Odanacatib, A Cathepsin K‐Specific Inhibitor, Inhibits Inflammation and Bone Loss Caused by Periodontal Diseases

Abstract

Background Periodontitis is a bacteria-induced inflammatory disease mainly affecting periodontal tissues, leading to periodontal inflammation, bone breakdown, and loss of the tooth. The main obstacle for treating periodontitis effectively is the difficulty in finding a target that can inhibit bone loss and inflammation simultaneously. Recent studies showed that cathepsin K (CTSK) might have functions in the immune system besides its role in osteoclasts. Thus, targeting CTSK would have a potential therapeutic effect in both the bone system and the immune system during the progression of periodontitis. Methods In the current study, a small molecular inhibitor (odanacatib [ODN]) is explored to inhibit the function of CTSK in a bacteria-induced periodontitis mouse model. Results The application of ODN decreased the number of osteoclasts, macrophages, and T cells, as well as the expression of Toll-like receptors (TLRs) in the periodontitis lesion area. Furthermore, lack of CTSK inhibited the expression of TLR4, TLR5, and TLR9 and their downstream cytokine signaling in the gingival epithelial cells in periodontitis lesions, demonstrating that the innate immune response was inhibited in periodontitis. Conclusion The present results show that inhibition of CTSK can prevent bone loss and the immune response during the progression of periodontitis, indicating that CTSK is a promising target for treating inflammatory diseases such as periodontitis by affecting both osteoclasts and the immune system.

Aminothiazoles inhibit RANKL‐ and LPS‐mediated osteoclastogenesis and PGE2 production in RAW 264.7 cells

“…This suggestion is further supported by Hao et al . reporting that inhibition of CTSK may reduce both osteoclast function and inflammation in a mouse model of experimental periodontitis .…”

Inhibition of angiotensin II receptor I prevents inflammation and bone loss in periodontitis

“…The strain was grown in anaerobic conditions (80% N 2 , 10% H 2 , and 10% CO 2 ) at 37°C in an anaerobic chamber (Coy Laboratory Products, Grass Lake, MI) . An equal volume of sterile 2% (w/v) carboxymethylcellulose (CMC) (Invitrogen, Thermo Fisher Scientific, Nazareth, PA) was added to the bacteria and mixed thoroughly; 100 ul (5 × 10 9 cells P. gingivalis per ml) was administered by oral and anal topical application to induce periodontitis as previously described …”

The effect of cathepsin K inhibitor surface treatment on delayed tooth replantation in dogs

“…This may be caused by the invasion of bacteria into the dentinal tubules or the PDL space through the gingival pocket in the early healing period, or injury of the root due to the action of the surgical forceps. Other in vivo studies investigating the effect of ODN in the field of dentistry, although not concerned with replantation of avulsed teeth, administered ODN orally and periodically, 17,26 or injected it into the periodontium every 3 days. 24 Other anti-osteoporotic drugs, such as alendronate and zoledronate-nitrogen-containing bisphosphonates that have been shown to exhibit preventive effects against root resorption after topical application in animal studies-maintain their pharmacological activity over a long period because of their high binding affinity to bone.…”