Background and Purpose Recent evidence suggests that postmenopausal
osteoporosis is associated with increased bone resorption function in
osteoclasts, of which Cathepsin K is a key molecule. In this study, we
aimed to screen small molecule compounds targeting Cathepsin K and
evaluate whether they affect osteoclast bone resorption function.
Experimental Approach We screened out the small-molecule compound
NVP-BHG712 targeting CTSK by molecular docking, and studied its
pharmacological effect on bone resorption function of osteoclasts. To
this end, we evaluated bone mass changes in postmenopausal mice by μCT,
ELISA, and H&E staining. In addition, we also investigated the effects
of NVP-BHG712 on osteoclast differentiation, bone resorption function
and expression of osteoclast differentiation related factors in vitro.
Key Results Surprisingly, we found that oral NVP-BHG712 treatment
significantly reduced bone loss in postmenopausal mice. In vitro
osteoclast culture, it was found that this effect was achieved by
inhibiting osteoclast differentiation and bone resorption. Meanwhile,
NVP-BHG712 significantly decreased the expression of genes related to
osteoclast differentiation, including CTSK, MMP9, CTR, IP3R1, IP3R3, and
OC-STAMP. Conclusion and Implications The present findings suggest that
NVP-BHG712 reduces bone resorption function by inhibiting osteoclast
differentiation, and is a potential drug for preventing and treating
postmenopausal osteoporosis and other diseases.