Public Health Issue - Harvard School of Dental Medicine

esearch focusNew Hope for Treating OsteoporosisBy Kevin Jiang, Harvard Medicine NewsResearchers have discovered a new role for a wellknownsignaling protein that regulates how bonemarrow stem cells turn into either bone or fat. Thediscovery could potentially lead to new treatmentsfor osteoporosis.“It shifts the thinking about whatcontrols the differentiation of stem cells tobone cells instead of fat cells, and how to makesure this mechanism stays active with aging,”said Bjorn R. Olsen, HSDM dean for researchand professor of developmental biology andHersey professor of cell biology at HarvardMedical School. The finding was publishedin the Journal of Clinical Investigation inSeptember 2012.Osteoporosis, a common bone disease Bjorn R. Olsencharacterized by thinning of bone tissue, affectsone in five American women over the age of 50. In healthyindividuals, bone is continuously formed and reabsorbed bythe body. This balance is upset in osteoporotic patients. Intheir systems, stem cells that normally differentiate into boneformingcells seem to become fat cells instead over time.To study this process, Olsen, the senior investigator onthe paper, and his team of two postdoctoral researchers, AgnesBerendsen and Yanqiu Liu, and collaborators, focused on therole of vascular endothelial growth factor, or VEGF, a commonsignaling protein vital to blood vessel formation in early bonedevelopment and skeletal maintenance in mammals.The researchers developed a genetically modified mousethat lacked the ability to produce VEGF in bone marrow stemcells. They found that these mice developed an osteoporosislikeskeleton after birth, including reduced bone tissue and abuildup of fat in the bone. Stem cells isolated from these micein culture were more likely to differentiate into fat cells ratherthan bone-forming cells.Using a technique called RNA interference, theresearchers switched off VEGF in the stem cells of wild-typemice. This produced the same result, verifying the importanceof the protein for normal differentiation of stem cells to boneformingcells.Since VEGF is typically a secretedprotein that works by activating receptorson the surface of cells, the team introducedextra VEGF protein to the cell cultures in anattempt to restore normal differentiation.They found no effect.However, when they introduced a viruscontaining a coding segment of VEGF, thestem cells began producing the protein anddifferentiated into bone-forming cells at ratesJan Reisstypical of normal cells.This and other data provided strongevidence that the ability of bone marrow stem cells todifferentiate into bone-forming cells relies on intracellularVEGF function, the researchers concluded. This unexpectedfinding was verified through additional biochemical andcontrol experiments.The team also determined that VEGF regulateskey molecules that affect bone formation and fat celldifferentiation, as well as a nuclear protein that has beenassociated with premature aging.The researchers now plan on further characterizing thepathways involved with VEGF signaling in bone marrow stemcells and on discovering potential drug targets.“We need to understand the mechanisms better andfind targets that can allow us to increase intracellular VEGFfunction in these cells,” said Olsen. “If we find such targets,we’d like to examine whether increasing levels of VEGFin mouse models of osteoporosis can restore their boneformation to normal levels. That would be quite exciting.” •harvard dental bulletin • winter 2012–1321