A CCAAT/Enhancer Binding Protein β Isoform, Liver-Enriched Inhibitory Protein, Regulates Commitment of Osteoblasts and Adipocytes

Abstract

Although both osteoblasts and adipocytes have a common origin, i.e., mesenchymal cells, the molecular mechanisms that define the direction of two different lineages are presently unknown. In this study, we investigated the role of a transcription factor, CCAAT/enhancer binding protein ␤ (C/EBP␤), and its isoform in the regulation of balance between osteoblast and adipocyte differentiation. We found that C/EBP␤, which is induced along with osteoblast differentiation, promotes the differentiation of mesenchymal cells into an osteoblast lineage in cooperation with Runx2, an essential transcription factor for osteogenesis. Surprisingly, an isoform of C/EBP␤, liver-enriched inhibitory protein (LIP), which lacks the transcriptional activation domain, stimulates transcriptional activity and the osteogenic action of Runx2, although LIP inhibits adipogenesis in a dominant-negative fashion. Furthermore, LIP physically associates with Runx2 and binds to the C/EBP binding element present in the osteocalcin gene promoter. These data indicate that LIP functions as a coactivator for Runx2 and preferentially promotes the osteoblast differentiation of mesenchymal cells. Thus, identification of a novel role of the C/EBP␤ isoform provides insight into the molecular basis of the regulation of osteoblast and adipocyte commitment.

Doubly Truncated FosB Isoform (Δ2ΔFosB) Induces Osteosclerosis in Transgenic Mice and Modulates Expression and Phosphorylation of Smads in Osteoblasts Independent of Intrinsic AP-1 Activity

“…As much as these positive effects on BMP signaling most probably contribute to the high bone formation observed in mice overexpressing ⌬FosB or ⌬2⌬FosB, they may not be the whole explanation of the phenotype. We have also identified other transcription factors that bind both ⌬FosB and ⌬2⌬FosB, including C/EBP␤ (19) and Runx2 (unpublished data), both of which have important transcriptional regulatory functions in mesenchymal cell differentiation, (61)(62)(63)(64)(65)(66)(67) as well as a novel zinc finger-containing factor, Zfp521, that is highly expressed in developing bones (unpublished data). However, whereas it is likely that at least some of these interactions with other transcription factors also participate in the induction of bone formation by the truncated FosB isoforms and by the Fra proteins, this study highlights the facts that the intrinsic AP-1 activity of ⌬FosB is dispensable for the cell autonomous effects on osteoblasts and that truncated FosB proteins are capable of enhancing BMP signaling in osteoblasts, thereby contributing to the osteosclerotic phenotype observed in transgenic mice overexpressing ⌬FosB or ⌬2⌬FosB.…”

C/EBPβ Promotes Transition from Proliferation to Hypertrophic Differentiation of Chondrocytes through Transactivation of p57Kip2

“…C/EBPβ acts as a co-activator of Runx2 [6], [37]. Generally, the complex of the members of the C/EBP and Runx families is known to interact in the activation of lineage-specific promoters during differentiation of osteoblasts, adipocytes, and granulocytes [6].…”

Rapamycin and the transcription factor C/EBPβ as a switch in osteoclast differentiation: implications for lytic bone diseases

“…Moreover, LIP enhanced osteoblast differentiation and function [3], possibly by acting as a coactivator for Runx2 [10]. …”