For orthopaedic surgery researcher Mei Wan, advancing anabolic treatments in osteoporosis and bone fracture repair is the long-term goal of her research on bone marrow mesenchymal stem cells (MSCs). Her core focus is identifying mechanisms that determine the multiple lineage differentiation potential of MSCs, particularly those that give rise to bone-making osteoblasts.
Over the past several years, Wan has made important findings in this area. “We found that the parathyroid hormone (PTH)—the only FDA-approved drug for osteoporosis—acts on a cell surface co-receptor called LRP6 (low-density lipoprotein receptor-related protein 6),” she explains. “LRP6 is required for MSC osteoblast differentiation and self-renewal.”
Wan is now studying how PTH and LRP6 function in disease conditions such as hyperlipidemia and diabetes, in which there is a high risk of osteoporosis. The importance of Wan’s research is underscored by the prevalence of these conditions. According to recent Centers for Disease Control and Prevention data, approximately 74 million American adults have hypercholesterolemia, and 22 million have diabetes.
Wan has found that oxidized lipids are harmful to bone cells, especially MSCs, because they directly bind to LRP6 and cause endocytosis, which restricts LRP6 from mediating PTH. These findings provide new understanding of the mechanisms by which osteoporosis and hyperlipidemia/atherosclerosis co-develop, and offer an important basis for the future development of new strategies to simultaneously treat both disorders.
Another of Wan’s findings came from a study of animal models treated for coronary artery disease. After damage to the endothelial layer of the vessels, bone marrow cells mobilized to repair the injury. In this setting, Wan found that “the molecular mechanism is the RhoA inhibitor. RhoA/Rho-associated protein kinase (ROCK) controls the lineage of the MSCs. The cells specifically differentiated into endothelial cells to repair the injury after the treatment of ROCK inhibitor.
“In the bone-related area, that is actually a generalized mechanism,” Wan says. “MSC therapy has been used in preclinical and clinical studies to improve fracture healing, especially for nonunion fracture. In our study, we found that after tissue injury, outside of the bone, the blood level of active transforming growth factor beta (TGF-ß) increased substantially, and the bone marrow cells mobilized. After we blocked TGF-ß, the cells just stayed in the bone marrow, rather than mobilizing and repairing the injury.”
Wan credits her colleague, Xu Cao, director of the Johns Hopkins Center for Musculoskeletal Research, for inspiring her to pursue this line of research. “He has motivated me because his research is cutting edge in terms of basic research, and then, most importantly, he can translate it into clinical trials to solve real patient problems,” says Wan.