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.

• Authors: Yexin Wang, Xuzhuo Chen, Xinwei Chen, Zhihang Zhou, Weifeng Xu, Feng Xu, Shanyong Zhang
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 234 Issue 7 Pg. 10432-10444 (07 2019) ISSN: 1097-4652 [Electronic] United States
• PMID: 30652303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• AZD8835
• Biomarkers
• NF-kappa B
• Oxadiazoles
• Piperidines
• RANK Ligand
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Cathepsin K

Topics

• Alveolar Bone Loss (drug therapy, metabolism)
• Animals
• Biomarkers (metabolism)
• Bone Resorption (drug therapy, metabolism)
• Cathepsin K (metabolism)
• Cell Line
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Osteoclasts (drug effects, metabolism)
• Osteogenesis (drug effects)
• Oxadiazoles (pharmacology)
• Periodontitis (drug therapy, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Piperidines (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• RANK Ligand (metabolism)
• Rats
• Signal Transduction (drug effects)