Osteoporosis is a disease characterized by low bone mass, disordered bone microarchitecture, and increased bone fragility. There is growing recognition of osteoporosis in younger populations, most often occurring in children who have genetic disorders or acute and chronic illnesses that affect the skeleton. However, osteoporosis is only diagnosed after several fractures and there are no FDA-approved medications to treat osteoporosis in childhood. The primary aim of my K08 proposal has been to understand signaling pathways that promote mesenchymal stem cell (MSC) differentiation towards osteoblasts for bone formation. The bone marrow microenvironment is critical for MSC differentiation. Osteogenesis is a highly metabolically active process and requires adequate vascularization to transport necessary nutrients, oxygen, minerals and metabolic wastes. We have discovered that preosteoclasts secrete platelet-derived growth factor type BB (PDGF-BB), which stimulates migration of endothelial precursor cells (EPCs) to form blood vessels. I have also developed a glucocorticoid- induced osteoporosis (GIO) in young mouse model. GIO in young mice is associated with suppressed preosteoclast PDGF-BB secretion and endothelial precursor production of vascular endothelial growth factor (VEGF). We hypothesis that glucocorticoids impair skeletal angiogenesis by decreasing PDGF-BB secretion from osteoclasts and results in decreased osteoblastic bone formation. In this proposal, we will validate my K08 basic science findings by conducting a cross-section case-control study of children with glucocorticoid-induced osteoporosis.
The first aim i s to characterize angiogenic potential in children with GIO.
The second aim i s to examine osteogenic potential in children with GIO. We will use novel techniques to isolate peripheral blood and bone marrow precursor cells for in vitro differentiation culture and characterization of osteoclast, osteoblast, and endothelial cell activity. PDGF-BB and VEGF concentrations will also be measured in serum. Findings with be compared to controls and correlated with GIO case?s bone mineral density and fracture history. Peripheral blood and bone marrow precursor cell differentiation and gene and protein expression will be compared to determine if peripheral blood mononuclear cells could be used as a less-invasive means to monitor bone health in childhood. This proposal will validate the correlation between GIO in children and angiogenesis, which could be used to identify biomarkers in peripheral blood to improve the diagnosis and potentially identify drug-targets for treatment or prevention of osteoporosis in childhood.
Osteoporosis in childhood is due to reductions in bone acquisition. Translational research of the pathobiological mechanisms that precede reductions in bone formation will identify potential biomarkers to non-invasively diagnose children at highest risk of osteoporosis and identify potential targets for the development of future anabolic therapies.
