Function of cGMP/PKGI signaling in osteogenic differentiation and disease

• Applicant: Professor Dr. Alexander Pfeifer, since 4/2015
• Subject Area: Pharmacology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249662281

Cyclic guanosine monophosphat (cGMP) mediates physiological effects of nitric oxide and natriuretic peptides on different processes in whole body, including bone formation and ossification. Osteoporotic bone loss, the most common metabolic bone disease affecting humans, is becoming major problem due to increasing ageing population. Novel therapies for osteoporosis are needed and cGMP modulating substances could be an interesting approach to treat osteoporosis. Once generated, cGMP activates three major downstream receptors in the cell: phosphodiesterases (PDEs) that hydrolyze cGMP, cyclic nucleotide-gated channels and cGMP-dependent protein kinases (protein kinase G, PKGI and PKGII), which in turn regulate the function of downstream proteins by phosphorylation of serine/threonine residues. Using osteogenic cell models and knockout mice, we recently demonstrated involvement of PKGII in bone development. In addition, PKGII initiates proliferative responses in mechanically stimulated osteoblast. Our preliminary data in mesenchymal stem cells show high expression of PKGI. Interestingly, deletion of PKGI in mesenchymal stem cells causes inhibition of adipogenic differentiation, while it promotes osteogenic differentiation in vitro. Furthermore, chronic treatment of human mesenchymal stem cells with cGMP decreases osteogenic differentiation. The aim of this proposal is to elucidate exact role of PKGI in osteoblast differentiation and function. Using in vitro and in vivo models, we will investigate cellular mechanisms of actions, signal transduction and interactions among key factors regulating bone metabolism. Our goal is to investigate whether cGMP signaling modulation in disease models (ovariectomised and bone breaking mice models) could lead to developing novel treatments in regenerative medicine.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Ana Kilic, until 4/2015