Postnatal deletion of Dlx5/6 in Osx-lineage cells drives bone hypertrophy by regulating osteoblast expansion and maturation
Abstract
Distal-less homeobox genes Dlx5 and Dlx6 are key regulators of osteoblast differentiation during skeletal development, but their role in postnatal bone remodeling remains poorly understood. To investigate this, we conditionally deleted Dlx5/6 in Osterix-lineage cells after 4 wk of birth using an inducible Osx-Cre system. Dlx5/6Δ/Δ Osx-Cre and control mice were analyzed in terms of bone architecture (micro-CT), remodeling (histomorphometry), gene expression profiling, and single-cell RNA sequencing. Postnatal deletion of Dlx5/6 induced a complex skeletal phenotype characterized by radial bone hypertrophy and altered cortical remodeling. Enhanced periosteal activity was associated with increased Osx expression in periosteal cells, confirmed by BaseScope and immunofluorescence analyses. In parallel, cortical bone became thinner and more porous, while trabecular bone displayed reduced bone formation and thinner trabeculae, despite paradoxical accumulation within the diaphysis. These alterations were associated with increased Osx expression in periosteal and diaphyseal compartments, indicating abnormal spatial regulation of osteolineage cell expansion and bone remodeling. Single-cell transcriptomic analysis in BM cells identified altered mesenchymal stromal cell populations with dysregulated extracellular matrix and Wnt signaling pathways, including downregulation of the Wnt antagonist Sfrp1, validated in situ by RNAscope. Consistently, osteoblasts derived from Dlx5/6Δ/Δ Osx-Cre displayed impaired terminal differentiation in vitro, with reduced expression of late osteogenic markers and decreased matrix mineralization. Collectively, these findings identify Dlx5/6 as critical regulators of postnatal bone homeostasis that coordinate osteolineage expansion and terminal osteoblast maturation during postnatal bone remodeling.
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BibTeX
@article{bourmaud2026postnatal,
title = {{Postnatal deletion of Dlx5/6 in Osx-lineage cells drives bone hypertrophy by regulating osteoblast expansion and maturation}},
author = {Morgane Bourmaud and Nicolas Narboux-Neme and Mylène Zarka and Camille Blandin and Sebastien Mella and Valentina Libri and Milena Hasan and Eric Hay and Giovanni Levi and Martine Cohen-Solal},
journal = {Journal of Bone and Mineral Research},
year = {2026},
month = jul,
doi = {10.1093/jbmr/zjag112},
url = {https://hal.science/hal-05771254v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Postnatal deletion of Dlx5/6 in Osx-lineage cells drives bone hypertrophy by regulating osteoblast expansion and maturation
AU - Morgane Bourmaud
AU - Nicolas Narboux-Neme
AU - Mylène Zarka
AU - Camille Blandin
AU - Sebastien Mella
AU - Valentina Libri
AU - Milena Hasan
AU - Eric Hay
AU - Giovanni Levi
AU - Martine Cohen-Solal
PY - 2026
DA - 2026/07/21
JO - Journal of Bone and Mineral Research
DO - 10.1093/jbmr/zjag112
UR - https://hal.science/hal-05771254v1
AB - Distal-less homeobox genes Dlx5 and Dlx6 are key regulators of osteoblast differentiation during skeletal development, but their role in postnatal bone remodeling remains poorly understood. To investigate this, we conditionally deleted Dlx5/6 in Osterix-lineage cells after 4 wk of birth using an inducible Osx-Cre system. Dlx5/6Δ/Δ Osx-Cre and control mice were analyzed in terms of bone architecture (micro-CT), remodeling (histomorphometry), gene expression profiling, and single-cell RNA sequencing. Postnatal deletion of Dlx5/6 induced a complex skeletal phenotype characterized by radial bone hypertrophy and altered cortical remodeling. Enhanced periosteal activity was associated with increased Osx expression in periosteal cells, confirmed by BaseScope and immunofluorescence analyses. In parallel, cortical bone became thinner and more porous, while trabecular bone displayed reduced bone formation and thinner trabeculae, despite paradoxical accumulation within the diaphysis. These alterations were associated with increased Osx expression in periosteal and diaphyseal compartments, indicating abnormal spatial regulation of osteolineage cell expansion and bone remodeling. Single-cell transcriptomic analysis in BM cells identified altered mesenchymal stromal cell populations with dysregulated extracellular matrix and Wnt signaling pathways, including downregulation of the Wnt antagonist Sfrp1, validated in situ by RNAscope. Consistently, osteoblasts derived from Dlx5/6Δ/Δ Osx-Cre displayed impaired terminal differentiation in vitro, with reduced expression of late osteogenic markers and decreased matrix mineralization. Collectively, these findings identify Dlx5/6 as critical regulators of postnatal bone homeostasis that coordinate osteolineage expansion and terminal osteoblast maturation during postnatal bone remodeling.
SN - 0884-0431
SN - 1523-4681
ER -