Osteoporosis, the most common degenerative disease in the Western Hemisphere, is characterized by a decrease in bone density. The disease comes in two varieties: post-menopausal, primarily affecting post-menopausal women, and age-related, affecting older men as well as women. A study published this week in the early online edition of the Proceedings of the National Academy of Sciences found that mice genetically engineered to lack a molecule called Stem Cell Antigen-1 (Sca-1) experienced normal bone development and maintained normal bone density well into adulthood but exhibited dramatically decreased bone mass and brittle bones as they aged - similar to the symptoms of age-related osteoporosis in humans.
"In these Sca-1-deficient mice, the number of stem cells that normally give rise to new bone cells - called mesenchymal stem cells - declined with age, leading to fewer bone-forming cells," says lead author, Mortaza Bonyadi, a post-doctoral fellow who conducted the research in the labs of senior co-authors and U of T professors William Stanford and Jane Aubin. "We believe that one reason for age-dependent osteoporosis in humans may be defective maintenance of these stem cells. If we can learn how Sca-1 influences the number of stem cells, we may be able to develop new drugs to combat this disabling disease."
Understanding of the causes of age-related osteoporosis is poor compared to the hormonally driven post-menopausal variety, although age-related osteoporosis has a greater mortality and morbidity rate, says Aubin, a professor in the Department of Molecular and Medical Genetics, the Department of Medical Biophysics and the Department of Medical Biophysics and the Institute of Biomaterials and Biomedical Engineering (IBBME).
"While previous studies have suggested that older individuals - especially those with osteoporosis - have fewer bone-forming cells, this is the first research to say, 'You're running out of bone-forming cells for this stem cell-related reason,'" she says.
Stem cells, which in adults play key roles in repairing injured organs, have the ability to either make copies of themselves or divide into other kinds of cells, such as bone cells. The new study suggests that if the Sca-1 molecule is absent, the mesenchymal stem cells are less likely to make copies of themselves. This means that the number of stem cells will decrease as an individual ages so that there may not be enough stem cells left to make the bone cells needed to maintain bone density, explains Stanford, a professor at the IBBME, an associate scientist at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital and a member of the Centre for Modeling Human Disease.
"Sca-1 is somehow influencing the decision to make more stem cells when the stem cell divides," he says. "We think that there are probably many types of proteins or molecules that influence stem cell self-renewal and Sca-1 is one of them. We think that Sca-1 is probably important in maintaining the stem cells' ability to make more stem cells and that, with its loss, individuals would probably lose stem cells and bone faster."
The genetically engineered mice created to analyze the connection between Sca-1 and stem cells may be useful for studying cellular and genetic connections to other types of degenerative diseases, adds Stanford.
Other researchers involved in the study include Marc Grynpas, a professor in IBBME and the Department of Laboratory Medicine and Pathobiology at U of T and a senior investigator in the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, as well as Stephen Waldman and Danmei Liu, post-doctoral fellows in the Grynpas lab. The research received funding from the Institute of Musculoskeletal Health and Arthritis, the Canadian Institutes of Health Research and the Stem Cell Network of Canada.
CONTACT:
William Stanford
Institute of Biomaterials and Biomedical Engineering
416-946-8379
william.stanford@utoronto.ca
Jane Aubin
Department of Molecular and Medical Genetics
416-978-4220
jane.aubin@utoronto.ca
Jessica Whiteside
U of T Public Affairs
416-978-5948
jessica.whiteside@utoronto.ca
Journal
Proceedings of the National Academy of Sciences