Understanding the basic molecular pathways that control the proliferation of osteoprogenitor cells and their subsequent differentiation into mature osteoblasts capable of synthesizing bone, forms the fundamental basis of all strategies aimed at growing new bone in a reparative or regenerative setting. We have focussed on two intracellular pathways that we have shown previously using in vivo and in vitro approaches to be critical for regulating osteoblast growth and bone formation. First, the c- Fos/AP-1 transcription factor causes osteoblast transformation and osteosarcoma formation when overexpressed in transgenic mice, and we suggest here that one possible underlying mechanism is the ability of c-Fos to deregulate osteoblast growth and proliferation by targeting specific components of the cell cycle machinery, such as cyclin A. Second, we show that the activity of the Rho family GTPase, RhoA and its downstream target Rho kinase (ROCK) are crucial for regulating bone formation in vitro. Specifically, we show that Rho activation inhibits calvarial osteogenic cell differentiation and bone formation in vitro, while treatment of osteogenic cultures with ROCK inhibitors gives an anabolic response, markedly stimulating bone formation. The implications for bone remodelling and for bone tissue repair and regeneration are discussed.
Keywords: osteoblast, osteoclast, differentiation, remodelling, signalling pathways