Breast cancer metastases to bone poses a significant challenge for the administration of treatment strategies. The bone microenvironment, metastatic tumor cells, osteoclasts, and tumor-associated macrophages (TAMs) all play crucial and synergistic roles in creating a favorable environment for the proliferation, progression, and survival of the metastatic tumor, which in turn induces osteoclast-mediated bone destruction. In this study, we functionalized immunostimulatory cytosine–phosphate–guanosine (CpG)-loaded metal–organic framework (MOF) nanoparticles with bone targeting capabilities by surface modification with FDA approved antiresorptive bisphosphonate, zoledronic acid (ZOL). The functionalized bone targeting immunostimulatory MOF (BT-isMOF) nanoparticles demonstrates strong binding to calcium phosphate in vitro and exhibits specific targeting and accumulation in bone tissues in vivo. In vitro cellular and biochemical analyses demonstrated that the BT-isMOF nanoparticles could potently inhibit osteoclast formation and concomitantly induce macrophages polarization toward the M1 pro-inflammatory phenotype. Finally, using the intratibial murine model of breast cancer bone metastasis, we showed that the administration of BT-isMOF nanoparticles significantly suppressed osteoclast-mediated bone destruction and enhanced polarization of tumor-resident macrophages to M1 phenotype. Together, our data provides promising evidence for the potential therapeutic application of the BT-isMOF nanoparticles in the treatment of breast cancer bone metastases.
This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology. Postmenopausal osteoporosis (PMOP), which increases the risk of fracture, is the most common bone disease in women. PMOP not only increases the risk of death but also imposes a financial burden on countless families. At present, most of the drugs used to treat osteoporosis have significant side effects, so it is important to find effective anti-osteoporosis medications without major side effects. Sesamolin (Ses) is a kind of natural lignan extracted from sesame oil. Many researches have shown that Ses has anti-inflammatory, antioxidative, and anticancer effects, however it is still unknown whether it has any effect on osteoporosis. In this research, we explored the therapeutic effect of Ses in the process of osteoclast formation and bone resorption and found that Ses effectively inhibited osteoclast formation in vitro through TRAcP staining and hydroxyapatite resorption assays. Through Western blot analysis of the NF-κB pathway, MAPK pathway, c-Fos and NFATc1, it was found that Ses not only effectively inhibited the activation of NF-κB and MAPK signaling pathways induced by RANKL but also significantly reduced the protein expression of c-Fos and NFATc1. Several genes specifically expressed in osteoclasts were determined by qPCR, and Ses was also found to play a significant inhibitory role on the expression of these genes. Besides, an osteoporosis model induced in ovariectomized (OVX) mice was employed to verify that Ses could effectively reduce bone loss caused by estrogen deficiency in vivo. In conclusion, Ses showed promise as a new treatment for postmenopausal osteoporosis.
Aseptic prosthetic loosening and periprosthetic infection resulting in inflammatory osteolysis is a leading complication of total joint arthroplasty (TJA). Excessive bone destruction around the bone and prosthesis interface plays a key role in the loosening prostheses leading to revision surgery. The bacterial endotoxins or implant‐derived wear particles‐induced inflammatory response is the major cause of the elevated osteoclast formation and activity. Thus, agents or compounds that can attenuate the inflammatory response and/or inhibit the elevated osteoclastogenesis and excessive bone resorption would provide a promising therapeutic avenue to prevent aseptic prosthetic loosening in TJA. Daphnetin (DAP), a natural coumarin derivative, is clinically used in Traditional Chinese Medicine for the treatment of rheumatoid arthritis due to its anti‐inflammatory properties. In this study, we report for the first time that DAP could protect against lipopolysaccharide‐induced inflammatory bone destruction in a murine calvarial osteolysis model in vivo. This protective effect of DAP can in part be attributed to its direct inhibitory effect on RANKL‐induced osteoclast differentiation, fusion, and bone resorption in vitro. Biochemical analysis found that DAP inhibited the activation of the ERK and NFATc1 signaling cascades. Collectively, our findings suggest that DAP as a natural compound has potential for the treatment of inflammatory osteolysis.
Bone homeostasis only exists when the physical function of osteoblast and osteoclast stays in the balance between bone formation and resorption. Bone resorption occurs when the two processes are uncoupled, shifting the balance in favour of bone resorption. Excessive activation of osteoclasts leads to a range of osteolytic bone diseases including osteoporosis, aseptic prosthesis loosening, rheumatoid arthritis, and osteoarthritis. Receptor activator of nuclear factor kappa-B ligand (RANKL) and its downstream signaling pathways are recognized as key mediators that drive the formation and activation of osteoclastic function. Hence, osteoclast formation and/or its function remain as dominant targets for research and development of agents reaching the treatment towards osteolytic diseases. Chrysin (CHR) is a flavonoid with a wide range of anti-inflammatory and anti-tumor effects. However, its effect on osteoclasts remains unknown. In this study, we found the effects of CHR on inhibiting osteoclast differentiation which were assessed in terms of the number and size of TRAcP positive multinucleated osteoclasts (OCs). Further, the inhibitory effects of CHR on bone resorption and osteoclast fusion of pre-OC were assessed by hydroxyapatite resorption pit assay and F-actin belts staining; respectively. Western blotting analysis of RANKL-induced signaling pathways and immunofluorescence analysis for p65 nuclear translocation in response to RANKL-induced osteoclasts were used to analyze the mechanism of action of CHR affecting osteoclasts. Lastly, the murine calvarial osteolysis model revealed that CHR could protect against particle-induced bone destruction in vivo. Collectively, our data strongly suggested that CHR with its promising anti-tumor effects would also be a potential therapeutic agent for osteolytic diseases.
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