PF-3845, a Fatty Acid Amide Hydrolase Inhibitor, Directly Suppresses Osteoclastogenesis through ERK and NF-κB Pathways In Vitro and Alveolar Bone Loss In Vivo.

Abstract

Alveolar bone loss, the major feature of periodontitis, results from the activation of osteoclasts, which can consequently cause teeth to become loose and fall out; the development of drugs capable of suppressing excessive osteoclast differentiation and function is beneficial for periodontal disease patients. Given the difficulties associated with drug discovery, drug repurposing is an efficient approach for identifying alternative uses of commercially available compounds. Here, we examined the effects of PF-3845, a selective fatty acid amide hydrolase (FAAH) inhibitor, on receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclastogenesis, its function, and the therapeutic potential for the treatment of alveolar bone destruction in experimental periodontitis. PF-3845 significantly suppressed osteoclast differentiation and decreased the induction of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific markers. Actin ring formation and osteoclastic bone resorption were also reduced by PF-3845, and the anti-osteoclastogenic and anti-resorptive activities were mediated by the suppression of phosphorylation of rapidly accelerated fibrosarcoma (RAF), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase, (ERK) and nuclear factor κB (NF-κB) inhibitor (IκBα). Furthermore, the administration of PF-3845 decreased the number of osteoclasts and the amount of alveolar bone destruction caused by ligature placement in experimental periodontitis in vivo. The present study provides evidence that PF-3845 is able to suppress osteoclastogenesis and prevent alveolar bone loss, and may give new insights into its role as a treatment for osteoclast-related diseases.

• Authors: Hye-Jung Ihn, Yi-Seul Kim, Soomin Lim, Jong-Sup Bae, Jae-Chang Jung, Yeo-Hyang Kim, Jin-Woo Park, Zhao Wang, Jeong-Tae Koh, Yong-Chul Bae, Moon-Chang Baek, Eui-Kyun Park
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 4 (Feb 15 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33671948 (Publication Type: Journal Article)

Chemical References

• NF-kappa B
• PF 3845
• Piperidines
• Pyridines
• RANK Ligand
• Tnfsf11 protein, mouse
• Amidohydrolases
• fatty-acid amide hydrolase

Topics

• Alveolar Bone Loss (drug therapy)
• Amidohydrolases (antagonists & inhibitors)
• Animals
• Bone Resorption (drug therapy)
• Cells, Cultured
• Disease Models, Animal
• MAP Kinase Signaling System (drug effects)
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Osteoclasts (metabolism)
• Osteogenesis (drug effects)
• Periodontitis (drug therapy)
• Piperidines (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• RANK Ligand (metabolism)
• Treatment Outcome