so that new bone replaces old bone in the right quantity, at the right time, and in the right place. When bone formation fails to keep pace with bone resorption, bone loss and, eventually, osteoporosis can result.
Approximately two-thirds of people with HIV have low bone mineral density (BMD), a measure of bone strength. (The low BMD is evident even before HIV-infected people begin antiretroviral treatment, an HIV therapy that can itself contribute to bone loss.) Although many factors, such as smoking, lack of exercise, and other diseases associated with HIV infection, can add to bone loss, researchers have recently begun to suspect that HIV infection might somehow alter the bone renewal process indirectly, as a result of immune system changes caused by the infection.
Lead study author M. Neale Weitzmann, Ph.D., of Emory University’s School of Medicine, and his colleagues studied HIV-1 transgenic rats – rats developed to carry HIV genes – in order to learn more about bone renewal in the context of HIV. As the rats aged, the team found significantly more bone loss and destruction in the HIV rats versus control rats. Furthermore, they were able to demonstrate that the rats’ reduced BMD resulted from a severely increased rate of bone resorption.
Using powerful digital imaging, the researchers discovered that the rats’ bone structure was dramatically impaired. This effect was caused by an increase in the number of osteoclasts and osteoclast precursor cells active in bone, and it drove the increased rate of resorption. The increase in osteoclasts was, in turn, driven by an alteration in the ratio at which immune system cells called B cells produced two key proteins associated with bone turnover, RANK ligand (RANKL) and osteoprotegerin (OPG). RANKL stimulates osteoclast formation. OPG, by binding to RANKL, blocks its action.
In the healthy rats, B cells produced a lot of OPG and an almost imperceptible amount of RANKL. In the rats with HIV, however, this ratio had flip-flopped: the B cells had virtually stopped making OPG and produced RANKL, instead.
The researchers hope their discoveries about the immune cell-driven changes underlying bone loss in HIV will contribute to a greater awareness of the problem and to the development of new bone loss therapies. Such therapies will be increasingly necessary. As antiretroviral treatment lengthens the lives of people with HIV, the biology driving age-related bone loss could intersect with HIV-driven bone loss to cause an epidemic of osteoporosis in this population.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.
Vikulina T, Fan X, Yamaguchi M, Roser-Page S, Zayzafoon M, Guidot DM, Ofotokun I, Weitzmann MN. Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats. Proc Natl Acad Sci. 2010 Aug 3;107(31):13848-53. Epub 2010 Jul 19.