Within human bone, cells called osteoblasts make new bone and without the constant activity of osteoblasts, bone becomes thin and fragile. Osteoblasts are derived from mesenchymal stem cells in the bone marrow. When bones break, orthopedic surgeons try to use growth factors to push more mesenchymal stems and their progeny to become osteoblasts. The growth factor in question is bone morphogen protein (BMP). BMP, however, does not work consistently, and it has some rather nasty side effects (cancer, The specific complications that are drawing the most concern include swelling in the neck and throat, radiating leg pain, and male sterility). Therefore, an alternative method for converting mesenchymal stem cells into osteoblasts is highly desirable.
Kurt Hankenson from the University of Pennsylvania School of Veterinary Medicine has worked on this very problem and described the situation this way, “In the field, we’re always searching for new ways for progenitor cells to become osteoblasts so we became interested in the Notch signaling pathway.” When it comes to BMP, Hankenson said, “it has become clear that BMPs have some issues with safety and efficacy.”
Is there a better way to make bone? There seems to be. A protein called Jagged-1 has been shown by Hankenson’s team to be highly expressed in bone. Jagged-1 is a component of the widely used Notch signaling pathway, which is found in the nervous system and in many other cells as well.
In mouse stem cells, introducing Jagged-1 blocks the progression of mesenchymal stem cells to osteoblasts. This finding has actually hampered osteoblast research for the last two years. Hankenson again, “That had been our operating dogma for a year or two.”
However, as is so often the case in science, you never truly know the result of an experiment until you actually do it. When Jagged-1 was added to human mesenchymal stem cells, the results were very different. Hankenson said, “It was remarkable to find that just putting the cells onto the Jagged-1 ligand seemed sufficient for driving the formation of bone-producing cells.”
From a developmental genetics perspective, this makes perfect sense, since mutations in the Jagged-1 gene cause an inherited disease known as Alagille syndrome which causes liver problems, abnormal metabolisms, and fragile bones that break easily. Also, genome-wide association studies have shown that particular versions of the Jagged-1 gene cause low bone density.
Hankenson and his collaborators are examining ways to manipulate the levels of the Jagged-1 protein in patients with bone problems. To that end, Hankenson is collaborating with Kathleen Loomes of Penn’s Perelman School of Medicine and the Children’s Hospital of Pennsylvania to study pediatric patients with Alagille syndrome to determine if bone abnormalities in these patients are indeed connected to Jagged-1 malfunctions.
Hankenson and his former graduate student Mike Dishowitz started a company called Skelegen through the University of Pennsylvania’s Center for Technology Transfer (CTT) UPstart program. The goal of Skelegen is to develop and improve a system for delivering Jagged-1 to sites that require new bone growth in the hopes of treating bone fractures and other skeletal problems.
See Fengchang Zhu et al., “Pkcdelta is required for Jagged-1 induction of hMSC osteogenic differentiation.” Stem Cells 2013; DOI 10.1002/stem.1353.