Loss of the Hematopoietic Stem Cell Factor GATA2 in the Osteogenic Lineage Impairs Trabecularization and Mechanical Strength of Bone

ABSTRACT

The transcription factor GATA2 is required for expansion and differentiation of hematopoietic stem cells (HSCs). In mesenchymal stem cells (MSCs), GATA2 blocks adipogenesis, but its biological relevance and underlying genomic events are unknown. We report a dual function of GATA2 in bone homeostasis. GATA2 in MSCs binds near genes involved in skeletal system development and colocalizes with motifs for FOX and HOX transcription factors, known regulators of skeletal development. Ectopic GATA2 blocks osteoblastogenesis by interfering with SMAD1/5/8 activation. MSC-specific deletion of GATA2 in mice increases the numbers and differentiation capacity of bone-derived precursors, resulting in elevated bone formation. Surprisingly, MSC-specific GATA2 deficiency impairs the trabecularization and mechanical strength of bone, involving reduced MSC expression of the osteoclast inhibitor osteoprotegerin and increased osteoclast numbers. Thus, GATA2 affects bone turnover via MSC-autonomous and indirect effects. By regulating bone trabecularization, GATA2 expression in the osteogenic lineage may contribute to the anatomical and cellular microenvironment of the HSC niche required for hematopoiesis.

KEYWORDS:

• GATA2
• bone
• cell differentiation
• mesenchymal stem cell
• osteoblast
• trabecularization

View publisher note:

Articles of Significant Interest in This Issue

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00599-17.

ACKNOWLEDGMENTS

This work was supported by the Einstein Foundation Berlin (grant no. A-2011-83 to M. Schupp and S. Sauer), by a Career Integration Grant from the European Commission (CIG 291867), by the German Research Foundation (DFG) (Emmy Noether grant SCHU 2546/1-1), by the Deutsche Diabetes Stiftung (grant no. 280-12-10 to M. Schupp), and by a DynAge Focus Area grant to M. Schupp and T. J. Schulz.

We thank Mathias Treier (Max-Delbrück Center, Berlin Buch) for sharing Prx1-Cre mice and Christian Freise (Charité) for sharing WNT reporter constructs. We thank Dag Wulsten and Britt Wildemann (Berlin-Brandenburger Centrum für Regenerative Therapien and Julius Wolff Institut, Charité Universitätsmedizin Berlin) for the biomechanical characterization of bone and helpful comments on bone histology, respectively. pGL3 BRE luciferase was a gift from Martine Roussel and Peter ten Dijke (Addgene plasmid 45126). We thank Jan Tuckermann and colleagues (University of Ulm) for methodological help on bone characterization. This study was initiated in the laboratory of Mitch Lazar (Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA), and we are deeply grateful for his support.

A. Tolkachov and M. Schupp conceived and designed experiments. A. Tolkachov, C. Fischer, T. H. Ambrosi, M. Bothe, C.-T. Han, M. Muenzner, S. Mathia, M. Thiele, S. H. Meijsing, S. Sauer, T. J. Schulz, and M. Schupp performed experiments and/or analyzed data. M. Salminen provided a genetic mouse model, and G. Seifert assisted with blood analyses. G. N. Duda assisted with bone characterization. A. Tolkachov, C. Fischer, T. H. Ambrosi, S. H. Meijsing, S. Sauer, T. J. Schulz, and M. Schupp wrote and edited the manuscript.

Charité-Universitätsmedizin Berlin is a corporate member of Freie Universität Berlin, Berlin, Germany.