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Deletion of absent in melanoma (AIM) 2 gene drives bone marrow adipogenesis

ABSTRACT: Absent in Melanoma (AIM) 2 is a gene that is induced by interferon and acts as a cytosolic sensor for double-stranded (ds) DNA. It forms the AIM2 inflammasome, leading to the production of interleukin (IL)-1β and IL-18. Our previous study demonstrated that mice lacking AIM2 exhibit spontaneous obesity, insulin resistance, and inflammation in adipose tissue. In this study, we aimed to explore the impact of AIM2 gene deletion on the bone marrow microenvironment and bone morphology in adult and aged mice. Utilizing micro-computed tomography (micro-CT), we discovered that female mice lacking AIM2 showed an increase in the total cross-sectional area at 5 months of age, accompanied by an increase in cortical thickness in the mid-diaphysis of the femur at both 5 and 15 months of age. At 15 months of age, the cortical bone mineral density (BMD) significantly decreased in AIM2 null females compared to wild-type (WT) mice. In AIM2 null mice, both trabecular bone volume and BMD at the distal metaphysis of the femur and the lumbar vertebra-4 significantly decreased at 5 and 15 months of age. Histological examination of femurs from aged mice demonstrated increased bone marrow adiposity in AIM2 null mice, accompanied by a significant increase in CD45-/CD31-/Sca1+/Pdgfa+ adipose progenitor cells, and a decrease in the ratio of CD31-/CD31+ osteogenic progenitor cells, as determined by flow cytometry of bone marrow cells. RNAseq analysis of the bone marrow revealed significant increase in interferon-stimulated genes with Ifi202b as the top upregulated gene in the bone marrow of AIM2 null mice. Our findings suggest that AIM2 deficiency affects bone health by promoting adipogenesis in bone marrow cells and inducing a pro-inflammatory environment, potentially contributing to the decreased bone mineral density.

ORGANISM(S): Mus musculus

PROVIDER: GSE272915 | GEO | 2025/03/12

REPOSITORIES: GEO

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Project description:Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis was used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal and femoral BMD revealed four significant associations (-log10P > 5.39) affecting at least one BMD trait on chromosomes (Chrs.) 7, 11, 12 and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS) SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2) gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism though which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression gene module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cell of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits. RNA from cortical bone (femoral diaphysis free of marrow) were profiled from 99 Hybrid Mouse Diversity Panel strains were profiled. Sixteen-week old male mice were used in this study. A total of 1-3 mice per strain were arrayed.

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Deletion of absent in melanoma (AIM) 2 gene drives bone marrow adipogenesis

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