AZD8835 inhibits osteoclastogenesis and periodontitis‐induced alveolar bone loss in rats

Abstract

Chronic periodontitis (CP) is one of the most common oral diseases, which is characterized by the loss of connective tissue and alveolar bone in adults. AZD8835, a novel dual phosphoinositide‐3‐kinase (PI3K) inhibitor, is currently in phase 1 clinical evaluation to treat breast cancer. However, whether AZD8835 has any effect on teeth and alveolar bone health remains unclear. In the current study, we aimed to investigate the potential effect of AZD8835 in treating CP in vitro and in vivo. We found that AZD8835 could inhibit osteoclast differentiation, bone resorption, and downregulate the expression of osteoclast marker genes, such as tartrate‐resistant acid phosphatase (Trap), cathepsin K (Ctsk), V‐ATPase d2 (Atp6v0d2), and calcitonin receptor (Ctr). In addition, AZD8835 suppressed osteoclastogenesis by inhibiting receptor activator of nuclear factor kappa B ligand (RANKL)‐induced PI3K/protein kinase B (AKT), extracellular signal‐regulated kinase, and nuclear factor‐κB signaling in BMMs. In vivo, AZD8835 greatly ameliorated alveolar bone (ABL) loss in rats with CP. Meanwhile, histological examination showed fewer osteoclasts in the treatment group. In conclusion, these results indicated that AZD8835 is a promising agent to reduce ABL in CP.

Porphyromonas gingivalis Outer Membrane Vesicles Promote Apoptosis via msRNA-Regulated DNA Methylation in Periodontitis

“…The Gram-negative anaerobic bacterium P. gingivalis has been considered the keystone pathogen in periodontitis ( 6 ). Recent findings have suggested P. gingivalis plays an essential role in systemic diseases, such as cardiovascular diseases, rheumatoid arthritis, diabetes, pregnancy problems, Alzheimer’s disease, and insulin resistance ( 35 – 38 ). Henceforth, it is imperative to form a deeper understanding of the mechanism of P. gingivalis in periodontitis.…”

Dlk2 interacts with Syap1 to activate Akt signaling pathway during osteoclast formation

“…RANKL treatment facilitated the phosphorylation of GSK3β and induced its interaction and co-localization with heterogeneous nuclear ribonucleoprotein K (hnRNPK), leading to enhanced NFATc1 expression and osteoclast formation [ 42 , 43 ]. Inhibition of Akt by PI3K inhibitors results in deficient osteoclast formation and protects mice from osteolytic bone loss [ 44 , 45 ]. A previous study reported that Syap1 was induced by mTORC2 and facilitated the interaction between Syap1 and Akt1 [ 35 ].…”

Dominoes with interlocking consequences triggered by zinc: Involvement of microelement- stimulated MSC-derived small extracellular vesicles in senile osteogenesis and osteoclast dialogue

“…BMMs were prepared for osteoclast culture as previously described [34]. Brie y, primary BMMs were isolated immediately from the femurs and tibias of C57BL/6 mice.…”