curcumin and Osteolysis

Curcumin could inhibit periprosthetic osteolysis induced by wear debris and adherent endotoxin, which commonly cause prosthesis loosening and negatively influence the long-term survival of joint arthroplasty. However, its limited water solubility and poor stability pose challenges for its further clinical application. To address these issues, we developed curcumin liposomes for intraarticular injection, as liposomes possess good lubricant capacity and pharmacological synergy with curcumin. Additionally, a nanocrystal dosage form was prepared to enable comparison with the liposomes based on their ability to disperse curcumin effectively. A microfluidic method was used for its controllability, repeatability, and scalability. The Box-Behnken Design was employed to screen the formulations and flow parameters, while computational fluid dynamics was used to simulate the mixing process and predict the formation of liposomes. The optimized curcumin liposomes (Cur-LPs) had a size of 132.9 nm and an encapsulation efficiency of 97.1%, whereas the curcumin nanocrystals (Cur-NCs) had a size of 172.3 nm. Both Cur-LPs and Cur-NCs inhibited LPS-induced pro-inflammatory polarization of macrophages and reduced the expression and secretion of inflammatory factors. The mouse air pouch model further demonstrated that both dosage forms attenuated inflammatory cell infiltration and inflammatory fibrosis in subcutaneous tissues. Interestingly, the anti-inflammatory effect of Cur-LPs was more potent than that of Cur-NCs, both in vitro and in vivo, although the cellular uptake of Cur-NCs was quicker. In conclusion, the results demonstrate that Cur-LPs have great potential for the clinical treatment of inflammatory osteolysis and that the therapeutic effect is closely related to the liposomal dosage form.

Topics: Animals; Curcumin; Lipopolysaccharides; Liposomes; Mice; Nanoparticles; Osteolysis

Wear particle-stimulated inflammatory bone destruction and the consequent aseptic loosening remain the primary causes of artificial prosthesis failure and revision. Previous studies have demonstrated that curcumin has a protective effect on bone disorders and inflammatory diseases and can ameliorate polymethylmethacrylate-induced osteolysis in vivo. However, the effect on immunomodulation and the definitive mechanism by which curcumin reduces the receptor activators of nuclear factor-kappa B ligand (RANKL)-stimulated osteoclast formation and prevents the activation of osteoclastic signalling pathways are unclear. In this work, the immunomodulation effect and anti-osteoclastogenesis capacities exerted by curcumin on titanium nanoparticle-stimulated macrophage polarization and on RANKL-mediated osteoclast activation and differentiation in osteoclastic precursor cells in vitro were investigated. As expected, curcumin inhibited RANKL-stimulated osteoclast maturation and formation and had an immunomodulatory effect on macrophage polarization in vitro. Furthermore, studies aimed to identify the potential molecular and cellular mechanisms revealed that this protective effect of curcumin on osteoclastogenesis occurred through the amelioration of the activation of Akt/NF-κB/NFATc1 pathways. Additionally, an in vivo mouse calvarial bone destruction model further confirmed that curcumin ameliorated the severity of titanium nanoparticle-stimulated bone loss and destruction. Our results conclusively indicated that curcumin, a major biologic component of Curcuma longa with anti-inflammatory and immunomodulatory properties, may serve as a potential therapeutic agent for osteoclastic diseases.

Topics: Actins; Animals; Bone Resorption; Cell Death; Cell Differentiation; Cell Polarity; Curcumin; Cytokines; Immunomodulation; Macrophages; Male; Mice; Mice, Inbred C57BL; Models, Biological; Nanoparticles; NF-kappa B; Osteoclasts; Osteogenesis; Osteolysis; Phosphorylation; Protective Agents; Proto-Oncogene Proteins c-akt; RANK Ligand; RAW 264.7 Cells; Signal Transduction; Titanium; Up-Regulation

Curcumin prevents bone loss in resorptive bone diseases and inhibits osteoclast formation, a key process driving bone loss. Curcumin circulates as an inactive glucuronide that can be deconjugated in situ by bone's high β-glucuronidase (GUSB) content, forming the active aglycone. Because curcumin is a common remedy for musculoskeletal disease, effects of microenvironmental changes consequent to skeletal development or disease on bone curcumin metabolism are explored.. Across sexual/skeletal development or between sexes in C57BL/6 mice ingesting curcumin (500 mg kg. Dietary polyphenols circulating as glucuronides may require in situ deconjugation for bone-protective effects, a process influenced by bone microenvironmental changes.

Topics: Aging; Animals; Bone and Bones; Bone Neoplasms; Curcumin; Female; Glucuronidase; Glucuronides; Male; Mice, Inbred C57BL; Osteogenesis; Osteolysis; Osteoporosis; Ovariectomy; Polyphenols; Quercetin

BACKGROUND Periprosthetic osteolysis, induced by wear particles and inflammation, is a common reason for failure of primary arthroplasty. Curcumin, a nature phenol from plants, has been reported to reduce the inflammation in macrophages. This study aimed to investigate the potential effect of curcumin on macrophage involved, wear particle-induced osteolysis and its mechanism. MATERIAL AND METHODS RAW264.7 macrophages were used to test the effects of polyethylene (PE) particles and curcumin on macrophage cholesterol efflux and phenotypic changes. A mouse model of PE particle-induced calvarial osteolysis was established to test the effects of curcumin in vivo. After 14 days of treatment, the bone quality of the affected areas was analyzed by micro-computed tomography (micro-CT) and histology, and the bone surrounding soft tissues were analyzed at the cellular and molecular levels. RESULTS We found that PE particles can stimulate osteoclastogenesis and produce an M1-like phenotype in macrophages in vitro. Curcumin enhanced the cholesterol efflux in macrophages, and maintained the M0-like phenotype under the influence of PE particles in vitro. Additionally, the cholesterol transmembrane regulators ABCA1, ABCG1, and CAV1 were enhanced by curcumin in vivo. We also found enhanced bone density, reduced osteoclastogenesis, and fewer inflammatory responses in the curcumin treated groups in our mouse osteolysis model. CONCLUSIONS Our study findings indicated that curcumin can inhibit macrophage involved osteolysis and inflammation via promoting cholesterol efflux. Maintaining the cholesterol efflux might be a potential strategy to prevent periprosthetic osteolysis after total joint arthroplasty surgery.

Topics: Animals; Curcumin; Disease Models, Animal; Inflammation; Joint Prosthesis; Macrophages; Male; Mice; Mice, Inbred BALB C; Osteoclasts; Osteolysis; Polyethylene; Prosthesis Failure; RAW 264.7 Cells; Skull; X-Ray Microtomography

Aseptic loosening is a common reason for failed artificial hip replacement after total hip arthroplasty. Aseptic loosening is mostly the result of wear debris that causes osteolysis and weakens the structures that support the prosthesis. Wear debris plays a crucial role in osteolysis during the loosening process, and polyethylene (PE) particles are found as wear debris more frequently than any other type of particle. In the absence of effective therapeutic agents, osteolysis has been hard to treat. Previous studies have demonstrated that curcumin influences signalosome-associated kinases and the proteasome-ubiquitin system during osteoclastogenesis. The aims of this study were to explore the anti-osteolysis effect of curcumin and if possible to identify the signaling pathway involved in a model of PE-induced osteolysis.. Differentiation of osteoclasts was induced in vitro by PE particles in RAW264.7 (monocyte/macrophage) cells and in vivo by calvarial and air pouch models of osteolysis established by PE stimulation in mice. We performed a set of TRAP staining, realtime polymerase chain reaction (PCR), and Western blot experiments to evaluate the anti-osteolytic effect of curcumin by comparing specimens that were exposed and not exposed to curcumin.. Curcumin had a promising inhibitory effect on osteolysis induced by wear debris and suppressed the RANK/c-Fos/NFATc1 signaling pathway.. Curcumin can prevent PE-induced osteolysis and bone loss. An inhibitory effect on the RANK/c-Fos/NFATc1 signaling pathway may explain the anti-osteolysis activity of curcumin.

Topics: Animals; Cell Differentiation; Curcumin; I-kappa B Kinase; Male; Mice; Mice, Inbred BALB C; NF-kappa B; NFATC Transcription Factors; Osteoclasts; Osteolysis; Polyethylene; Proto-Oncogene Proteins c-fos; RANK Ligand; RAW 264.7 Cells; Signal Transduction; Skull; X-Ray Microtomography

Effects of curcuminoids on breast cancer cell secretion of the bone-resorptive peptide parathyroid hormone-related protein (PTHrP) and on lytic breast cancer bone metastasis were evaluated. In vitro, transforming growth factor (TGF)-β-stimulated PTHrP secretion was inhibited by curcuminoids (IC50 = 24 μM) in MDA-MB-231 human breast cancer cells independent of effects on cell growth inhibition. Effects on TGF-β signaling revealed decreases in phospho-Smad2/3 and Ets-1 protein levels with no effect on p-38 MAPK-mediated TGF-β signaling. In vivo, mice were inoculated with MDA-MB-231 cells into the left cardiac ventricle and treated ip every other day with curcuminoids (25 or 50 mg/kg) for 21 days. Osteolytic bone lesion area was reduced up to 51% (p < 0.01). Consistent with specific effects on bone osteolysis, osteoclast number at the bone-tumor interface was reduced up to 53% (p < 0.05), while tumor area within bone was unaltered. In a separate study, tumor mass in orthotopic mammary xenografts was also unaltered by treatment. These data suggest that curcuminoids prevent TGF-β induction of PTHrP and reduce osteolytic bone destruction by blockade of Smad signaling in breast cancer cells.

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Curcumin; Disease Models, Animal; Female; Humans; Mice; Molecular Structure; Osteolysis; Parathyroid Hormone-Related Protein; Signal Transduction; Transforming Growth Factor beta