IADR Abstract Archives
miR-23a Cluster is a Potent Regulator of Bone Formation and Maintenance
Objectives: Asymmetry in osteoclastic bone resorption is pivotal to low bone mineral density (BMD) in osteoporosis and other bone diseases. Studies indicated that dysregulation of the miR-23aCL is associated with low bone mineral density (BMD), however, we do not know how miR-23aCL controls osteoclast activities for asymmetric resorption. Our central hypothesis posits that miR-23aCL is a crucial regulator of bone mass and strength, primarily through its control over sex-hormone-regulated osteoclast activity, affecting bone remodeling processes.
Methods: We studied bone characteristics and gene expression in wild-type and osteoclast and osteoblast specific miR-23aCL knockdown mice. We studied gene expression changes in osteoclast precursors (OCPs) and calvarial osteoblasts from miR-23a cluster knockdown using shRNA and CRISPR methods. ChIP-seq was employed to analyze H3K27 repression and chromatin remodeling during differentiation on days 3 and 6, comparing control and miR-23a knockdown mice.
Results: Our initial findings indicate that bone-specific miR-23aCL loss (miR-23aCLZIP) increased trabecular and cortical bone, osteoblast count, dynamic bone formation, and bone strength during formation (2-month) and maintenance (6-month)1. Histomorphometric analysis indicated significantly lower osteoclast numbers per bone surface (OCs/BS) at 6 months in miR-23aCLZIP mice compared to no change in 2 months. RNA-seq and chromatin accessibility analysis from OB-specific miR-23aCLZIP mice showed a significant increase of osteogenic genes with enhanced PBAF complex and reduced PRC2 complex expression, leading to higher levels of histone H3k27 acetylation. These results highlight the novel interplay between miR-23aCL regulation, H3k27 acetylation, and gene expression in bone biology. Osteoclast-specific loss of miR-23aCL resulted in an increased trabecular bone volume, trabecular thickness, and decreased trabecular space in 2-month-old males. Interestingly, it increased all the above bone parameters in 2-month females.
Conclusions: By unraveling the complex interactions between miR-23aCL, sex hormones, epigenetic switches, and osteoclast activity, we can pave the way for innovative treatments that more effectively maintain or restore physiological bone mass and strength in a sex-specific manner.
Methods: We studied bone characteristics and gene expression in wild-type and osteoclast and osteoblast specific miR-23aCL knockdown mice. We studied gene expression changes in osteoclast precursors (OCPs) and calvarial osteoblasts from miR-23a cluster knockdown using shRNA and CRISPR methods. ChIP-seq was employed to analyze H3K27 repression and chromatin remodeling during differentiation on days 3 and 6, comparing control and miR-23a knockdown mice.
Results: Our initial findings indicate that bone-specific miR-23aCL loss (miR-23aCLZIP) increased trabecular and cortical bone, osteoblast count, dynamic bone formation, and bone strength during formation (2-month) and maintenance (6-month)1. Histomorphometric analysis indicated significantly lower osteoclast numbers per bone surface (OCs/BS) at 6 months in miR-23aCLZIP mice compared to no change in 2 months. RNA-seq and chromatin accessibility analysis from OB-specific miR-23aCLZIP mice showed a significant increase of osteogenic genes with enhanced PBAF complex and reduced PRC2 complex expression, leading to higher levels of histone H3k27 acetylation. These results highlight the novel interplay between miR-23aCL regulation, H3k27 acetylation, and gene expression in bone biology. Osteoclast-specific loss of miR-23aCL resulted in an increased trabecular bone volume, trabecular thickness, and decreased trabecular space in 2-month-old males. Interestingly, it increased all the above bone parameters in 2-month females.
Conclusions: By unraveling the complex interactions between miR-23aCL, sex hormones, epigenetic switches, and osteoclast activity, we can pave the way for innovative treatments that more effectively maintain or restore physiological bone mass and strength in a sex-specific manner.