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Military Medical Research Aug 2022Wear 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...
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 nucleation-induced 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.
CONCLUSION
Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.
Topics: Alloys; Animals; Butyrates; Humans; Inflammasomes; Macrophages; Mice; Osteogenesis; Osteolysis; Propionates; Pyroptosis
PubMed: 35996168
DOI: 10.1186/s40779-022-00404-0 -
Nature Communications Nov 2022The impact of bone cell activation on bacterially-induced osteolysis remains elusive. Here, we show that matrix-embedded osteocytes stimulated with bacterial...
The impact of bone cell activation on bacterially-induced osteolysis remains elusive. Here, we show that matrix-embedded osteocytes stimulated with bacterial pathogen-associated molecular patterns (PAMPs) directly drive bone resorption through an MYD88-regulated signaling pathway. Mice lacking MYD88, primarily in osteocytes, protect against osteolysis caused by calvarial injections of bacterial PAMPs and resist alveolar bone resorption induced by oral Porphyromonas gingivalis (Pg) infection. In contrast, mice with targeted MYD88 restoration in osteocytes exhibit osteolysis with inflammatory cell infiltration. In vitro, bacterial PAMPs induce significantly higher expression of the cytokine RANKL in osteocytes than osteoblasts. Mechanistically, activation of the osteocyte MYD88 pathway up-regulates RANKL by increasing binding of the transcription factors CREB and STAT3 to Rankl enhancers and by suppressing K48-ubiquitination of CREB/CREB binding protein and STAT3. Systemic administration of an MYD88 inhibitor prevents jawbone loss in Pg-driven periodontitis. These findings reveal that osteocytes directly regulate inflammatory osteolysis in bone infection, suggesting that MYD88 and downstream RANKL regulators in osteocytes are therapeutic targets for osteolysis in periodontitis and osteomyelitis.
Topics: Mice; Animals; Osteocytes; Osteolysis; Myeloid Differentiation Factor 88; Pathogen-Associated Molecular Pattern Molecules; RANK Ligand; Porphyromonas gingivalis; Alveolar Bone Loss; Periodontitis; Signal Transduction; Adaptor Proteins, Signal Transducing; Osteomyelitis; Osteoclasts
PubMed: 36333322
DOI: 10.1038/s41467-022-34352-z -
Orthopaedic Surgery Feb 2019This article reviews the recent updates in revision of total knee arthroplasty (RTKA). We reviewed the recent articles on RTKA in databases including PubMed, Google... (Review)
Review
This article reviews the recent updates in revision of total knee arthroplasty (RTKA). We reviewed the recent articles on RTKA in databases including PubMed, Google Scholar, and SCOPUS. Total knee arthroplasty (TKA) involves the replacement of all three compartments of the knee in surgery of the knee joint to restore capacity and function. TKA is one of the most common and reliable surgical treatment options for the treatment of knee diseases. However, some patients require revision of TKA (RTKA) after primary TKA for various reasons, including mechanical wear, implant loosening or breakage, malalignment, infection, instability, periprosthetic fracture, and persistent stiffness. Unfortunately, the overall outcome of RTKA is not as satisfactory as for primary TKA due to the uncertainty regarding the actual success rate and the risk factors for failure. Cementation, modular metal augmentation, bone grafting, autologous bone grafting, allogenic bone grafting, impactation bone grafting, structural bone allografting, metaphyseal fixation, using porous titanium coated press fit metaphyseal sleeves and porous tantalum structural cones, and megaprostheses or customized prostheses are the currently available management options for RTKA. However, most of the management systems possess specific complications. Novel approaches should be developed to improve functional capacity, implant survival rates, and quality of life in a cost-efficient manner.
Topics: Arthroplasty, Replacement, Knee; Bone Transplantation; Cementation; Humans; Knee Joint; Knee Prosthesis; Osteolysis; Prosthesis Design; Prosthesis Failure; Radiography; Reoperation
PubMed: 30809942
DOI: 10.1111/os.12425 -
Cancer Letters Oct 2020Hypoxia is a common feature in tumors, driving pathways that promote epithelial-to-mesenchymal transition, invasion, and metastasis. Clinically, high levels of... (Review)
Review
Hypoxia is a common feature in tumors, driving pathways that promote epithelial-to-mesenchymal transition, invasion, and metastasis. Clinically, high levels of hypoxia-inducible factor (HIF) expression and stabilization at the primary site in many cancer types is associated with poor patient outcomes. Experimental evidence suggests that HIF signaling in the primary tumor promotes their dissemination to the bone, as well as the release of factors such as LOX that act distantly on the bone to stimulate osteolysis and form a pre-metastatic niche. Additionally, the bone itself is a generally hypoxic organ, fueling the activation of HIF signaling in bone resident cells, promoting tumor cell homing to the bone as well as osteoclastogenesis. The hypoxic microenvironment of the bone also stimulates the vicious cycle of tumor-induced bone destruction, further fueling tumor cell growth and osteolysis. Furthermore, hypoxia appears to regulate key tumor dormancy factors. Thus, hypoxia acts both on the tumor cells as well as the metastatic site to promote tumor cell metastasis.
Topics: Animals; Bone Neoplasms; Cell Hypoxia; Humans; Neoplasm Metastasis; Osteolysis
PubMed: 32561416
DOI: 10.1016/j.canlet.2020.06.004 -
Biomolecules Nov 2022Periprosthetic osteolysis (PPO) along with aseptic loosening (AL) caused by wear particles after artificial joint replacement is the key factor in surgical failure and... (Review)
Review
Periprosthetic osteolysis (PPO) along with aseptic loosening (AL) caused by wear particles after artificial joint replacement is the key factor in surgical failure and subsequent revision surgery, however, the precise molecular mechanism underlying PPO remains unclear. Aseptic inflammation triggered by metal particles, resulting in the imbalance between bone formation by osteoblasts and bone resorption by osteoclasts may be the decisive factor. Pyroptosis is a new pro-inflammatory pattern of regulated cell death (RCD), mainly mediated by gasdermins (GSDMs) family, among which GSDMD is the best characterized. Recent evidence indicates that activation of NLRP3 inflammasomes and pyroptosis play a pivotal role in the pathological process of PPO. Here, we review the pathological process of PPO, the molecular mechanism of pyroptosis and the interventions to inhibit the inflammation and pyroptosis of different cells during the PPO. Conclusively, this review provides theoretical support for the search for new strategies and new targets for the treatment of PPO by inhibiting pyroptosis and inflammation.
Topics: Humans; Osteolysis; Pyroptosis; Osteoclasts; Osteoblasts; Inflammation
PubMed: 36551161
DOI: 10.3390/biom12121733 -
Theranostics 2023Inflammatory osteolysis, characterized by abundant immune cell infiltration and osteoclast (OC) formation, is a common complication induced by bacterial products and/or...
Inflammatory osteolysis, characterized by abundant immune cell infiltration and osteoclast (OC) formation, is a common complication induced by bacterial products and/or wear particles at the bone-prosthesis interface that severely reduces long-term stability after implantation. Molecular nanoclusters are ultrasmall particles with unique physicochemical and biological properties that have great potential as theranostic agents for treating inflammatory diseases. In this study, heterometallic PtAu nanoclusters with sensitive nitric oxide-responsive phosphorescence turn-on characteristics and strong binding interactions with cysteine were designed, making them desirable candidates for the treatment of inflammatory osteolysis. PtAu clusters exhibited satisfactory biocompatibility and cellular uptake behavior, with potent anti-inflammatory and anti-OC activities . In addition, PtAu clusters alleviated lipopolysaccharide-induced calvarial osteolysis and activated nuclear factor erythroid 2-related factor 2 (Nrf2) expression by disrupting its association with Kelch-like ECH-associated protein 1 (Keap1), thereby upregulating the expression of endogenous anti-inflammatory and anti-oxidative products. Through the rational design of novel heterometallic nanoclusters that activate the endogenous anti-inflammatory system, this study provides new insights into the development of multifunctional molecular therapeutic agents for inflammatory osteolysis and other inflammatory diseases.
Topics: Animals; Mice; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Osteoclasts; Osteolysis; Inflammation; Antioxidants; Metal Nanoparticles
PubMed: 36793859
DOI: 10.7150/thno.80514 -
Molecular Medicine Reports Nov 2023Wear particle‑induced osteolysis is a serious complication that occurs in individuals with titanium (Ti)‑based implants following long‑term usage due to loosening...
Wear particle‑induced osteolysis is a serious complication that occurs in individuals with titanium (Ti)‑based implants following long‑term usage due to loosening of the implants. The control of excessive osteoclast differentiation and inflammation is essential for protecting against wear particle‑induced osteolysis. The present study evaluated the effect of britanin, a pseudoguaianolide sesquiterpene isolated from , on osteoclastogenesis and Ti particle‑induced osteolysis . The effect of britanin was examined in the osteoclastogenesis of mouse bone marrow‑derived macrophages (BMMs) using TRAP staining, RT‑PCR, western blotting and immunocytochemistry. The protective effect of britanin was examined in a mouse calvarial osteolysis model and evaluated using micro‑CT and histomorphometry. Britanin inhibited osteoclast differentiation and F‑actin ring formation in the presence of macrophage colony‑stimulating factor and receptor activator of nuclear factor kB ligand in BMMs. The expression of osteoclast‑specific marker genes, including tartrate‑resistant acid phosphatase, cathepsin K, dendritic cell‑specific transmembrane protein, matrix metallopeptidase 9 and nuclear factor of activated T‑cells cytoplasmic 1, in the BMMs was significantly reduced by britanin. In addition, britanin reduced the expression of B lymphocyte‑induced maturation protein‑1, which is a transcriptional repressor of negative osteoclastogenesis regulators, including interferon regulatory factor‑8 and B‑cell lymphoma 6. Conversely, britanin increased the expression levels of anti‑oxidative stress genes, namely nuclear factor erythroid‑2‑related factor 2, NAD(P)H quinone oxidoreductase 1 and heme oxygenase 1 in the BMMs. Furthermore, the administration of britanin significantly reduced osteolysis in a Ti particle‑induced calvarial osteolysis mouse model. Based on these findings, it is suggested that britanin may be a potential therapeutic agent for wear particle‑induced osteolysis and osteoclast‑associated disease.
Topics: Humans; Animals; Mice; Osteogenesis; Osteolysis; Titanium; Osteoclasts; Actin Cytoskeleton; Disease Models, Animal
PubMed: 37732549
DOI: 10.3892/mmr.2023.13092 -
Frontiers in Immunology 2023Gorham syndrome, also known as "vanishing osteopathy" and "invasive hemangiomatosis," is a rare clinical syndrome whose etiology is unknown and can invade the whole-body... (Review)
Review
Gorham syndrome, also known as "vanishing osteopathy" and "invasive hemangiomatosis," is a rare clinical syndrome whose etiology is unknown and can invade the whole-body skeleton. At present, more than 300 cases have been reported at home and abroad, usually manifesting as spontaneous chronic osteolysis with no periosteal reaction at the lysis site and occult onset, often with fractures, scoliosis, chylothorax, etc. When waiting for medical treatment, the condition is serious, and the prognosis is poor. At present, there is no effective treatment. The main pathological manifestations of Gorham syndrome are the non-neoplastic abnormal proliferation of lymphatic vessels or blood vessels and osteolysis caused by osteoclast proliferation or increased activity. At present, there is no unified conclusion regarding Gorham syndrome's pathogenesis. This paper starts with the two most studied osteolysis methods at present, osteoclast osteolysis and osteolysis caused by vascular and lymphatic proliferation and summarizes the corresponding most possible molecular mechanisms in recent years to provide more ideas for Gorham syndrome treatment.
Topics: Humans; Osteolysis; Osteolysis, Essential; Syndrome; Chylothorax; Osteoclasts
PubMed: 37215116
DOI: 10.3389/fimmu.2023.1165091 -
International Journal of Oral Science Nov 2023Peri-implantitis is one of the most important biological complications in the field of oral implantology. Identifying the causative factors of peri-implant inflammation... (Review)
Review
Peri-implantitis is one of the most important biological complications in the field of oral implantology. Identifying the causative factors of peri-implant inflammation and osteolysis is crucial for the disease's prevention and treatment. The underlying risk factors and detailed pathogenesis of peri-implantitis remain to be elucidated. Titanium-based implants as the most widely used implant inevitably release titanium particles into the surrounding tissue. Notably, the concentration of titanium particles increases significantly at peri-implantitis sites, suggesting titanium particles as a potential risk factor for the condition. Previous studies have indicated that titanium particles can induce peripheral osteolysis and foster the development of aseptic osteoarthritis in orthopedic joint replacement. However, it remains unconfirmed whether this phenomenon also triggers inflammation and bone resorption in peri-implant tissues. This review summarizes the distribution of titanium particles around the implant, the potential roles in peri-implantitis and the prevalent prevention strategies, which expects to provide new directions for the study of the pathogenesis and treatment of peri-implantitis.
Topics: Humans; Peri-Implantitis; Titanium; Dental Implants; Osteolysis; Inflammation
PubMed: 37996420
DOI: 10.1038/s41368-023-00256-x -
The Journal of Clinical Investigation Jun 2017There are many causes of inflammatory osteolysis, but regardless of etiology and cellular contexts, the osteoclast is the bone-degrading cell. Thus, the impact of... (Review)
Review
There are many causes of inflammatory osteolysis, but regardless of etiology and cellular contexts, the osteoclast is the bone-degrading cell. Thus, the impact of inflammatory cytokines on osteoclast formation and function was among the most important discoveries advancing the treatment of focal osteolysis, leading to development of therapeutic agents that either directly block the bone-resorptive cell or do so indirectly via cytokine arrest. Despite these advances, a substantial number of patients with inflammatory arthritis remain resistant to current therapies, and even effective anti-inflammatory drugs frequently do not repair damaged bone. Thus, insights into events such as those impacted by inflammasomes, which signal through cytokine-dependent and -independent mechanisms, are needed to optimize treatment of inflammatory osteolysis.
Topics: Animals; Bone and Bones; Cytokines; Humans; Inflammasomes; Osteoclasts; Osteocytes; Osteolysis
PubMed: 28569732
DOI: 10.1172/JCI93356