Pharmacologic inhibitors of IκB kinase suppress growth and migration of mammary carcinosarcoma cells in vitro and prevent osteolytic bone metastasis in vivo

The NF-κB signaling pathway is known to play an important role in the regulation of osteoclastic bone resorption and cancer cell growth. Previous studies have shown that genetic inactivation of IκB kinase (IKK), a key component of NF-κB signaling, inhibits osteoclastogenesis, but the effects of pharmacologic IKK inhibitors on osteolytic bone metastasis are unknown. Here, we studied the effects of the IKK inhibitors celastrol, BMS-345541, parthenolide, and wedelolactone on the proliferation and migration of W256 cells in vitro and osteolytic bone destruction in vivo. All compounds tested inhibited the growth and induced apoptosis of W256 cells as evidenced by caspase-3 activation and nuclear morphology. Celastrol, BMS-345541, and parthenolide abolished IL1β and tumor necrosis factor α–induced IκB phosphorylation and prevented nuclear translocation of NF-κB and DNA binding. Celastrol and parthenolide but not BMS-345541 prevented the activation of both IKKα and IKKβ, and celastrol inhibited IKKα/β activation by preventing the phosphorylation of TAK1, a key receptor–associated factor upstream of IKK. Celastrol and parthenolide markedly reduced the mRNA expression of matrix metalloproteinase 9 and urinary plasminogen activator, and inhibited W256 migration. Administration of celastrol or parthenolide at a dose of 1 mg/kg/day suppressed trabecular bone loss and reduced the number and size of osteolytic bone lesions following W256 injection in rats. Histomorphometric analysis showed that both compounds decreased osteoclast number and inhibited bone resorption. In conclusion, pharmacologic inhibitors of IKK are effective in preventing osteolytic bone metastasis in this model and might represent a promising class of agents to the prevention and treatment of metastatic bone disease associated with breast cancer

Fabrication of a silver nanoparticle-coated collagen membrane with anti-bacterial and anti-inflammatory activities for guided bone regeneration

Alveolar bone loss is a common problem that affects dental implant placement. A barrier between the bone substitute and gingiva that can prevent fibro-tissue ingrowth, bacterial infection and induce bone formation is a key factor in improving the success of alveolar ridge reconstruction. This study aims to develop a bioactive collagen barrier material for guided bone regeneration, that is coupled with anti-bacterial and anti-inflammatory properties. We have evaluated two silver coating methods and found controllable and precise coating achieved by sonication compared with sputtering. The optimized AgNP-coated collagen membrane exhibited excellent anti-bacterial effects against Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) with limited cellular toxicity. It also displayed effective anti-inflammatory effects by reducing the expression and release of inflammatory cytokines including IL-6 and TNF-alpha. Additionally, AgNP-coated collagen membranes were able to induce osteogenic differentiation of mesenchymal stem cells that guide bone regeneration. These findings demonstrate the potential application of AgNP-coated collagen membranes to prevent infection after bone graft introduction in alveolar ridge reconstruction

Horizontal fissuring at the osteochondral interface: A novel and unique pathological feature in patients with obesity-related osteoarthritis

Objectives: Obesity is a well-recognised risk factor for osteoarthritis (OA). Our aim is to characterise body mass index (BMI)-associated pathological changes in the osteochondral unit and determine if obesity is the major causal antecedent of early joint replacement in patients with OA. Methods: We analysed the correlation between BMI and the age at which patients undergo total knee replacement (TKR) in 41 023 patients from the Australian Orthopaedic Association National Joint Replacement Registry. We then investigated the effect of BMI on pathological changes of the tibia plateau of knee joint in a representative subset of the registry. Results: 57.58% of patients in Australia who had TKR were obese. Patients with overweight, obese class I & II or obese class III received a TKR 1.89, 4.48 and 8.08 years earlier than patients with normal weight, respectively. Microscopic examination revealed that horizontal fissuring at the osteochondral interface was the major pathological feature of obesity-related OA. The frequency of horizontal fissure was strongly associated with increased BMI in the predominant compartment. An increase in one unit of BMI (1 kg/m2) increased the odds of horizontal fissures by 14.7%. 84.4% of the horizontal fissures were attributable to obesity. Reduced cartilage degradation and alteration of subchondral bone microstructure were also associated with increased BMI. Conclusions: The key pathological feature in OA patients with obesity is horizontal fissuring at the osteochondral unit interface. Obesity is strongly associated with a younger age of first TKR, which may be a result of horizontal fissures

Fabrication of a silver nanoparticle-coated collagen membrane with anti-bacterial and anti-inflammatory activities for guided bone regeneration

Alveolar bone loss is a common problem that affects dental implant placement. A barrier between the bone substitute and gingiva that can prevent fibro-tissue ingrowth, bacterial infection and induce bone formation is a key factor in improving the success of alveolar ridge reconstruction. This study aims to develop a bioactive collagen barrier material for guided bone regeneration, that is coupled with anti-bacterial and anti-inflammatory properties. We have evaluated two silver coating methods and found controllable and precise coating achieved by sonication compared with sputtering. The optimized AgNP-coated collagen membrane exhibited excellent anti-bacterial effects against Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) with limited cellular toxicity. It also displayed effective anti-inflammatory effects by reducing the expression and release of inflammatory cytokines including IL-6 and TNF-alpha. Additionally, AgNP-coated collagen membranes were able to induce osteogenic differentiation of mesenchymal stem cells that guide bone regeneration. These findings demonstrate the potential application of AgNP-coated collagen membranes to prevent infection after bone graft introduction in alveolar ridge reconstruction