Ras-MAPK signaling in osteogenic differentiation: friend or foe?

摘要

The role of Ras-mitogen-activated protein kinase (MAPK) signaling in osteogenic differentiation is currently a source of great controversy. On one side is robust evidence from in vitro studies, pharmacological therapy, and genetic disease indicating that increased Ras-MAPK signaling can antagonize bone formation. In this model, committed osteoprogenitors have a choice of either proliferation or further differentiation, with Ras-MAPK being a key regulator of that balance. In contrast, several conflicting in vitro studies have implied that Ras-MAPK is vital for supporting Runx2/Cbfa1 activity and subsequent osteogenic gene expression. As evidence mounts on both sides of the argument, it is important to step back and critically analyze the approaches taken thus far and the relative strength of their conclusions.This perspective attempts to provide a concise and unbiased summary of both lines of evidence to better understand the conflicting models. A particular focus has been placed on comparing differences in methodology. Whereas no single factor emerges as expedient to account for the divergent views, a clear lack of uniformity in experimental methods is evident. Perhaps the greatest variation was seen in the use of numerous cell lines and primary cell types at various stages of osteogenic commitment and differentiation. We speculate that uncommitted multipotent progenitors, committed osteoprogenitors, mature osteoblasts, and cells derived from other lineages may respond differently to identical stimuli, thus explaining some of the apparent conflict in the literature. As well as experimental consistency, we propose that systematic approaches for the independent examination of osteogenic commitment and osteogenic differentiation are of paramount importance for future progress.