Bioinformatics analysis identification of AKT3 and RAC1 as key genes in postmenopausal osteoporosis

Abstract

Postmenopausal osteoporosis (PMO) is an aging-associated disease that manifests as degradation of bone tissue microstructure leading to decreased bone mass and increased bone fragility. Differentiation of peripheral blood mononuclear cells into osteoclasts is an important process in the development of PMO and identification of key genes that drive differentiation is essential to reveal the mechanism of PMO. The present study combined bioinformatics analysis of a Gene Expression Omnibus dataset of PMO and drug (bisphosphonate) target prediction using the STITCH database to identify hub genes in patients with PMO. Next, the expression of candidate hub genes was assessed in osteoclasts differentiated from THP-1 cells and small interfering RNA assays were performed to assess the function of selected hub genes. The present study identified 10 hub genes including WNT1, AKT3 , disheveled segment polarity protein 1, cyclin D1, H2B clustered histone 17, JUN, EGFR, RAC1 , actinin α1 (ACTN1) and ACTN2 . Among these, AKT3 and RAC1 were highly upregulated during osteoclast differentiation, and knockdown of AKT3 and RAC1 using small interfering RNA enhanced the inhibitory effect of bisphosphonates on osteoclast differentiation and apoptosis of monocytes as assessed by tartrate-resistant acid phosphatase staining and flow cytometry examining Annexin V-FITC/PI staining, respectively. In conclusion, AKT3 and RAC1 were key for development of PMO and inhibiting AKT3 and RAC1 may improve the therapeutic efficacy of bisphosphonates.

Potential therapeutic role of spermine via Rac1 in osteoporosis: Insights from zebrafish and mice

“…The zebrafish rac1 gene, also known as rac1a , belongs to the Rac family of small GTPases and plays a vital role in a variety of cellular processes, including cytoskeletal assembly ( Ding et al, 2022 ), cell development ( Tejada-Simon, 2015 ), DNA damage reparation ( Fritz & Henninger, 2015 ), cell motility, and migration ( Chan et al, 2005 ), and has thus become an attractive anti-tumor target ( Bailly et al, 2022 ; Ma et al, 2023 ). During osteoclast differentiation, Rac1 is highly up-regulated ( Zhang et al, 2022 ; Zhou et al, 2020 ) and thought to be involved in mediating the inhibition of osteoclast differentiation ( Guo et al, 2021 ), although other studies have reported different results ( Li et al, 2023a ). Rac1 is also necessary for normal osteogenic function and bone mineral density maintenance ( Huck et al, 2020 ).…”

RNA sequencing-based approaches to identifying disulfidptosis-related diagnostic clusters and immune landscapes in osteoporosis

“…As a small GTPase, RAC1 (Ras-related C3 botulinum toxin substrate 1) is upregulated to activate disulfidptosis [ 10 ]. During osteoclast differentiation, RAC1 undergoes significant upregulation; its knockdown suppresses osteoclast differentiation and monocyte apoptosis [ 34 ]. PRDX1 (peroxiredoxin 1) is a known modulator of reactive oxygen species that regulates oxidative stress and BMP signalling-driven osteogenesis [ 35 ].…”

Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use

“…ACTN1 (Alpha-Actinin-1) encodes a non-muscle cytoskeletal protein that binds actin to the cell membrane [ 54 ]. Genetic variants and differential expression of the ACTN1 have been reported in various diseases, including congenital macrothrombocytopenia, Angelman syndrome, Bowen disease, postmenopausal osteoporosis, lupus erythematosus, and COVID-19 [ 54 – 57 , 69 , 70 ]. There is evidence that cannabinoids can attenuate seizures and EEG abnormalities in Angelman syndrome [ 71 , 72 ], effective in treating individuals with osteoporosis [ 73 ], reduce cell proliferation and induce apoptosis in melanoma cells [ 74 ], as well as downregulate the immune response in lupus erythematosus [ 75 ].…”