Background/Purpose: Innate sensing pathways and inflammasomes play an important role in autoimmunity and aging. AIM2 is a DNA sensor that triggers inflammasome assembly in myeloid cells upon activation by cytosolic DNA. The AIM2 gene is localized on chromosome 1, in an area associated with bone mineral density (BMD) regulation. Although AIM2 has been shown to activate inflammasome assembly, promote IL-1ß and IL-18 processing, and induce pyroptotic cell death, its potential roles in other contexts are just beginning to be explored. This study addresses the role of AIM2 in regulating bone homeostasis during aging.

Methods: We aged both female and male AIM2-deficient mice and littermate controls, analyzing their long bones over time using micro-CT. To investigate the underlying causes of observed changes in bone homeostasis, we employed dynamic histomorphometry, evaluated serum bone anabolic factors, and conducted in vitro differentiation assays for osteoclastogenesis and osteoblastogenesis. Mechanistically, we assessed the activation of DNA-sensing and inflammasome pathways in vitro. Finally, we performed RNA-sequencing of bone progenitor cells isolated from AIM2-deficient mice and littermate controls.

Results: AIM2-deficient mice exhibit increased bone mass with aging, particularly in females. Most strikingly, trabecular and cortical bone volume fractions (BV/TV) are significantly higher in female AIM2-deficient mice compared with littermate control mice. Contrary to initial expectations, AIM2 does not influence osteoclastogenesis or bone resorption in vitro, diverging from the role of the NRLP3 inflammasome in regulating osteoclast function. Notably, however, AIM2-deficient osteoblast progenitors show enhanced osteogenic differentiation in vitro without indication for differential IL-1ß expression and inflammasome activation. Dynamic histomorphometry confirms an increase in bone formation in AIM2-deficient mice, and serum bone turnover markers show an increase in markers of bone formation with no increase in markers of bone resorption. RNA-sequencing highlighted differentially expressed genes in the PI3K-AKT pathway in AIM2-deficient bone progenitor cells compared to controls.

Conclusion: AIM2 regulates bone homeostasis and bone progenitor cell differentiation, potentially through the PI3K-AKT pathway, representing a novel non-canonical function for AIM2. Investigation to further elucidate this mechanism is ongoing.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-cytosolic-dna-sensor-aim2-regulates-bone-homeostasis-through-bone-progenitor-cell-differentiation/