Bisphosphonate‐enoxacin inhibit osteoclast formation and function by abrogating RANKL‐induced JNK signalling pathways during osteoporosis treatment

Abstract

Osteoporosis is an age‐related disease characterized by low mineral density, compromised bone strength and increased risk of fragility fracture. Most agents for treating osteoporosis focus primarily on anti‐resorption by inhibiting osteoclast activity. Bisphosphonate (BP) is a potent anti‐resorptive agent that has been used clinically for decades and is proven to be effective. However, BP has a variety of side effects and is far from being an ideal anti‐osteoporosis agent. BP selectively binds to calcium crystals, which are subsequently taken up or released by osteoclasts. Based on the action of BP, we previously demonstrated the inhibitory effect of a novel bone‐targeting BP derivative, bisphosphonate‐enoxacin (BE). In the current study, we used bone marrow‐derived osteoclast cultures to further assess the inhibitory effect of BE on osteoclastogenesis and employed reverse transcription PCR and real‐time PCR to examine expression of osteoclast‐specific genes. Additionally, we used bone resorption and F‐actin immunofluorescence assays to evaluate the effect of BE on osteoclast function and investigated the potential mechanisms affecting osteoclast differentiation and function in vitro. Furthermore, an ovariectomized (OVX) rat model was established to evaluate the therapeutic effects of BE on preventing bone loss. Results showed that BE exerted potent inhibitory effects on osteoclast formation and bone resorption by specifically abrogating RANKL‐induced JNK signalling, and that it preserved OVX rat bone mass in vivo without any notable side effects. Collectively, these results indicated that the BP derivative BE may have significant potential as a treatment for osteoporosis and other osteolytic diseases.

Cilengitide inhibits osteoclast adhesion through blocking the αvβ3-mediated FAK/Src signaling pathway

“…To detect differential gene expression, a real-time quantitative RT-PCR system (QuantStudio 3, ThermoFisher, Waltham, USA) was employed. The sequences of the primers employed are presented in Table 1 [ 27 , 28 ].…”

In vivo and in vitro analysis in a rat model using zoledronate and alendronate medication: microbiological and scanning electron microscopy findings on peri-implant rat tissue

“…With regard to the reduced activity of osteoclasts in our test groups, the results were in agreement with the literature. Bisphosphonates show signs of lower osteoclast activity [ 41 , 42 ]. Furthermore, medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy specimens had considerably more osteoclasts in terms of quantity, diameter, and nuclearity than the control specimens [ 43 ].…”

The New Face of a Well-Known Antibiotic: A Review of the Anticancer Activity of Enoxacin and Its Derivatives

“…Interestingly, the introduction of a bisphosphonate moiety increased the bone binding affinity [102]. Another confirmed mechanism of osteoclast formation was the interference of the JNK pathway in a rat model [103]. However, unlike ENX, its derivative increased the caspase 3 activity in osteoclast-like cells [82].…”