Doubly truncated FosB isoform (Delta2DeltaFosB) induces osteosclerosis in transgenic mice and modulates expression and phosphorylation of Smads in osteoblasts independent of intrinsic AP-1 activity.

Introduction: Activator protein (AP)-1 family members play important roles in the development and maintenance of the adult skeleton. Transgenic mice that overexpress the naturally occurring Delta fosB splice variant of FosB develop severe osteosclerosis. Translation of Afosb mRNA produces both Delta Fos13 and a further truncated isoform (Delta 2 Delta FosB) that lacks known transactivation domains but, like Delta FosB, induces increased expression of osteoblast marker genes. Materials and Methods: To test Delta 2AFosB's ability to induce bone formation in vivo, we generated transgenic mice that overexpress only Delta 2AFosB using the enolase 2 (ENO2) promoter-driven bitransgenic Tet-Off system. Results: Despite Delta 2AFosB's failure to induce transcription of an AP-1 reporter gene, the transgenic mice exhibited both the bone and the fat phenotypes seen in the EN02-Delta FosB mice. Both Delta Fos13 and Delta 2AFosB activated the BMP-responsive Xvent-luc reporter gene and increased Smadl expression. Delta 2AFosB enhanced BMP-induced Smad1 phosphorylation and the translocation of phospho-Smad1 (pSmad1) to the nucleus more efficiently than Delta Fos13 and showed a reduced induction of inhibitory Smad6 expression. Conclusions: Delta FosB's AP-1 transactivating function is not needed to induce increased bone formation, and Delta 2 Delta FosB may act, at least in part, by increasing Smadl expression, phosphorylation, and translocation to the nucleus.