Sexually Dimorphic Increases in Bone Mass Following Tissue-specific Overexpression of Runx1 in Osteoclast Precursors

Many metabolic bone diseases arise as a result excessive osteoclastic bone resorption, which has motivated efforts to identify new molecular targets that can inhibit the formation or activity of these bone-resorbing cells. Mounting evidence indicates that the transcription factor Runx1 acts as a tra...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2022-09, Vol.163 (9), p.1
Main Authors: Díaz-Hernández, Martha Elena, Kinter, Christopher W, Watson, Shana R, Mella-Velazquez, Giovanni, Kaiser, Jarred, Liu, Guanglu, Khan, Nazir M, Roberts, Joseph L, Lorenzo, Joseph, Drissi, Hicham
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biomechanics
Bone Density
Bone diseases
Bone mass
Bone remodeling
Bone resorption
Bone Resorption - genetics
Bone Resorption - metabolism
Bones
Cancellous bone
Cell Differentiation - genetics
Core Binding Factor Alpha 2 Subunit - genetics
Density
Endocrinology
Ethylenediaminetetraacetic acid
Female
Genes
Genetic engineering
Genetic transcription
Mechanical properties
Mice
Osteoclastogenesis
Osteoclasts
Osteogenesis - genetics
Osteoprogenitor cells
Precursors
RANK Ligand - metabolism
Runx1 protein
Sexual dimorphism
Transcriptomics
Transgenic mice
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Summary:Many metabolic bone diseases arise as a result excessive osteoclastic bone resorption, which has motivated efforts to identify new molecular targets that can inhibit the formation or activity of these bone-resorbing cells. Mounting evidence indicates that the transcription factor Runx1 acts as a transcriptional repressor of osteoclast formation. Prior studies using a conditional knockout approach suggested that Runx1 in osteoclast precursors acts as an inhibitor of osteoclastogenesis; however, the effects of upregulation of Runx1 on osteoclast formation remain unknown. In this study, we investigated the skeletal effects of conditional overexpression of Runx1 in preosteoclasts by crossing novel Runx1 gain-of-function mice (Rosa26-LSL-Runx1) with LysM-Cre transgenic mice. We observed a sex-dependent effect whereby overexpression of Runx1 in female mice increased trabecular bone microarchitectural indices and improved torsion biomechanical properties. These effects were likely mediated by delayed osteoclastogenesis and decreased bone resorption. Transcriptomics analyses during osteoclastogenesis revealed a distinct transcriptomic profile in the Runx1-overexpressing cells, with enrichment of genes related to redox signaling, apoptosis, osteoclast differentiation, and bone remodeling. These data further confirm the antiosteoclastogenic activities of Runx1 and provide new insight into the molecular targets that may mediate these effects.
ISSN:0013-7227
1945-7170
DOI:10.1210/endocr/bqac113