Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis

Diabetic osteoporosis(DOP) is the leading complication continuously threatening the bone health of patients with diabetes. A key pathogenic factor in DOP is loss of osteocyte viability. However, the mechanism of osteocyte death remains unclear. Here, we identified ferroptosis, which is iron-dependent programmed cell death, as a critical mechanism of osteocyte death in murine models of DOP. The diabetic microenvironment significantly enhanced osteocyte ferroptosis in vitro, as shown by the substantial lipid peroxidation, iron overload, and aberrant activation of the ferroptosis pathway. RNA sequencing showed that heme oxygenase-1(HO-1) expression was notably upregulated in ferroptotic osteocytes. Further findings revealed that HO-1 was essential for osteocyte ferroptosis in DOP and that its promoter activity was controlled by the interaction between the upstream NRF2 and c-JUN transcription factors. Targeting ferroptosis or HO-1 efficiently rescued osteocyte death in DOP by disrupting the vicious cycle between lipid peroxidation and HO-1 activation, eventually ameliorating trabecular deterioration. Our study provides insight into DOP pathogenesis, and our results provide a mechanism-based strategy for clinical DOP treatment.

Immunomodulatory biomaterials against bacterial infections:Progress,challenges,and future perspectives

Bacterial infectious diseases are one of the leading causes of death worldwide.Even with the use of multiple antibiotic treatment strategies,4.95 million people died from drug-resistant bacterial infections in 2019.By 2050,the number of deaths will reach 10 milion annually.The increasing mortality may be partly due to bacterial heterogeneity in the infection microenvironment,such as drug-resistant bacteria,biofilms,persister cells,intracellular bacteria,and small colony variants.In addition,the complexity of the immune microenvironment at different stages of infection makes biomaterials with direct antimicrobial activity unsatisfactory for the longterm treatment of chronic bacterial infections.The increasing mortality may be partly attributed to the biomaterials failing to modulate the active antimicrobial action of immune cells.Therefore,there is an urgent need for effective alternatives to treat bacterial infections.Accordingly,the development of immunomodulatory antimicrobial biomaterials has recently received considerable interest;however,a comprehensive review of their research progress is lacking.In this review,we focus mainly on the research progress and future perspectives of immunomodulatory antimicrobial biomaterials used at different stages of infection.First,we describe the characteristics of the immune microenvironment in the acute and chronic phases of bacterial infections.Then,we highlight the immunomodulatory strategies for antimicrobial biomaterials at different stages of infection and their corresponding advantages and disadvantages.Moreover,we discuss biomaterial-mediated bacterial vaccines'potential applications and challenges for activating innate and adaptive immune memory.This review will serve as a reference for future studies to develop next-generation immunomodulatory biomaterials and accelerate their translation into clinical practice.

Kinsenoside attenuates osteoarthritis by repolarizing macrophages through inactivating NF-κB/MAPK signaling and protecting chondrocytes

The objective was to investigate the effect of kinsenoside(Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis(OA) progression.RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction(q RT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium(CM) and IL-1β were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection(ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of P65 in nuclear factor-κB(NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases(MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages,promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.

Zinc alloy-based bone internal fixation screw with antibacterial and anti-osteolytic properties

There is no targeted effective treatment for patients undergoing internal fixation surgery/two-stage total joint revision surgery with a high risk of postoperative infection and osteolysis,while the rate of reoperation due to infection and osteolysis remains high.In this study,we report a pioneering application of implants made of biodegradable Zn-Ag alloy with active antibacterial and anti-osteolytic properties in three classical animal models,illustrating antibacterial,anti-osteolysis,and internal fixation for fractures.The antibacterial activity of the Zn-2Ag alloy was verified in a rat femur osteomyelitis prevention model,while the anti-osteolytic properties were evaluated using a mouse cranial osteolysis model.Moreover,the Zn-2Ag based screws showed similar performance in bone fracture fixation compared to the Ti-6Al-4V counterpart.The fracture healed completely after 3 months in the rabbit femoral condyle fracture model.Furthermore,the underlying antibacterial mechanism may include inhibition of biofilm formation,autolysis-related pathways,and antibiotic resistance pathways.Osseointegration mechanisms may include inhibition of osteoclast-associated protein expression,no effect on osteogenic protein expression,and no activation of related inflammatory protein expression.The empirical findings here reveal the great potential of Zn-Ag-based alloys for degradable biomaterials in internal fixation surgery/two-stage total joint revision surgery for patients with a high risk of postoperative infection and osteolysis.

A 3D-bioprinted scaffold with doxycycline-controlled BMP2-expressing cells for inducing bone regeneration and inhibiting bacterial infection

Large bone defects face a high risk of pathogen exposure due to open wounds,which leads to high infection rates and delayed bone union.To promote successful repair of infectious bone defects,fabrication of a scaffold with dual functions of osteo-induction and bacterial inhibition is required.This study describes creation of an engineered progenitor cell line(C3H10T1/2)capable of doxycycline(DOX)-mediated release of bone morphogenetic protein-2(BMP2).Three-dimensional bioprinting technology enabled creation of scaffolds,comprising polycaprolactone/mesoporous bioactive glass/DOX and bioink,containing these engineered cells.In vivo and in vitro experiments confirmed that the scaffold could actively secrete BMP2 to significantly promote osteoblast differentiation and induce ectopic bone formation.Additionally,the scaffold exhibited broad-spectrum antibacterial capacity,thereby ensuring the survival of embedded engineered cells when facing high risk of infection.These findings demonstrated the efficacy of this bioprinted scaffold to release BMP2 in a controlled manner and prevent the occurrence of infection;thus,showing its potential for repairing infectious bone defects.

Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus,persisters and biofilms

Methicillin-resistant Staphylococcus aureus(MRSA),biofilms,and persisters are three major factors leading to recurrent and recalcitrant implant infections.Although antibiotics are still the primary treatment for chronic implant infections in clinical,only few drugs are effective in clearing persisters and formed biofilms.Here,felodipine,a dihydropyridine calcium channel blocker,was reported for the first time to have antibacterial effects against MRSA,biofilm,and persisters.Even after continuous exposure to sub-lethal concentrations of felodipine,bacteria are less likely to develop resistance.Besides,low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance(aacA-aphD).Next,biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters.Furthermore,the result of protein profiling,and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence(agrABC),biofilm formation and TCA cycle.Then,molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease,which could lead to substantial protein degradation.Furthermore,murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response.In conclusion,low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA,biofilm,and persisters.