Activation of AKT1 enhances the capacity of senescent BMSCs to regulate osteoclast activation

Senescent bone mesenchymal stromal cells (BMSCs) play an essential role in bone homeostasis imbalance in osteoporosis; however, the mechanisms through which they regulate osteoclast activation remain unclear. In the present study, highly expressed genes in BMSCs from patients with osteoporosis group were screened using transcriptomic data from the GSE35959 dataset. Subsequently, the AKT1, MAPK3, RELA and colony stimulating factor 1 genes were found to be linked to the PI3K/AKT and MAPK signaling pathways and osteoclast differentiation following Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Principal component analysis revealed a distinct clustering of samples by age and disease status. Gene Set Enrichment Analysis further identified significant enrichment of the PI3K/AKT signaling pathway in osteoporosis progression. Considering the notable involvement of the PI3K/AKT signaling pathway in various cellular ageing processes, AKT1 was prioritized for further investigation. Analysis of a replicative ageing model of mouse BMSCs showed that AKT1 protein expression was increased in senescent BMSCs and that overexpression of AKT1 accelerated the initiation of replicative senescence in this model. Finally, the expression levels of osteoclast differentiation markers (receptor activator of nuclear factor κB, nuclear factor of activated T cells, cytoplasmic 1 and tumor necrosis factor receptor-associated factor 6) were assessed using tartrate-resistant acid phosphatase staining. The results from the present study suggested that AKT1 plays a role in fostering the replicative senescence of BMSCs and that AKT1 activation in senescent BMSCs contributes to osteoclast differentiation. To the best of the authors' knowledge, the present study is the first to demonstrate that AKT1 upregulation in BMSCs with replicative ageing exacerbates senescence and enhances osteoclast differentiation, offering a novel mechanistic insight into senile osteoporosis.