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 DeltaFosB splice variant of FosB develop severe osteosclerosis. Translation of Deltafosb mRNA produces both DeltaFosB and a further truncated isoform (Delta2DeltaFosB) that lacks known transactivation domains but, like DeltaFosB, induces increased expression of osteoblast marker genes.

Downregulation of cAMP-dependent protein kinase inhibitor gamma is required for BMP-2-induced osteoblastic differentiation.

Osteoblasts, normally derived from undifferentiated mesenchymal precursor cells, acquire their characteristic phenotypes when induced by various regulatory factors, one of which is bone morphogenetic protein-2 (BMP-2). Our recent studies suggest that expression of cAMP-dependent protein kinase (PKA) inhibitor G (PKIG) is down-regulated as human mesenchymal stromal cells (MSCs) undergo BMP-2-induced osteoblastic differentiation. This raises our hypothesis that the PKA pathway is involved in osteogenesis.

DeltaFosB induces osteosclerosis and decreases adipogenesis by two independent cell-autonomous mechanisms.

Osteoblasts and adipocytes may develop from common bone marrow mesenchymal precursors. Transgenic mice overexpressing DeltaFosB, an AP-1 transcription factor, under the control of the neuron-specific enolase (NSE) promoter show both markedly increased bone formation and decreased adipogenesis. To determine whether the two phenotypes were linked, we targeted overexpression of DeltaFosB in mice to the osteoblast by using the osteocalcin (OG2) promoter.

The increased bone mass in deltaFosB transgenic mice is independent of circulating leptin levels.

Transgenic mice overexpressing deltaFosB, a naturally occurring splice variant of FosB, develop an osteosclerotic phenotype. The increased bone formation has been shown to be due, at least in part, to autonomous effects of deltaFosB isoforms on cells of the osteoblast lineage. However, abdominal fat and marrow adipocytes are also markedly decreased in deltaFosB mice, leading to low serum leptin levels.