There is convincing evidence that particles produced by the wear of joint prostheses are causal in the periprosthetic loss of bone,or osteolysis,which,if it progresses,leads to the phenomenon of aseptic loosening.It i...There is convincing evidence that particles produced by the wear of joint prostheses are causal in the periprosthetic loss of bone,or osteolysis,which,if it progresses,leads to the phenomenon of aseptic loosening.It is important to fully understand the biology of this bone loss because it threatens prosthesis survival,and loosened implants can result in peri-prosthetic fracture,which is disastrous for the patient and presents a difficult surgical scenario.The focus of this review is the bioactivity of polyethylene(PE)particles,since there is evidence that these are major players in the development and progression of osteolysis around prostheses which use PE as the bearing surface.The review describes the biological consequences of interaction of PE particles with macrophages,osteoclasts and cells of the osteoblast lineage,including osteocytes.It explores the possible cellular mechanisms of action of PE and seeks to use the findings to date to propose potential nonsurgical treatments for osteolysis.In particular,a nonsurgical approach is likely to be applicable to implants containing newer,highly cross-linked PEs(HXLPEs),for which osteolysis seems to occur with much reduced PE wear compared with conventional PEs.The caveat here is that we know little as yet about the bioactivity of HXLPE particles and addressing this constitutes our next challenge.展开更多
BACKGROUND Among the various complications associated with total hip arthroplasty(THA)periprosthetic osteolysis and wear phenomena due to the release of metal particles,are two of the most common and have been reporte...BACKGROUND Among the various complications associated with total hip arthroplasty(THA)periprosthetic osteolysis and wear phenomena due to the release of metal particles,are two of the most common and have been reported to be correlated because of inflammatory responses directed towards released particles that generally activate macrophagic osteolytic effects.Therein,new masses known as pseudotumors can appear in soft tissues around a prosthetic implant.To date,there is paucity of reliable data from studies investigating for any association between the above mentioned adverse events.AIM To investigate for the existence of any association between serum and urine concentrations of metal-ions released in THA and periprosthetic osteolysis for modular neck and monolithic implants.METHODS Overall,76 patients were divided into three groups according to the type of hip prosthesis implants:Monoblock,modular with metal head and modular with ceramic head.With an average f-up of 4 years,we conducted a radiological evaluation in order to detect any area of osteolysis around the prosthesis of both the femur and the acetabulum.Moreover,serum and urinary tests were performed to assess the values of Chromium and Cobalt released.Statistical analysis was performed to determine any association between the ion release and osteolysis.RESULTS For the 3 study groups,the monolithic,modular ceramic-headed and modular metal-headed implants had different incidences of osteolysis events,which were higher for the modular implants.Furthermore,the most serious of these(grade 3)were detected almost exclusively for the modular implants with metal heads.A mapping of the affected areas was performed revealing that the highest incidences of osteolysis were evidenced in the pertrochanteric region at the femur level,and in the supero-external region at the acetabular level.Regarding the evaluation of the release of metals-ions from wear processes,serum and urinary chromium and cobalt values were found to be higher in cases of modularity,and even more so for those with metal head.Statistical linear correlation test results suggested positive correlations between increasing metal concentrations and incidences areas of osteolysis.However,no cases of pseudo-tumor were detected.CONCLUSION Future studies are needed to identify risk factors that increase peri-prosthetic metal ion levels and whether these factors might be implicated in the triggering of local events,including osteolysis and aseptic loosening.展开更多
Extensive macrophage inflammatory responses and osteoclast formation are predominant during inflammatory or infective osteolysis.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(MSC-sEV)have been shown ...Extensive macrophage inflammatory responses and osteoclast formation are predominant during inflammatory or infective osteolysis.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(MSC-sEV)have been shown to exert therapeutic effects on bone defects.However,cultured MSCs are typically exposed to normoxia(21%O2)in vitro,which differs largely from the oxygen concentration in vivo under hypoxic conditions.It is largely unknown whether sEV derived from dental pulp stem cells(DPSCs)cultured under hypoxic conditions(Hypo-sEV)exert better therapeutic effects on lipopolysaccharide(LPS)-induced inflammatory osteolysis than those cultured under normoxic conditions(Nor-sEV)by simultaneously inhibiting the macrophage inflammatory response and osteoclastogenesis.In this study,we show that hypoxia significantly induces the release of sEV from DPSCs.Moreover,Hypo-sEV exhibit significantly improved efficacy in promoting M2 macrophage polarization and suppressing osteoclast formation to alleviate LPS-induced inflammatory calvarial bone loss compared with Nor-sEV.Mechanistically,hypoxia preconditioning markedly alters the miRNA profiles of DPSC-sEV.MiR-210-3p is enriched in Hypo-sEV,and can simultaneously induce M2 macrophage generation and inhibit osteoclastogenesis by targeting NF-κB1 p105,which attenuates osteolysis.Our study suggests a promising potential for hypoxia-induced DPSC-sEV to treat inflammatory or infective osteolysis and identifies a novel role of miR-210-3p in concurrently hindering osteoclastogenesis and macrophage inflammatory response by inhibiting NF-kB1 expression.展开更多
Aseptic prosthesis loosening(APL)is one of the most prevalent complications associated with arthroplasty.The main cause is the periprosthetic osteolysis induced by wear particles.However,the specific mechanisms of cro...Aseptic prosthesis loosening(APL)is one of the most prevalent complications associated with arthroplasty.The main cause is the periprosthetic osteolysis induced by wear particles.However,the specific mechanisms of crosstalk between immune cells and osteoclasts/osteoblasts during osteolysis are unclear.In this study,we report the role and mechanism of macrophage-derived exosomes in wear particle-induced osteolysis.The results of exosomes up-taken experiments revealed that osteoblast and mature osteoclasts capture macrophage-derived exosomes(M-Exo).Next-generation sequencing and RT-qPCR on M-Exo revealed that exosomal microRNA miR-3470b was downregulated in wear particle-induced osteolysis.The results of analysis on Luciferase reporter assays/fluorescence in situ hybridization(FISH)/immunofluorescence(IF)/immunohistochemistry(IHC)and co-culture experiments demonstrated that wear particles induced osteoclast differentiation by increasing the expression of NFatc1 via M-Exo miR-3470b targeting TAB3/NF-κB signaling.We also illustrate that engineered exosomes enriching miR-3470b facilitated to suppressed the osteolysis;the microenvironment enriching with miR-3470b could suppress wear particle-induced osteolysis via inhibition of TAB3/NF-κB in vivo.In summary,our findings indicate that macrophage-derived exosomes transfer to osteoclasts to induce osteolysis in wear particle-induced APL.Engineering exosomes enriching with miR-3470b might be a novel strategy for the targeting treatment of bone resorption-related diseases.展开更多
Joint replacement surgery is one of the orthopedic surgeries with high successful rates;however,wear debris generated from prostheses can ultimately lead to periprosthetic osteolysis and failure of the implant.The imp...Joint replacement surgery is one of the orthopedic surgeries with high successful rates;however,wear debris generated from prostheses can ultimately lead to periprosthetic osteolysis and failure of the implant.The implant-derived particulate debris such as ultrahigh molecular weight polyethylene(UHMWPE)can initiate the local immune response and recruit monocytic cells to phagocytose particles for generating reactive oxygen species(ROS).ROS induces osteoclastogenesis and macrophages to secrete cytokines which ultimately promote the development of osteolysis.In this work,we develop the few-layered Nb_(2)C(FNC)as an antioxidant which possesses the feature of decreasing the production of cytokines and inhibiting osteoclastogenesis by its ROS adsorption.Moreover,local injection of FNC attenuates the UHMWPE-induced osteolysis in a mouse calvarial model.In sum,our results suggest that FNC can be used for treating osteolytic bone disease caused by excessive osteoclastogenesis.展开更多
Background:Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty.Up to now,there is no effective treatment for wear particles-induced osteolysis except for the revision sur...Background:Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty.Up to now,there is no effective treatment for wear particles-induced osteolysis except for the revision surgery,which is a heavy psychological and economic burden to patients.A metabolite of gut microbiota,short chain fatty acids(SCFAs),has been reported to be beneficial for many chronic inflammatory diseases.This study aimed to investigate the therapeutic effect of SCFAs on osteolysis.Methods:A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium.After two weeks of intervention,the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by micro-CT analysis and immunohistochemistry staining.In vitro study,lipopolysaccharide(LPS)primed bone marrow-derived macrophages(BMDMs)and Tohoku hospital pediatrics-1(THP-1)macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate(C2),propionate(C3),and butyrate(C4).Western blotting,enzyme-linked immunosorbent assay,and immunofluorescence were used to detect the activation of NLRP3 inflammasome.The effects of SCFAs on osteoclasts were evaluate by qRT-PCR,Western blotting,immunofluorescence,and tartrate-resistant acid phosphatase(TRAP)staining.Additionally,histone deacetylase(HDAC)inhibitors,agonists of GPR41,GPR43,and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis.Results:C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits(P<0.001),higher level of bone volume to tissue volume(BV/TV,P<0.001),bone mineral density(BMD,P<0.001),and a lower total porosity(P<0.001).C3 and C4 prevented CoCrMo alloy particles-induced ASC speck formation and nucleationinduced oligomerization,suppressing the cleavage of caspase-1(P<0.05)and IL-1β(P<0.05)stimulated by CoCrMo alloy particles.C3 and C4 also inhibited the generation of gasdermin D-N-terminal fragment(GSDMD-NT)to regulate pyroptosis.Besides,C3 and C4 have a negative impact on osteoclast differentiation(P<0.05)and its function(P<0.05),affecting the podosome arrangement and morphologically normal podosome belts formation.Conclusions:Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.展开更多
Background: The Buechel-Pappas (BP) meniscal bearing total ankle replace-ment was initially developed as a “shallow-sulcus” talar component device using cobalt-chromium-molybdenum alloy, in 1978, and later, modified...Background: The Buechel-Pappas (BP) meniscal bearing total ankle replace-ment was initially developed as a “shallow-sulcus” talar component device using cobalt-chromium-molybdenum alloy, in 1978, and later, modified to a “deep-sulcus” talar component device using titanium nitride (TiN) ceramic and porous coating in 1989. Wear related osteolytic cysts were noted in the tibia and talus surrounding these devices that compromised long term fixation and stability when using standard ultra-high molecular weight polyethylene (UHMWPe) as a bearing material. This study explores the use of highly cross-linked UHMWPe (HXLPe) to minimize osteolysis by replacing standard UHMWPe with this more wear-resistant material. Methods: There were 12 primary and 8 revision total ankle replacements followed for 13 to 15 years. HXLPe was used in all meniscal bearings, either as primary or revision implants. All stable metallic tibial and talar components were retained in revision cases. Osteolytic cysts greater than 10 mm in diameter were bone grafted with homologous morselized banked bone through cortical windows in the tibia or talus. No adjuvant screw fixation was used to stabilize any metallic implant. Results: No HXLPe bearings failed in this study, and no re-revisions were performed. No primary total ankle replacement failed in this study, and there were no substantial osteolytic cysts (>2 mm) observed in primary total ankle replacements on plain X-rays. All bone grafted osteolytic cysts in revision ankle replacements remained stable, even though partial resorption of the grafted material was identified in most of the ankles. No loosening of porous coated and TiN coated tibial and talar components were seen;the longest surviving metal components in the revision group was 24 years with the revised bearing at 15 years. Conclusions: HXLPe has greatly improved wear resistance in meniscal-bearing BP total ankle replacements in both primary and revision arthroplasties. Osteolytic cysts can be successfully bone grafted during bearing exchange revisions. Primary and revision, cementless BP metallic total ankle components have remained well-fixed to bone in the long term (greater than 20 years), without the use of adjuvant screw fixation.展开更多
Joint arthroplasty had revolutionized the outcome of orthopaedic surgery. Extensive and collaborative work of many innovator surgeons had led to the development of durable bearing surfaces, yet no single material is c...Joint arthroplasty had revolutionized the outcome of orthopaedic surgery. Extensive and collaborative work of many innovator surgeons had led to the development of durable bearing surfaces, yet no single material is considered absolutely perfect. Generation of wear debris from any part of the prosthesis is unavoidable. Implant loosening secondary to osteolysis is the most common mode of failure of arthroplasty. Osteolysis is the resultant of complex contribution of the generated wear debris and the mechanical instability of the prosthetic components. Roughly speaking, all orthopedic biomaterials may induce a universal biologic hostresponse to generated wear débris with little specific characteristics for each material; but some debris has been shown to be more cytotoxic than others. Prosthetic wear debris induces an extensive biological cascade of adverse cellular responses, where macrophages are the main cellular type involved in this hostile inflammatory process. Macrophages cause osteolysis indirectly by releasing numerous chemotactic inflammatory mediators, and directly by resorbing bone with their membrane microstructures. The bio-reactivity of wear particles depends on two major elements: particle characteristics(size, concentration and composition) and host characteristics. While any particle type may enhance hostile cellular reaction, cytological examination demonstrated that more than 70% of the debris burden is constituted of polyethylene particles. Comprehensive understanding of the intricate process of osteolysis is of utmost importance for future development of therapeutic modalities that may delay or prevent the disease progression.展开更多
BACKGROUND Primary bone lymphoma(PBL)is an uncommon extranodal disease that represents approximately 1%-3%of lymphomas.Anaplastic lymphoma kinase(ALK)positive anaplastic large-cell lymphoma(ALCL)is an extremely rare t...BACKGROUND Primary bone lymphoma(PBL)is an uncommon extranodal disease that represents approximately 1%-3%of lymphomas.Anaplastic lymphoma kinase(ALK)positive anaplastic large-cell lymphoma(ALCL)is an extremely rare type of PBL.The aim of this report is describe the symptoms,diagnosis,and treatment of primary bone ALK-positive ALCL.CASE SUMMARY A 66-year-old man presented to our hospital with neck and shoulder pain and intermittent fever that lasted for 1 mo.After extensive evaluation,positron emission tomography-computed tomography(CT)examination showed multiple osteolytic bone lesions without other sites lesions.CT-guided biopsy of the T10 vertebral body was performed,and the pathology results showed that neoplastic cells were positive for ALK-1,CD30,and CD3.A diagnosis of primary bone ALK positive ALCL was ultimately made.The patient was in partial response after four cycle soft cyclophosphamide,doxorubicin,vincristine,and prednisone chemotherapy,and we planned to repeat the biopsy and radiological examination after completion of the fifth cycle of therapy.CONCLUSION Primary bone ALK positive ALCL is a rare disease and physicians should keep in mind that ALCL can present with isolated osseous involvement without nodal involvement,and lymphoma should be considered in the differential diagnosis of primary bone lesions.展开更多
Purpose: Acromioclavicular (AC) joint dislocation is commonly treated using a clavicle hook plate (HP). However, previous reports have indicated that acromial fractures may occur after HP fixation. The purpose of this...Purpose: Acromioclavicular (AC) joint dislocation is commonly treated using a clavicle hook plate (HP). However, previous reports have indicated that acromial fractures may occur after HP fixation. The purpose of this study was to identify risk factors for acromial fractures. Methods: A retrospective study was conducted on 39 patients with AC joint dislocation who were treated using clavicle HP fixation in our hospital between 2006 and 2017. Related parameters, including Rockwood classification, hook angle, the degree of reduction, the coverage of the hook under the acromion, and the anteroposterior position of the hook under the acromion, were evaluated to identify risk factors for acromial fractures. Results: The mean age of the participants was 51.7 (range 19 - 81) years;34 were men and 5 were women. Injury occurred on the right side in 18 patients and on the left side in 21. Injuries were categorized as follows: 24 were Rockwood type III, one was type IV, and 14 were type V. Four of the 39 patients (10%) experienced acromial fractures. Statistical analyses indicated that the degree of reduction at the final follow-up was moderately correlated with the Constant score. Posterior positioning of the hook was the only identified risk factor for acromial fractures. Hook angle and the degree of reduction at the time of surgery were not significantly associated with acromial fractures. Conclusions: Postoperative shoulder function was associated with the degree of reduction at the final follow-up, suggesting that anatomical reduction is recommended for AC joint dislocation. Posterior positioning of the hook is a risk factor for acromial fractures;however, clavicle HP fixation provides a positive outcome for AC joint dislocation. Therefore, careful positioning of the hook is required for preventing acromial fractures.展开更多
Gorham-Stout (GS) syndrome or the vanishing bone disease is a very rare chronic disease characterized by the destruction of the osseous matrix and proliferation of vascular structures. Review of the general anesthesia...Gorham-Stout (GS) syndrome or the vanishing bone disease is a very rare chronic disease characterized by the destruction of the osseous matrix and proliferation of vascular structures. Review of the general anesthesia showed only a few cases till date. We report general anesthesia for tooth extraction in a 21-year-old male patient with Gorham-Stout syndrome. In this case, the most concerning issue was limited mouth opening due to mandible osteolysis and difficult intubation was anticipated. To anticipate difficult airway management, it is very important to consider the preoperative airway assessment including the cervical spine screening. In this case, the McGrath video laryngoscope prevented the anticipated difficult intubation due to the limited mouth opening due to mandible osteolysis.展开更多
Objective: There are two monocyte populations in human blood: CD14+CD16- classical monocytes and CD14+CD16+ inflammatory monocytes. CD14+CD16+ inflammatory monocytes, account for approximately 10% of the total monocyt...Objective: There are two monocyte populations in human blood: CD14+CD16- classical monocytes and CD14+CD16+ inflammatory monocytes. CD14+CD16+ inflammatory monocytes, account for approximately 10% of the total monocytes, may be expanded in various types of inflammatory conditions. The purpose of this study was to investigate whether the expansion of the CD14+CD16+ monocyte population represents a risk factor of aseptic loosening (AL). Methods: Peripheral monocytes subsets were measured in revision patients with AL (n = 35) and in patients with stable implants (SI, n = 56). The gene profiles of TNFα, IL-1β, CD16, CD68 and TRAP5B from collected loosening periprosthetic tissues were analyzed. Results: There were no significant differences in the CD14+CD16+ monocyte populations between the SI and AL patients. The CD14+CD16+ monocytes were marginally higher in revision patients with osteolysis (n = 30), compared to patients without osteolysis (n = 5) though no statistically difference was found. There was an association between the CD14+CD16+ monocyte subpopulation and the tissue gene profiles, including IL-1β (p = 0.063), CD68 (p = 0.036), and TRAP5B (p = 0.073). Conclusion: It was demonstrated that the expansion of CD14+CD16+ monocytes reflects, to some extent, the inflammatory status of the loosening periprosthetic tissues. It is unclear if some of those SI patients (no pain and negative radiograph) who have a higher frequency of CD14+CD16+ monocytes may be at the early stage of AL. Further evaluation of CD14+CD16+ monocyte population, independently or combined with other factors, will be useful to design a risk profile for AL incidence and progression.展开更多
Intrapelvic prosthetic migration prosthesis following hip arthroplasty can occur due to aseptic loosening, infection, injury and malposition of the cup with chronic instability. Revision surgery is the treatment optio...Intrapelvic prosthetic migration prosthesis following hip arthroplasty can occur due to aseptic loosening, infection, injury and malposition of the cup with chronic instability. Revision surgery is the treatment option, but is often complex, is high risk owing to the co-morbidities of the patient, has higher complications and sometimes even patients refuse for the surgery. Osteoclast mediated bone resorption at the prosthetic bone interface is the main pathophysiology process involved in aseptic loosening associated intrapelvic migration. RANK/RANKL (Receptor Activated Nuclear factor κB Ligand) is the primary pathway responsible for the periprosthetic osteolysis, therefore, we have offered Denosumab which binds to RANKL and inhibits osteoclasts mediated bone resorption, to our two patients with intrapelvic prosthetic migration who have refused for the revision surgery. Here, we report the outcome of these two cases of Intrapelvic prosthetic migration following a hip arthroplasty that was treated using subcutaneous injection of 120 mg denosumab monthly for 3 months. Both the cases had good functional outcomes and radiographs showed good consolidation of bone around the prosthesis. These cases suggest denosumab can be repurposed to arrest further intrapelvic prosthetic migration due to its anti-resorptive and bone forming action and can avoid the need for a complex revision surgery.展开更多
Gorham-Stout disease(GSD)is a sporadic chronic disease characterized by progressive bone dissolution,absorption,and disappearance along with lymphatic vessel infiltration in bone-marrow cavities.Although the osteolyti...Gorham-Stout disease(GSD)is a sporadic chronic disease characterized by progressive bone dissolution,absorption,and disappearance along with lymphatic vessel infiltration in bone-marrow cavities.Although the osteolytic mechanism of GSD has been widely studied,the cause of lymphatic hyperplasia in GSD is rarely investigated.In this study,by comparing the RNA expression profile of osteoclasts(OCs)with that of OC precursors(OCPs)by RNA sequencing,we identified a new factor,semaphorin 3A(Sema3A),which is an osteoprotective factor involved in the lymphatic expansion of GSD.Compared to OCPs,OCs enhanced the growth,migration,and tube formation of lymphatic endothelial cells(LECs),in which the expression of Sema3A is low compared to that in OCPs.In the presence of recombinant Sema3A,the growth,migration,and tube formation of LECs were inhibited,further confirming the inhibitory effect of Sema3A on LECs in vitro.Using an LEC-induced GSD mouse model,the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in vivo.We found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss,whereas the injection of lentivirus expressing Sema3A short hairpin RNA(shRNA)into the tibiae caused GSD-like phenotypes.Histological staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment,compared with the control.Based on the above results,we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.展开更多
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 reoperatio...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.展开更多
Periprosthetic osteolysis(PPO)remains the key factor in implant failure and subsequent revision surgery and is mainly triggered by wear particles.Previous studies have shown that inhibition of osteoblastic differentia...Periprosthetic osteolysis(PPO)remains the key factor in implant failure and subsequent revision surgery and is mainly triggered by wear particles.Previous studies have shown that inhibition of osteoblastic differentiation is the most widespread incident affecting the interface of trabecular and loosening prostheses.Additionally,the NLRP3 inflammasome is activated by prosthetic particles.Sirtuin3,an NAD+-dependent deacetylase of mitochondria,regulates the function of mitochondria in diverse activities.However,whether SIRT3 can mitigate wear debris-induced osteolysis by inhibiting the NLRP3 inflammasome and enhancing osteogenesis has not been previously reported.Therefore,we investigated the role of SIRT3 during the process of titanium(Ti)particle-induced osteolysis.We revealed that upregulated SIRT3 dramatically attenuated Ti particle-induced osteogenic inhibition through suppression of the NLRP3 inflammasome and improvement of osteogenesis in vivo and in vitro.Moreover,we found that SIRT3 interference in the process of Ti particle-induced osteolysis relied on the GSK-3β/β-catenin signalling pathway.Collectively,these findings indicated that SIRT3 may serve as a rational new treatment against debris-induced PPO by deacetylase-dependent inflammasome attenuation.展开更多
Wear debris-induced aseptic loosening is an inflammatory bone disorder,which compromises the long-term success of total joint replacement.Despite the extensive research and great progress in treating inflammation-indu...Wear debris-induced aseptic loosening is an inflammatory bone disorder,which compromises the long-term success of total joint replacement.Despite the extensive research and great progress in treating inflammation-induced osteolysis for inflammatory arthritis,no drug has been proven for treatment/prevention of aseptic implant loosening.Also,there is very limited research on developing effective drug delivery systems for this pathological condition.In this review,we will discuss different therapeutic interventions and various delivery systems that have been developed for aseptic implant loosening.To provide the prospective for the future research in this area,the biology of wear particles-induced osteolysis,animal models developed for aseptic implant loosening and the potential challenges the field is facing are also presented in the discussion.展开更多
The"vicious cycle"established between tumor growth and osteolysis aggravates the process of breast cancer bone metastasis,leading to life-threatening skeletal-related events that severely reduce survival and...The"vicious cycle"established between tumor growth and osteolysis aggravates the process of breast cancer bone metastasis,leading to life-threatening skeletal-related events that severely reduce survival and quality of life.To effectively interrupt the"vicious cycle",innovative therapeutic strategies that not only reduce osteolysis but also relieve tumor burden are urgently needed.Herein,a bone-seeking moiety,alendronate(ALN),functionalized coordination polymer nanoparticles(DZ@ALN)co-delivering cisplatin prodrug(DSP)and antiresorptive agent zoledronate(ZOL)via Zn2+crosslinking for combination therapy was reported.The versatile DZ@ALN with a diameter of about 40 nm can cross the fissure in the bone marrow sinus capillaries,and possesses an excellent bone-seeking ability both in vitro and in vivo.Additionally,DZ@ALN could synergistically inhibit the proliferation of cancer cells,suppress the formation of osteoclast-like cells and induce the apoptosis of osteoclasts in vitro.Importantly,it could preferentially accumulate in bone affected site,remarkably inhibit the proliferation of tumor cells,relieving bone pain,and significantly inhibit the activation of osteoclasts,protecting the bone from destruction in vivo,eventually leading to the breakdown of"vicious cycle"without inducing obvious systemic toxicity.This innovative nanoagent combines chemotherapy and osteolysis inhibition,exhibiting an inspiring strategy for effective treatment of bone metastasis.展开更多
Aim:Estrogen receptorα-positive(ER+)subtypes of breast cancer have the greatest predilection for forming osteolytic bone metastases(BMETs).Because tumor-derived factors mediate osteolysis,a possible role for tumoral...Aim:Estrogen receptorα-positive(ER+)subtypes of breast cancer have the greatest predilection for forming osteolytic bone metastases(BMETs).Because tumor-derived factors mediate osteolysis,a possible role for tumoral ERαsignaling in driving ER+BMET osteolysis was queried using an estrogen(E2)-dependent ER+breast cancer BMET model.Methods:Female athymic Foxn1nu mice were inoculated with human ER+MCF-7 breast cancer cells via the left cardiac ventricle post-E2 pellet placement,and age-and dose-dependent E2 effects on osteolytic ER+BMET progression,as well as direct bone effects of E2,were determined.Results:Osteolytic BMETs,which did not form in the absence of E2 supplementation,occurred with the same frequency in young(5-week-old)vs.skeletally mature(16-week-old)E2(0.72 mg)-treated mice,but were larger in young mice where anabolic bone effects of E2 were greater.However,in mice of a single age and across a range of E2 doses,anabolic E2 bone effects were constant,while osteolytic ER+BMET lesion incidence and size increased in an E2 dose-dependent fashion.Osteoclasts in ER+tumor-bearing(but not tumor-naive)mice increased in an E2-dose dependent fashion at the bone-tumor interface,while histologic tumor size and proliferation did not vary with E2 dose.E2-inducible tumoral secretion of the osteolytic factor parathyroid hormone-related protein(PTHrP)was dose-dependent and mediated by ERα,with significantly greater levels of secretion from ER+BMET-derived tumor cells.Conclusion:These results suggest that tumoral ERαsignaling may contribute to ER+BMET-associated osteolysis,potentially explaining the greater predilection for ER+tumors to form clinically-evident osteolytic BMETs.展开更多
文摘There is convincing evidence that particles produced by the wear of joint prostheses are causal in the periprosthetic loss of bone,or osteolysis,which,if it progresses,leads to the phenomenon of aseptic loosening.It is important to fully understand the biology of this bone loss because it threatens prosthesis survival,and loosened implants can result in peri-prosthetic fracture,which is disastrous for the patient and presents a difficult surgical scenario.The focus of this review is the bioactivity of polyethylene(PE)particles,since there is evidence that these are major players in the development and progression of osteolysis around prostheses which use PE as the bearing surface.The review describes the biological consequences of interaction of PE particles with macrophages,osteoclasts and cells of the osteoblast lineage,including osteocytes.It explores the possible cellular mechanisms of action of PE and seeks to use the findings to date to propose potential nonsurgical treatments for osteolysis.In particular,a nonsurgical approach is likely to be applicable to implants containing newer,highly cross-linked PEs(HXLPEs),for which osteolysis seems to occur with much reduced PE wear compared with conventional PEs.The caveat here is that we know little as yet about the bioactivity of HXLPE particles and addressing this constitutes our next challenge.
文摘BACKGROUND Among the various complications associated with total hip arthroplasty(THA)periprosthetic osteolysis and wear phenomena due to the release of metal particles,are two of the most common and have been reported to be correlated because of inflammatory responses directed towards released particles that generally activate macrophagic osteolytic effects.Therein,new masses known as pseudotumors can appear in soft tissues around a prosthetic implant.To date,there is paucity of reliable data from studies investigating for any association between the above mentioned adverse events.AIM To investigate for the existence of any association between serum and urine concentrations of metal-ions released in THA and periprosthetic osteolysis for modular neck and monolithic implants.METHODS Overall,76 patients were divided into three groups according to the type of hip prosthesis implants:Monoblock,modular with metal head and modular with ceramic head.With an average f-up of 4 years,we conducted a radiological evaluation in order to detect any area of osteolysis around the prosthesis of both the femur and the acetabulum.Moreover,serum and urinary tests were performed to assess the values of Chromium and Cobalt released.Statistical analysis was performed to determine any association between the ion release and osteolysis.RESULTS For the 3 study groups,the monolithic,modular ceramic-headed and modular metal-headed implants had different incidences of osteolysis events,which were higher for the modular implants.Furthermore,the most serious of these(grade 3)were detected almost exclusively for the modular implants with metal heads.A mapping of the affected areas was performed revealing that the highest incidences of osteolysis were evidenced in the pertrochanteric region at the femur level,and in the supero-external region at the acetabular level.Regarding the evaluation of the release of metals-ions from wear processes,serum and urinary chromium and cobalt values were found to be higher in cases of modularity,and even more so for those with metal head.Statistical linear correlation test results suggested positive correlations between increasing metal concentrations and incidences areas of osteolysis.However,no cases of pseudo-tumor were detected.CONCLUSION Future studies are needed to identify risk factors that increase peri-prosthetic metal ion levels and whether these factors might be implicated in the triggering of local events,including osteolysis and aseptic loosening.
基金This work was supported by National Natural Science Foundation of China(No.81870750,81970925,81900994)the Guangdong Financial Fund for High-Caliber Hospital Construction(174-2018-XMZC-0001-03-0125/D-08).
文摘Extensive macrophage inflammatory responses and osteoclast formation are predominant during inflammatory or infective osteolysis.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(MSC-sEV)have been shown to exert therapeutic effects on bone defects.However,cultured MSCs are typically exposed to normoxia(21%O2)in vitro,which differs largely from the oxygen concentration in vivo under hypoxic conditions.It is largely unknown whether sEV derived from dental pulp stem cells(DPSCs)cultured under hypoxic conditions(Hypo-sEV)exert better therapeutic effects on lipopolysaccharide(LPS)-induced inflammatory osteolysis than those cultured under normoxic conditions(Nor-sEV)by simultaneously inhibiting the macrophage inflammatory response and osteoclastogenesis.In this study,we show that hypoxia significantly induces the release of sEV from DPSCs.Moreover,Hypo-sEV exhibit significantly improved efficacy in promoting M2 macrophage polarization and suppressing osteoclast formation to alleviate LPS-induced inflammatory calvarial bone loss compared with Nor-sEV.Mechanistically,hypoxia preconditioning markedly alters the miRNA profiles of DPSC-sEV.MiR-210-3p is enriched in Hypo-sEV,and can simultaneously induce M2 macrophage generation and inhibit osteoclastogenesis by targeting NF-κB1 p105,which attenuates osteolysis.Our study suggests a promising potential for hypoxia-induced DPSC-sEV to treat inflammatory or infective osteolysis and identifies a novel role of miR-210-3p in concurrently hindering osteoclastogenesis and macrophage inflammatory response by inhibiting NF-kB1 expression.
基金supported by the National Natural Science Foundation of China[grant numbers 82172405,81972050,81802179].
文摘Aseptic prosthesis loosening(APL)is one of the most prevalent complications associated with arthroplasty.The main cause is the periprosthetic osteolysis induced by wear particles.However,the specific mechanisms of crosstalk between immune cells and osteoclasts/osteoblasts during osteolysis are unclear.In this study,we report the role and mechanism of macrophage-derived exosomes in wear particle-induced osteolysis.The results of exosomes up-taken experiments revealed that osteoblast and mature osteoclasts capture macrophage-derived exosomes(M-Exo).Next-generation sequencing and RT-qPCR on M-Exo revealed that exosomal microRNA miR-3470b was downregulated in wear particle-induced osteolysis.The results of analysis on Luciferase reporter assays/fluorescence in situ hybridization(FISH)/immunofluorescence(IF)/immunohistochemistry(IHC)and co-culture experiments demonstrated that wear particles induced osteoclast differentiation by increasing the expression of NFatc1 via M-Exo miR-3470b targeting TAB3/NF-κB signaling.We also illustrate that engineered exosomes enriching miR-3470b facilitated to suppressed the osteolysis;the microenvironment enriching with miR-3470b could suppress wear particle-induced osteolysis via inhibition of TAB3/NF-κB in vivo.In summary,our findings indicate that macrophage-derived exosomes transfer to osteoclasts to induce osteolysis in wear particle-induced APL.Engineering exosomes enriching with miR-3470b might be a novel strategy for the targeting treatment of bone resorption-related diseases.
基金supported by National Key R&D Program of China(2018YFC1105904,2016YFA0201104)National Science Foundation of China(81772335,81941009,81802196,11874200)+2 种基金Natural Science Foundation of Jiangsu Province,China(BK20180127)Jiangsu Provincial Key Medical Talent FoundationSix Talent Peaks Project of Jiangsu Province(WSW-079).
文摘Joint replacement surgery is one of the orthopedic surgeries with high successful rates;however,wear debris generated from prostheses can ultimately lead to periprosthetic osteolysis and failure of the implant.The implant-derived particulate debris such as ultrahigh molecular weight polyethylene(UHMWPE)can initiate the local immune response and recruit monocytic cells to phagocytose particles for generating reactive oxygen species(ROS).ROS induces osteoclastogenesis and macrophages to secrete cytokines which ultimately promote the development of osteolysis.In this work,we develop the few-layered Nb_(2)C(FNC)as an antioxidant which possesses the feature of decreasing the production of cytokines and inhibiting osteoclastogenesis by its ROS adsorption.Moreover,local injection of FNC attenuates the UHMWPE-induced osteolysis in a mouse calvarial model.In sum,our results suggest that FNC can be used for treating osteolytic bone disease caused by excessive osteoclastogenesis.
基金supported by the National Natural Science Foundation of China(81871789,81802200,82172387)the Natural Science Foundation of Jiangsu Province(BK20180052)the Gusu Health Talents Program(GSWS2020023)。
文摘Background:Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty.Up to now,there is no effective treatment for wear particles-induced osteolysis except for the revision surgery,which is a heavy psychological and economic burden to patients.A metabolite of gut microbiota,short chain fatty acids(SCFAs),has been reported to be beneficial for many chronic inflammatory diseases.This study aimed to investigate the therapeutic effect of SCFAs on osteolysis.Methods:A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium.After two weeks of intervention,the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by micro-CT analysis and immunohistochemistry staining.In vitro study,lipopolysaccharide(LPS)primed bone marrow-derived macrophages(BMDMs)and Tohoku hospital pediatrics-1(THP-1)macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate(C2),propionate(C3),and butyrate(C4).Western blotting,enzyme-linked immunosorbent assay,and immunofluorescence were used to detect the activation of NLRP3 inflammasome.The effects of SCFAs on osteoclasts were evaluate by qRT-PCR,Western blotting,immunofluorescence,and tartrate-resistant acid phosphatase(TRAP)staining.Additionally,histone deacetylase(HDAC)inhibitors,agonists of GPR41,GPR43,and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis.Results:C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits(P<0.001),higher level of bone volume to tissue volume(BV/TV,P<0.001),bone mineral density(BMD,P<0.001),and a lower total porosity(P<0.001).C3 and C4 prevented CoCrMo alloy particles-induced ASC speck formation and nucleationinduced oligomerization,suppressing the cleavage of caspase-1(P<0.05)and IL-1β(P<0.05)stimulated by CoCrMo alloy particles.C3 and C4 also inhibited the generation of gasdermin D-N-terminal fragment(GSDMD-NT)to regulate pyroptosis.Besides,C3 and C4 have a negative impact on osteoclast differentiation(P<0.05)and its function(P<0.05),affecting the podosome arrangement and morphologically normal podosome belts formation.Conclusions:Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.
文摘Background: The Buechel-Pappas (BP) meniscal bearing total ankle replace-ment was initially developed as a “shallow-sulcus” talar component device using cobalt-chromium-molybdenum alloy, in 1978, and later, modified to a “deep-sulcus” talar component device using titanium nitride (TiN) ceramic and porous coating in 1989. Wear related osteolytic cysts were noted in the tibia and talus surrounding these devices that compromised long term fixation and stability when using standard ultra-high molecular weight polyethylene (UHMWPe) as a bearing material. This study explores the use of highly cross-linked UHMWPe (HXLPe) to minimize osteolysis by replacing standard UHMWPe with this more wear-resistant material. Methods: There were 12 primary and 8 revision total ankle replacements followed for 13 to 15 years. HXLPe was used in all meniscal bearings, either as primary or revision implants. All stable metallic tibial and talar components were retained in revision cases. Osteolytic cysts greater than 10 mm in diameter were bone grafted with homologous morselized banked bone through cortical windows in the tibia or talus. No adjuvant screw fixation was used to stabilize any metallic implant. Results: No HXLPe bearings failed in this study, and no re-revisions were performed. No primary total ankle replacement failed in this study, and there were no substantial osteolytic cysts (>2 mm) observed in primary total ankle replacements on plain X-rays. All bone grafted osteolytic cysts in revision ankle replacements remained stable, even though partial resorption of the grafted material was identified in most of the ankles. No loosening of porous coated and TiN coated tibial and talar components were seen;the longest surviving metal components in the revision group was 24 years with the revised bearing at 15 years. Conclusions: HXLPe has greatly improved wear resistance in meniscal-bearing BP total ankle replacements in both primary and revision arthroplasties. Osteolytic cysts can be successfully bone grafted during bearing exchange revisions. Primary and revision, cementless BP metallic total ankle components have remained well-fixed to bone in the long term (greater than 20 years), without the use of adjuvant screw fixation.
文摘Joint arthroplasty had revolutionized the outcome of orthopaedic surgery. Extensive and collaborative work of many innovator surgeons had led to the development of durable bearing surfaces, yet no single material is considered absolutely perfect. Generation of wear debris from any part of the prosthesis is unavoidable. Implant loosening secondary to osteolysis is the most common mode of failure of arthroplasty. Osteolysis is the resultant of complex contribution of the generated wear debris and the mechanical instability of the prosthetic components. Roughly speaking, all orthopedic biomaterials may induce a universal biologic hostresponse to generated wear débris with little specific characteristics for each material; but some debris has been shown to be more cytotoxic than others. Prosthetic wear debris induces an extensive biological cascade of adverse cellular responses, where macrophages are the main cellular type involved in this hostile inflammatory process. Macrophages cause osteolysis indirectly by releasing numerous chemotactic inflammatory mediators, and directly by resorbing bone with their membrane microstructures. The bio-reactivity of wear particles depends on two major elements: particle characteristics(size, concentration and composition) and host characteristics. While any particle type may enhance hostile cellular reaction, cytological examination demonstrated that more than 70% of the debris burden is constituted of polyethylene particles. Comprehensive understanding of the intricate process of osteolysis is of utmost importance for future development of therapeutic modalities that may delay or prevent the disease progression.
基金Supported by National Science and Technology Major Subproject of China,No.2018ZX10302205-002Chinese Foundation for Hepatitis Prevention and Control-Tianqing Liver Disease Research Fund Subject,No.TQGB2020168.
文摘BACKGROUND Primary bone lymphoma(PBL)is an uncommon extranodal disease that represents approximately 1%-3%of lymphomas.Anaplastic lymphoma kinase(ALK)positive anaplastic large-cell lymphoma(ALCL)is an extremely rare type of PBL.The aim of this report is describe the symptoms,diagnosis,and treatment of primary bone ALK-positive ALCL.CASE SUMMARY A 66-year-old man presented to our hospital with neck and shoulder pain and intermittent fever that lasted for 1 mo.After extensive evaluation,positron emission tomography-computed tomography(CT)examination showed multiple osteolytic bone lesions without other sites lesions.CT-guided biopsy of the T10 vertebral body was performed,and the pathology results showed that neoplastic cells were positive for ALK-1,CD30,and CD3.A diagnosis of primary bone ALK positive ALCL was ultimately made.The patient was in partial response after four cycle soft cyclophosphamide,doxorubicin,vincristine,and prednisone chemotherapy,and we planned to repeat the biopsy and radiological examination after completion of the fifth cycle of therapy.CONCLUSION Primary bone ALK positive ALCL is a rare disease and physicians should keep in mind that ALCL can present with isolated osseous involvement without nodal involvement,and lymphoma should be considered in the differential diagnosis of primary bone lesions.
文摘Purpose: Acromioclavicular (AC) joint dislocation is commonly treated using a clavicle hook plate (HP). However, previous reports have indicated that acromial fractures may occur after HP fixation. The purpose of this study was to identify risk factors for acromial fractures. Methods: A retrospective study was conducted on 39 patients with AC joint dislocation who were treated using clavicle HP fixation in our hospital between 2006 and 2017. Related parameters, including Rockwood classification, hook angle, the degree of reduction, the coverage of the hook under the acromion, and the anteroposterior position of the hook under the acromion, were evaluated to identify risk factors for acromial fractures. Results: The mean age of the participants was 51.7 (range 19 - 81) years;34 were men and 5 were women. Injury occurred on the right side in 18 patients and on the left side in 21. Injuries were categorized as follows: 24 were Rockwood type III, one was type IV, and 14 were type V. Four of the 39 patients (10%) experienced acromial fractures. Statistical analyses indicated that the degree of reduction at the final follow-up was moderately correlated with the Constant score. Posterior positioning of the hook was the only identified risk factor for acromial fractures. Hook angle and the degree of reduction at the time of surgery were not significantly associated with acromial fractures. Conclusions: Postoperative shoulder function was associated with the degree of reduction at the final follow-up, suggesting that anatomical reduction is recommended for AC joint dislocation. Posterior positioning of the hook is a risk factor for acromial fractures;however, clavicle HP fixation provides a positive outcome for AC joint dislocation. Therefore, careful positioning of the hook is required for preventing acromial fractures.
文摘Gorham-Stout (GS) syndrome or the vanishing bone disease is a very rare chronic disease characterized by the destruction of the osseous matrix and proliferation of vascular structures. Review of the general anesthesia showed only a few cases till date. We report general anesthesia for tooth extraction in a 21-year-old male patient with Gorham-Stout syndrome. In this case, the most concerning issue was limited mouth opening due to mandible osteolysis and difficult intubation was anticipated. To anticipate difficult airway management, it is very important to consider the preoperative airway assessment including the cervical spine screening. In this case, the McGrath video laryngoscope prevented the anticipated difficult intubation due to the limited mouth opening due to mandible osteolysis.
文摘Objective: There are two monocyte populations in human blood: CD14+CD16- classical monocytes and CD14+CD16+ inflammatory monocytes. CD14+CD16+ inflammatory monocytes, account for approximately 10% of the total monocytes, may be expanded in various types of inflammatory conditions. The purpose of this study was to investigate whether the expansion of the CD14+CD16+ monocyte population represents a risk factor of aseptic loosening (AL). Methods: Peripheral monocytes subsets were measured in revision patients with AL (n = 35) and in patients with stable implants (SI, n = 56). The gene profiles of TNFα, IL-1β, CD16, CD68 and TRAP5B from collected loosening periprosthetic tissues were analyzed. Results: There were no significant differences in the CD14+CD16+ monocyte populations between the SI and AL patients. The CD14+CD16+ monocytes were marginally higher in revision patients with osteolysis (n = 30), compared to patients without osteolysis (n = 5) though no statistically difference was found. There was an association between the CD14+CD16+ monocyte subpopulation and the tissue gene profiles, including IL-1β (p = 0.063), CD68 (p = 0.036), and TRAP5B (p = 0.073). Conclusion: It was demonstrated that the expansion of CD14+CD16+ monocytes reflects, to some extent, the inflammatory status of the loosening periprosthetic tissues. It is unclear if some of those SI patients (no pain and negative radiograph) who have a higher frequency of CD14+CD16+ monocytes may be at the early stage of AL. Further evaluation of CD14+CD16+ monocyte population, independently or combined with other factors, will be useful to design a risk profile for AL incidence and progression.
文摘Intrapelvic prosthetic migration prosthesis following hip arthroplasty can occur due to aseptic loosening, infection, injury and malposition of the cup with chronic instability. Revision surgery is the treatment option, but is often complex, is high risk owing to the co-morbidities of the patient, has higher complications and sometimes even patients refuse for the surgery. Osteoclast mediated bone resorption at the prosthetic bone interface is the main pathophysiology process involved in aseptic loosening associated intrapelvic migration. RANK/RANKL (Receptor Activated Nuclear factor κB Ligand) is the primary pathway responsible for the periprosthetic osteolysis, therefore, we have offered Denosumab which binds to RANKL and inhibits osteoclasts mediated bone resorption, to our two patients with intrapelvic prosthetic migration who have refused for the revision surgery. Here, we report the outcome of these two cases of Intrapelvic prosthetic migration following a hip arthroplasty that was treated using subcutaneous injection of 120 mg denosumab monthly for 3 months. Both the cases had good functional outcomes and radiographs showed good consolidation of bone around the prosthesis. These cases suggest denosumab can be repurposed to arrest further intrapelvic prosthetic migration due to its anti-resorptive and bone forming action and can avoid the need for a complex revision surgery.
基金supported by the National Natural Science Foundation of China(No.81974321)the Discipline Innovation and Talent Introduction Program to Universities from Ministry of Education of China(Project 111)+3 种基金the Tackling Project for Science and Technology of Xinxiang City(No.GG2019003)the Natural Science Foundation of Henan Province of China(No.212300410173)the State Administration of Traditional Chinese Medicine Young Qi Huang Scholar,and the Innovation Team Project of Scientific Research of Traditional Chinese Medicine of Shanghai Health Committee(No.2022CX001)China.
文摘Gorham-Stout disease(GSD)is a sporadic chronic disease characterized by progressive bone dissolution,absorption,and disappearance along with lymphatic vessel infiltration in bone-marrow cavities.Although the osteolytic mechanism of GSD has been widely studied,the cause of lymphatic hyperplasia in GSD is rarely investigated.In this study,by comparing the RNA expression profile of osteoclasts(OCs)with that of OC precursors(OCPs)by RNA sequencing,we identified a new factor,semaphorin 3A(Sema3A),which is an osteoprotective factor involved in the lymphatic expansion of GSD.Compared to OCPs,OCs enhanced the growth,migration,and tube formation of lymphatic endothelial cells(LECs),in which the expression of Sema3A is low compared to that in OCPs.In the presence of recombinant Sema3A,the growth,migration,and tube formation of LECs were inhibited,further confirming the inhibitory effect of Sema3A on LECs in vitro.Using an LEC-induced GSD mouse model,the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in vivo.We found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss,whereas the injection of lentivirus expressing Sema3A short hairpin RNA(shRNA)into the tibiae caused GSD-like phenotypes.Histological staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment,compared with the control.Based on the above results,we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.
基金This work was supported by the National Natural Science Foundation of China(Grant No.51931001)International Cooperation Exchange project between NSFC(China)and CNR(Italy)(NSFC-CNR Grant No.52011530392)+2 种基金the Shanghai Rising-Star Program(21QA1405500)the Shanghai“Rising Stars of Medical Talent”Youth Development Program(Youth Medical Talents-Specialist Program,Grant No.201972)NSFC Advancing Targeted Projects(RJTJ-JX-005).
文摘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.
基金This work is supported by grants from the National Natural Science Foundation of China(Nos.82072425,82072498,81873991,81873990,81672238 and 81472077)the Young Medical Talents of Jiangsu Province(No.QNRC2016751)+1 种基金the Natural Science Foundation of Jiangsu Province(Nos.BK20180001)the Priority Academic Program Development of Jiangsu Higher Education Institutions and Special Project of Diagnosis and Treatment Technology for Key Clinical Diseases in Suzhou(LCZX202003).
文摘Periprosthetic osteolysis(PPO)remains the key factor in implant failure and subsequent revision surgery and is mainly triggered by wear particles.Previous studies have shown that inhibition of osteoblastic differentiation is the most widespread incident affecting the interface of trabecular and loosening prostheses.Additionally,the NLRP3 inflammasome is activated by prosthetic particles.Sirtuin3,an NAD+-dependent deacetylase of mitochondria,regulates the function of mitochondria in diverse activities.However,whether SIRT3 can mitigate wear debris-induced osteolysis by inhibiting the NLRP3 inflammasome and enhancing osteogenesis has not been previously reported.Therefore,we investigated the role of SIRT3 during the process of titanium(Ti)particle-induced osteolysis.We revealed that upregulated SIRT3 dramatically attenuated Ti particle-induced osteogenic inhibition through suppression of the NLRP3 inflammasome and improvement of osteogenesis in vivo and in vitro.Moreover,we found that SIRT3 interference in the process of Ti particle-induced osteolysis relied on the GSK-3β/β-catenin signalling pathway.Collectively,these findings indicated that SIRT3 may serve as a rational new treatment against debris-induced PPO by deacetylase-dependent inflammasome attenuation.
文摘Wear debris-induced aseptic loosening is an inflammatory bone disorder,which compromises the long-term success of total joint replacement.Despite the extensive research and great progress in treating inflammation-induced osteolysis for inflammatory arthritis,no drug has been proven for treatment/prevention of aseptic implant loosening.Also,there is very limited research on developing effective drug delivery systems for this pathological condition.In this review,we will discuss different therapeutic interventions and various delivery systems that have been developed for aseptic implant loosening.To provide the prospective for the future research in this area,the biology of wear particles-induced osteolysis,animal models developed for aseptic implant loosening and the potential challenges the field is facing are also presented in the discussion.
基金supported by the National Natural Science Foundation of China(Grant No.81973256/H3008)
文摘The"vicious cycle"established between tumor growth and osteolysis aggravates the process of breast cancer bone metastasis,leading to life-threatening skeletal-related events that severely reduce survival and quality of life.To effectively interrupt the"vicious cycle",innovative therapeutic strategies that not only reduce osteolysis but also relieve tumor burden are urgently needed.Herein,a bone-seeking moiety,alendronate(ALN),functionalized coordination polymer nanoparticles(DZ@ALN)co-delivering cisplatin prodrug(DSP)and antiresorptive agent zoledronate(ZOL)via Zn2+crosslinking for combination therapy was reported.The versatile DZ@ALN with a diameter of about 40 nm can cross the fissure in the bone marrow sinus capillaries,and possesses an excellent bone-seeking ability both in vitro and in vivo.Additionally,DZ@ALN could synergistically inhibit the proliferation of cancer cells,suppress the formation of osteoclast-like cells and induce the apoptosis of osteoclasts in vitro.Importantly,it could preferentially accumulate in bone affected site,remarkably inhibit the proliferation of tumor cells,relieving bone pain,and significantly inhibit the activation of osteoclasts,protecting the bone from destruction in vivo,eventually leading to the breakdown of"vicious cycle"without inducing obvious systemic toxicity.This innovative nanoagent combines chemotherapy and osteolysis inhibition,exhibiting an inspiring strategy for effective treatment of bone metastasis.
基金supported by the National Cancer Institute(NCI)of the National Institutes of Health(NIH)(R03CA181893 and R01CA174926 to JLF,T32CA00923,P30CA023074)METAvivor(Translational Research Award,JLF)+1 种基金the Phoenix Chapter of ARCS Foundation(JNC)and the Louise Foucar Marshall Foundation Dissertation Fellowship(JNC).
文摘Aim:Estrogen receptorα-positive(ER+)subtypes of breast cancer have the greatest predilection for forming osteolytic bone metastases(BMETs).Because tumor-derived factors mediate osteolysis,a possible role for tumoral ERαsignaling in driving ER+BMET osteolysis was queried using an estrogen(E2)-dependent ER+breast cancer BMET model.Methods:Female athymic Foxn1nu mice were inoculated with human ER+MCF-7 breast cancer cells via the left cardiac ventricle post-E2 pellet placement,and age-and dose-dependent E2 effects on osteolytic ER+BMET progression,as well as direct bone effects of E2,were determined.Results:Osteolytic BMETs,which did not form in the absence of E2 supplementation,occurred with the same frequency in young(5-week-old)vs.skeletally mature(16-week-old)E2(0.72 mg)-treated mice,but were larger in young mice where anabolic bone effects of E2 were greater.However,in mice of a single age and across a range of E2 doses,anabolic E2 bone effects were constant,while osteolytic ER+BMET lesion incidence and size increased in an E2 dose-dependent fashion.Osteoclasts in ER+tumor-bearing(but not tumor-naive)mice increased in an E2-dose dependent fashion at the bone-tumor interface,while histologic tumor size and proliferation did not vary with E2 dose.E2-inducible tumoral secretion of the osteolytic factor parathyroid hormone-related protein(PTHrP)was dose-dependent and mediated by ERα,with significantly greater levels of secretion from ER+BMET-derived tumor cells.Conclusion:These results suggest that tumoral ERαsignaling may contribute to ER+BMET-associated osteolysis,potentially explaining the greater predilection for ER+tumors to form clinically-evident osteolytic BMETs.
