Macrophage-derived PDGF-BB modulates glycolytic enzymes expression and pyroptosis in nucleus pulposus cells via PDGFR-ß/TXNIP pathway.

OBJECTIVE: Intervertebral Disc Degeneration (IVDD) is one of the leading causes of low back pain, significantly impacting both individuals and society. This study aimed to investigate the significance of macrophage infiltration and the role of macrophage-secreted platelet-derived growth factor-BB (PDGF-BB) in IVDD progression. METHODS: To confirm the protective function of macrophage-derived PDGF-BB on nucleus pulposus cells (NPCs), we employed Lysm-Cre transgenic mice to genetically ablate PDGF-B within the myeloid cells. Immunohistochemistry was utilized to detect the expression of glycolytic enzymes and pyroptosis-related proteins during the process of IVDD. Western blot, RT-PCR, ELISA and immunofluorescence were used to detect the protective effect of recombinant PDGF-BB on NPCs. RESULTS: Macrophage-derived PDGF-BB deficiency resulted in the loss of NPCs and the increased ossification of cartilage endplates during lumbar disc degeneration. Also, PDGF-BB deficiency triggered the inhibition of glycolytic enzymes' expression and the activation of pathways related to pyroptosis in the nucleus pulposus. Mechanistically, our results suggest that PDGF-BB predominantly conveys its protective influence on NPCs through the PDGF receptor- beta (PDGFR-ß)/ thioredoxin-interacting protein pathway. CONCLUSIONS: The absence of PDGF-BB originating from macrophages expedites the advancement of IVDD, whereas the application of PDGF-BB treatment holds the potential for retarding intervertebral disc degeneration in the human body.

Upregulation of cIAP1 induced by AZD8330 alleviates osteoarthritis progression by inhibiting the RIP1-associated necrosis signaling pathway.

BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative joint disease [1]. It has come to light that AZD8330 can suppress the generation of proinflammatory factors and deter the inflammatory response [2]. Given that inflammation is a primary causative factor in OA, it is posited that AZD8330 might exhibit superior efficacy in OA management. METHODS: In this study, we investigated the potential of intraperitoneal injection of AZD8330 to retard the progression of osteoarthritis in a murine model with surgically induced medial meniscus destruction (DMM). Concurrently, we employed ATDC5 cartilage cells to dissect the mechanism through which AZD8330 inhibits the TNF-α-induced NF-κB signaling pathway via modulation of RIP1. The findings revealed that AZD8330 mitigated cartilage degradation and the inflammatory response, leading to a substantial reduction in OARSI scores among DMM mice treated with AZD8330. Mechanistically, AZD8330 functioned as a suppressor of the TNF-α-induced NF-κB/p65 signaling pathway by facilitating the phosphorylation activation of cIAP1-mediated RIP1. The combination of data from both in vivo and in vitro experiments supports the conclusion that AZD8330 can attenuate chondrocyte degradation, thereby alleviating OA, by regulating the NF-κB/P65 signaling pathway through modulation of RIP1 activity. Consequently, the utilization of AZD8330 may hold potential in the prophylaxis of osteoarthritis. RESULTS: Our investigation delineates the role of AZD8330 in the regulation of inflammation in the context of OA treatment. Furthermore, we have unveiled that the inhibitory impact of AZD8330 on OA may hinge upon the activation of cIAP1, which in turn downregulates RIP1, thereby restraining the NF-κB/P65 signaling pathway. This study lends credence to the notion that AZD8330 may be a promising contender for osteoarthritis therapy. CONCLUSIONS: Our study provides compelling evidence attesting to the capacity of AZD8330 in managing inflammation within the realm of OA treatment. Likewise, our study has elucidated that the attenuation of OA by AZD8330 relies on the activation of cIAP1 to inhibit RIP1, consequently suppressing the NF-κB signaling pathway. On the strength of our present study, we may have identified a viable drug candidate for OA treatment.

Paroxetine Attenuates Chondrocyte Pyroptosis and Inhibits Osteoclast Formation by Inhibiting NF-κB Pathway Activation to Delay Osteoarthritis Progression.

Background: Osteoarthritis (OA), a common chronic joint disease, is characterized by cartilage degeneration and subchondral bone reconstruction. NF-κB signaling pathway-activated inflammation and NLRP3-induced pyroptosis play essential roles in the development of OA. In this study, we examine whether paroxetine can inhibit pyroptosis and reduce osteoclast formation, thereby delaying the destruction of knee joints. Methods: We employed high-density cultures, along with quantitative polymerase chain reactions and Western blotting techniques, to investigate the effects of paroxetine on extracellular matrix synthesis and degradation. The expression levels of NF-κB and pyroptosis-related signaling pathway proteins were examined by Western blotting and immunofluorescence. Furthermore, the impact of paroxetine on RANKL-induced osteoclast formation was evaluated through TRAP staining and F-actin ring fluorescence detection. To investigate the role of paroxetine in vivo, we constructed a mouse model with destabilization of the medial meniscus (DMM) surgery. Safranin O-Fast Green staining, Hematoxylin-Eosin staining, and immunohistochemistry were conducted to observe the extent of knee joint cartilage deformation. In addition, TRAP staining was used to observe the formation of osteoclasts in the subchondral bone. Results: In the in vitro experiments with ATDC5, paroxetine treatment attenuated IL-1ß-induced activation of the pyroptosis-related pathway and suppressed extracellular matrix catabolism by inhibiting the NF-kB signaling pathway. In addition, paroxetine treatment decreased the expression of RANKL-induced osteoclast marker genes and reduced osteoclast formation. In animal experiments conducted in vivo, mice treated with paroxetine exhibited thicker knee cartilage with a smoother surface compared to the DMM group. Additionally, the formation of osteoclasts in the subchondral bone was reduced in the paroxetine-treated mice. Further analysis revealed that paroxetine treatment played a role in preserving the balance of the extracellular matrix and delaying knee joint degeneration. Conclusion: Paroxetine can inhibit pyroptosis and reduce osteoclast formation via inhibiting the NF-κB signaling pathway, suggesting that it may have therapeutic effects in patients with OA.

EGFL6 promotes bone metastasis of lung adenocarcinoma by increasing cancer cell malignancy and bone resorption.

Lung adenocarcinoma is the most common and aggressive type of lung cancer with the highest incidence of bone metastasis. Epidermal growth factor-like domain multiple 6 (EGFL6) is an exocrine protein, and the expression of EGFL6 is correlated with survival of patient with lung adenocarcinoma. However, the association between EGFL6 expression in lung adenocarcinoma and bone metastasis has not been investigated. In this study, we found that EGFL6 levels in lung adenocarcinoma tissues correlate with bone metastasis and TNM stages in surgical patients. In vitro, overexpression of EGFL6 in lung adenocarcinoma cells promoted their proliferation, migration, and invasion ability compared with control by enhancing EMT process and activating Wnt/ß-catenin and PI3K/AKT/mTOR pathways. In the nude mouse model, overexpression of EGFL6 enhanced tumor growth and caused greater bone destruction. Moreover, the exocrine EGFL6 of human lung adenocarcinoma cells increased osteoclast differentiation of bone marrow mononuclear macrophages (BMMs) of mice via the NF-κB and c-Fos/NFATc1 signaling pathways. However, exocrine EGFL6 had no effect on osteoblast differentiation of bone marrow mesenchymal stem cells (BMSCs). In conclusion, high expression of EGFL6 in lung adenocarcinomas is associated with bone metastasis in surgical patients. The underlying mechanism may be the increased metastatic properties of lung adenocarcinoma cells with high EGFL6 level and the enhanced osteoclast differentiation and bone resorption by exocrine EGFL6 from tumors. Therefore, EGFL6 is a potential therapeutic target to reduce the ability of lung adenocarcinomas to grow and metastasize and to preserve bone mass in patients with bone metastases from lung adenocarcinomas.

PD184352 exerts anti-inflammatory and antioxidant effects by promoting activation of the Nrf2/HO-1 axis.

Osteoarthritis (OA) is a disabling joint disease characterized by cartilage degeneration. Reactive oxygen species (ROS)-induced oxidative stress is an important cause of early chondrocyte death. For this reason, we investigated PD184352, a small molecule inhibitor with potential anti-inflammatory and antioxidant activity. We evaluated the protective effect of PD184352 against destabilized medial meniscus (DMM)-induced OA in mice. The knee joints of the PD184352-treated group had higher Nrf2 expression and milder cartilage damage. Moreover, in in vitro experiments, PD184352 suppressed IL-1ß-induced NO, iNOS, PGE2 production, and attenuated pyroptosis. PD184352 treatment promoted antioxidant protein expression and reduced the accumulation of ROS by activating the Nrf2/HO-1 axis. Finally, the anti-inflammatory and antioxidant effects of PD184352 were shown to be partially dependent on Nrf2 activation. Our study reveals the potential role of PD184352 as an antioxidant and provides a new strategy for OA treatment.

Limonin delays the progression of intervertebral disc degeneration in vivo and in vitro: the key role of the MAPK/NF-κB and necroptosis pathways.

OBJECTIVES: Limonin has received significant attention due to its multiple biological effects, intervertebral disc degeneration (IDD) is also of interest due to the high prevalence of this disease. In this study, we determined the effects of limonin on IDD and the underlying mechanism of action to find novel ways to treat IDD. METHODS: An IL-1ß-induced cell inflammation model and a lumbar instability model inducing IDD were established to assess the progression of IDD with or without limonin treatment. We further evaluated MAPK/NF-κB and necroptosis pathways and alterations in the extracellular matrix specific within the disc. KEY FINDINGS: Limonin suppresses inflammation in the nucleus pulposus in vitro by reducing the production of pro-inflammatory markers such as iNOS and COX-2. Limonin reduced the activation of the MAPK/NF-κB signalling pathway and the RIP1/RIP3/MLKL necroptosis pathway in the NP cells. Moreover, limonin delays the IDD progression in the lumbar instability model. CONCLUSIONS: Limonin could potentially delay IDD by inhibiting NP cell necroptosis and modulating peripheral matrix proteins within the intervertebral disc and is a potential pharmacological research direction for the therapy in patients with IDD.

Metabolite asymmetric dimethylarginine (ADMA) functions as a destabilization enhancer of SOX9 mediated by DDAH1 in osteoarthritis.

Osteoarthritis (OA) is a degenerative disease with a series of metabolic changes accompanied by many altered enzymes. Here, we report that the down-regulated dimethylarginine dimethylaminohydrolase-1 (DDAH1) is accompanied by increased asymmetric dimethylarginine (ADMA) in degenerated chondrocytes and in OA samples. Global or chondrocyte-conditional knockout of ADMA hydrolase DDAH1 accelerated OA development in mice. ADMA induces the degeneration and senescence of chondrocytes and reduces the extracellular matrix deposition, thereby accelerating OA progression. ADMA simultaneously binds to SOX9 and its deubiquitinating enzyme USP7, blocking the deubiquitination effects of USP7 on SOX9 and therefore leads to SOX9 degradation. The ADMA level in synovial fluids of patients with OA is increased and has predictive value for OA diagnosis with good sensitivity and specificity. Therefore, activating DDAH1 to reduce ADMA level might be a potential therapeutic strategy for OA treatment.

PD0325901, an ERK inhibitor, attenuates RANKL-induced osteoclast formation and mitigates cartilage inflammation by inhibiting the NF-κB and MAPK pathways.

Osteoarthritis (OA), a degenerative disease affecting the joint, is characterized by degradation of the joint edge, cartilage injury, and subchondral bone hyperplasia. Treatment of early subchondral bone loss in OA can inhibit subsequent articular degeneration and improve the prognosis of OA. PD0325901, a specific inhibitor of ERK, is widely used in oncology and has potential as a therapeutic agent for osteoarthritis In this study, we investigated the biological function of PD0325901 in bone marrow monocytes/macrophages (BMMs)treated with RANKL and found that it inhibited osteoclast differentiation in vitro in a time- and dose-dependent manner. PD0325901 restrained the expression of osteoclast marker genes, such as c-Fos and NFATc1 induced by RANKL. We tested the biological effects of PD035901 on ATDC5 cells stimulated by IL-1ß and found that it had protective effects on ATDC5 cells. In animal studies, we used a destabilization of the medial meniscus (DMM) model and injected 5 mg/kg or 10 mg/kg of PD0325901 compound into each experimental group of mice. We found that PD0325901 significantly reduced osteochondral pathological changes in post-OA subchondral bone destruction.Finally, we found that PD0325901 down-regulated the pyroptosis level in chondrocytes to rescue cartilage degeneration. Therefore, PD0325901 is expected to be a new generation alternative therapy for OA.

Maltol ameliorates intervertebral disc degeneration through inhibiting PI3K/AKT/NF-κB pathway and regulating NLRP3 inflammasome-mediated pyroptosis.

OBJECTIVES: As one of the major causes of low back pain, intervertebral disc degeneration (IDD) has caused a huge problem for humans. Increasing evidence indicates that NLRP3 inflammasome-mediated pyroptosis of NP cells displays an important role in the progression of IDD. Maltol (MA) is a flavoring agent extracted from red ginseng. Due to its anti-inflammatory and antioxidant effects, MA has been widely considered by researchers. Therefore, we hypothesized that MA may be a potential IVD protective agent by regulating NP cells and their surrounding microenvironment. METHODS: In vitro, qRT-PCR, and Western blot were used to explore the effect of MA on the transcription and protein expression of the anabolic protein (ADAMTS5, MMP3, MMP9) catabolic protein (Aggrecan), and pro-inflammatory factor (iNOS COX-2). Next, the effects of MA on PI3K/AKT/NF-κB pathway and pyroptosis pathway were analyzed by Western blot and immunofluorescence. Molecular docking was used to investigate the relationship between PI3K and MA. Moreover, ELISA was also used to detect the effects of MA on inflammatory factors (TNF-α, PGE2, IL-1ß, and IL-18). In vivo, the effects of MA on the vertebral structure of IDD mice were studied by HE and SO staining and the effects of MA on ECM and PI3K/AKT/NF-κB and pyroptosis pathway of IDD mice were studied by immunohistochemical staining. RESULTS: MA can ameliorate intervertebral disc degeneration in vivo and in vitro. Specifically, the molecular docking results showed that the binding degree of MA and PI3K was significant. Second, in vitro studies showed that MA inhibited the degradation of ECM and inflammatory response by inhibiting the PI3K/AKT/NF-κB pathway and the pyroptosis mediated by NLRP3 inflammasome, which increased the expression of anabolic proteins, decreased the expression of catabolic proteins, and decreased the secretion of inflammatory mediators such as IL-18 and IL-1ß. In addition, according to the study results of the mouse lumbar instability model, MA also improved the tissue disorder and degradation of the intervertebral disc, reduced the loss of proteoglycan and glycosaminoglycan, and inhibited intervertebral disc inflammation, indicating that MA has a protective effect on the intervertebral disc to intervertebral disc in mice. CONCLUSIONS: Our results suggest that MA slowed IDD development through the PI3K/AKT/NF-κB signaling pathway and NLRP3 inflammasome-mediated pyroptosis, indicating that MA appeared to be a viable medication for IDD treatment.

Diagnostic value of MRI in coexistence of schwannoma and meningioma mimicking a single dumbbell-shaped tumor in high cervical level. Case series and literature review.

CONTEXT: Concurrent schwannoma and meningioma arising in the high cervical level mimicking a single dumbbell-shaped tumor is significantly rare, most of them were found during the surgeries or postoperative histological findings unexpectedly. The specific feature of schwannoma and meningioma coexistence in high cervical level on MR images has not been clearly described yet. FINDINGS: We presented four cases of concurrent extradural schwannoma and intradural meningioma mimicking a single dumbbell-shaped tumor arising in the high cervical level. There was no interconnection between intradural and extradural masses in any case. In MRI reviews, the signal intensity between intradural lesions and spinal cord was similar on T2 weighted MR images. However, on contrast-enhanced MR images, the intradural lesions were more enhanced than spinal cord and presented as crescent-shaped intradural minor lesions adjacent to the more significantly enhanced extradural major tumor. These MRI findings could not be easily identified without meticulous observation preoperatively. Postoperative pathological findings confirmed the discrete tumors arising in the same cervical level. CONCLUSION: The comparison of signal intensity changes among the spinal cord, intradural tumor and extradural tumor between T2 weighted and contrast-enhanced MR images may be helpful to predict coexistent schwannoma and meningioma in the high cervical level preoperatively. Intradural exploration is highly recommended when less enhanced crescent-shaped intradural minor lesion was observed adjacent to the significantly enhanced dumbbell-shaped major tumor in preoperative MRI findings.

Development and experimental verification of C-arm camera shooting locator.

This study aimed to develop a self-made C-arm camera shooting locator and verify its accuracy and advantages. A total of 60 physicians and nurses from the Surgical System of Sanmen People's Hospital, Zhejiang Province, China, were randomly selected as filming operators. The C-arm machine with a self-made locator and a C-arm machine without a locator were used to measure the center of the circular plate. The iron nails were used to shoot. The distance between the iron nail and the center point of the circular display area on display was defined as the shooting deviation. When it was less than 3 cm, the shooting was stopped. The number of shots, total shooting time, and first-shot deviation in the C-arm camera shooting groups with and without the locator were statistically analyzed, and the advantages and disadvantages of the two were compared. The average number of shots, average total shooting time, and average first-shot deviation of the C-arm camera using the locator were significantly better than those in the group without the locator, and the differences were statistically significant. When the shooting distance (X) was equal to 30 cm and the shooting angle (Y) was equal to 0°, the average number of shots, average total shooting time, and average first-shot deviation were optimal. The C-arm camera shooting locator can improve the shooting accuracy of the C-arm camera and effectively reduce the number of shots and total shooting time. Hence, it can be applied in clinical and surgical practice.

Delayed diagnosis of blunt thoracic aortic injury due to thoracic vertebral fracture: A case report and literature review.

Blunt vascular injury of the aorta combined with thoracolumbar fracture is rare. Delayed diagnosis may have a catastrophic outcome. We present a case of blunt thoracic aortic injury combined with a vertebral body fracture at T10 after a fall from height in which the diagnosis was delayed. After consultation with the vascular and spinal surgeons, we performed a thoracic endovascular aortic repair. When the patient's condition had stabilized, the fractures were reduced using posterior vertebral instrumentation. Prolonged compression of the thoracic aorta resulted in extensive necrosis of muscle tissues in the right lower leg. Fortunately, clinical and radiological examinations performed 7 months and 1 year later did not reveal any further damage. Cases of thoracic vertebral fracture with concomitant blunt thoracic aortic injury reported in the literature are reviewed. Thoracic endovascular aortic repair is a feasible, safe, and effective minimally invasive treatment for aortic injury when combined with thoracic vertebral fracture.

Selumetinib - a potential small molecule inhibitor for osteoarthritis treatment.

Objectives: Osteoarthritis (OA) is a common disease that mainly manifests as inflammation and destruction of cartilage and subchondral bone. Recently, necroptosis has been reported to play an important role in the development of OA. Selumetinib displays a contrasting expression pattern to necroptosis-related proteins. The present study aimed to investigate the potential therapeutic effects of selumetinib in OA process. Methods: In vitro experiments, interleukin-1ß (IL-1ß) was used to induce necroptosis of chondrocytes. We used high-density cell culture, Western Blot and PT-PCR to observe the effect of different concentrations of selumetinib on the extracellular matrix of cartilage. Afterwards, we visualized the effect of selumetinib on osteoclast formation by TRAP staining and F-actin rings. In vivo experiment, we induced experimental osteoarthritis in mice by surgically destabilizing the medial meniscus (DMM) while administering different concentrations of selumetinib intraperitoneally. Results: Selumetinib promoted cartilage matrix synthesis and inhibited matrix decomposition. We found that selumetinib exerted a protective function by inhibiting the activation of RIP1/RIP3/MLKL signaling pathways in chondrocytes. Selumetinib also inhibited the activation of RANKL-induced NF-κB and MAPK signaling pathways in BMMs, thereby interfering with the expression of osteoclast marker genes. In the DMM-induced OA model, a postsurgical injection of selumetinib inhibited cartilage destruction and lessened the formation of TRAP-positive osteoclasts in subchondral bone. Conclusion: Selumetinib can protect chondrocytes by regulating necroptosis to prevent the progression of OA and reduce osteoclast formation. In summary, our findings suggest that selumetinib has potential as a therapeutic agent for OA.

The core genes of cuproptosis assists in discerning prognostic and immunological traits of clear cell renal cell carcinoma.

Objective: Cuproptosis, a nascent and unique pattern of cell death, is poised to spark a new rush of biological research. Yet, the subsumed mechanism of cuproptosis in carcinoma is not wholly clarified. The exclusive aim of this work is to define a novel classification algorithm and risk-prognosis scoring framework based on the expression modalities of cuproptosis genes to monitor clear cell renal cell carcinoma (ccRCC) patients' prognosis and immunotherapeutic response. Methods: We pooled ccRCC data from three large-scale databases as the training subset and gathered a panel of clinical queues, termed the Taizhou cohort, which served as the validation setup. Wilcox test was conducted for comparison of expression variation, while the cox analysis and KM curves were utilized to visualize prognosis. Unsupervised clustering analysis was used to identify cuproptosis phenotypes in ccRCC. Concurrently, LASSO regression-based computational scoring model. A step further, gene set enrichment analysis (GSEA) was performed to check potential biological processes and the "CIBERSORT" R package was used to estimate the proportion of immune cells. To last, immunohistochemistry and qRT-PCR were carried out for the assay of critical genes for cuproptosis. Results: Here, we glimpse the prognostic power of cuproptosis genes in pan-cancer by investigating 33 cancers with multi-omics data to map their genetic heterogeneity landscape. In parallel, we devoted extra attention to their strategic potential role in ccRCC, identifying two phenotypes of cuproptosis with different immune microenvironmental characteristics by pooling ccRCC data from three large-scale databases. Additionally, we compiled a cuproptosis scoring system for clinicians to determine the prognosis, immunotherapy response, and chemosensitivity of ccRCC patients. Notably, we assembled a clinical cohort sample to validate the pivotal gene for cuproptosis, FDX1, to supply more clues to translate the biological significance of cuproptosis in ccRCC. Conclusion: In all, our investigations highlight that cuproptosis is involved in various components of ccRCC and assists in the formation of the tumor immune microenvironment. These results provide partial insights to further comprehend the molecular mechanisms of cuproptosis in ccRCC and could be helpful for the development of personalized therapeutic strategies targeting copper or cuproptosis.

Acyloxyacyl hydrolase deficiency induces chronic inflammation and bone loss in male mice.

Hormonal homeostasis is essential in bone remodeling. Recent studies have shown that the treatment of intestinal inflammation can result in the regulation of bone resorption in distant bones. Increased intestinal permeability may lead to systemic inflammation and bone loss, also known as gut-bone axis. However, the underlying mechanism remains to be elucidated. Lipopolysaccharide (LPS) is a component of gram-negative bacteria that can increase osteoclastic differentiation in vitro. Acyloxyacyl hydrolase (AOAH) is a specific degrading enzyme of LPS, but little is known about the role of AOAH in bone metabolism. In this study, adult Aoah-/- mice showed a chronic inflammatory state and osteopenic phenotype analyzed by micro-CT and HE staining. Tartrate-resistant acid phosphatase (TRAP) staining of femurs showed an increase in TRAP-positive cells from Aoah-/- mice. AOAH depletion enhanced the osteoclast differentiation and bone resorption capacity of bone marrow-derived macrophages (BMMs). The enhanced osteoclast differentiation and bone resorption capacity of Aoah-/- BMMs were reversed by rAOAH. In conclusion, the chronic inflammatory state of adult Aoah-/- mice promotes bone resorption. AOAH participates in bone metabolism, which is mainly mediated by inhibiting osteoclast differentiation. LPS may be a key mediator of the gut-bone axis, and targeting AOAH may represent a feasible strategy for the treatment of chronic inflammatory bone resorption. KEY MESSAGES : AOAH knockout mice exhibited chronic inflammation mediated by LPS, and LPS may also serve as an important mediator in the regulation of bone metabolism in the gut-bone axis. AOAH regulated bone resorption by blocking the osteoclast differentiation via classical ERK and JNK pathways. rAOAH could rescue the enhanced osteoclast differentiation caused by AOAH deficiency.

AZ-628 delays osteoarthritis progression via inhibiting the TNF-α-induced chondrocyte necroptosis and regulating osteoclast formation.

As a degenerative disease, the pathogenesis and treatment of osteoarthritis (OA) are still being studied. The prevailing view is that articular cartilage dysfunction plays an essential role in the development of osteoarthritis. Similarly, dynamic bone remodeling dramatically influences the development of osteoarthritis. The inflammatory response is caused by the overexpression of inflammatory factors, among which tumor necrosis factor-α is one of the main causes of OA, and its sources include the secretion of chondrocytes themselves and osteoclast secretion of subchondral bone. Moreover, TNF-α-induced activation of RIP1, RIP3, and MLKL has been shown to play an important role in cell necroptosis and inflammatory responses. In vitro, AZ-628 alleviates chondrocyte inflammation and necroptosis by inhibiting the NF-κB signaling pathway and RIP3 activation instead of RIP1 activation. AZ-628 also reduces osteoclast activity, proliferation and differentiation, and release of inflammatory substances by inhibiting autophagy, MAPK, and NF-κB pathways. Similarly, the in vivo study demonstrated that AZ-628 could inhibit chondrocyte breakdown and lower osteoclast formation and bone resorption, thereby slowing down subchondral bone changes induced by dynamic bone remodeling and reversing the progression of osteoarthritis in mice. The results of this study indicate that AZ-628 could be used to treat OA byinhibiting chondrocyte necroptosis and regulating osteoclast formation.

Neratinib exerts dual effects on cartilage degradation and osteoclast production in Osteoarthritis by inhibiting the activation of the MAPK/NF-κB signaling pathways.

Osteoarthritis (OA) is a degenerative disease caused by the progressive destruction of cartilage and subchondral bone [1]. Studies have shown that by inhibiting the degradation of cartilage cells and the loss of subchondral bone, OA can be prevented and treated. Neratinib, as a small molecule compound with anti-inflammatory and anti-tumor properties, is a very effective inhibitor of IL-1ß-induced chondrocyte inflammation and anabolic metabolism. By investigating the effect of neratinib in ATDC5 chondrocytes, the study finds that neratinib reduces inflammation by inhibiting the MAPK and NF-κB signaling pathways, and at the same time reduces pyrolysis (indicated by the results of reverse transcription quantitative PCR and western blotting). For anabolic metabolism, after high-density cell culture, IL-1ß-induced catalytic changes and degradation of the extracellular matrix were evaluated by toluidine blue staining. Since osteoclasts are key participants in the process of subchondral bone remodeling in OA, we also studied the effect of neratinib on the maturation of osteoclasts. The results showed that neratinib also acts as an anti-osteoclast agent in vitro. By inhibiting the NF-κB and MAPK pathways, it reduces the expression of osteoclast-related genes, thereby inhibiting RANKL-induced osteoclastogenesis. The results of in vivo animal experiments supported the conclusions from the experiments in vitro. Neratinib inhibited both the destruction of medial meniscus induced cartilage degradation and osteoclast formation, which proves that neratinib has a dual effect, protecting cartilage and inhibiting osteoclast formation. These results indicate that neratinib can be a brand-new latent strategy for the treatment of OA.

Maffucci syndrome complicated by giant chondrosarcoma in the left ankle with an IDH1 R132C mutation: a case report.

BACKGROUND: Maffucci syndrome (MS) is a rare, nonhereditary congenital mesodermal dysplasia characterized by multiple enchondromas and hemangiomas, associated with an increased risk of developing malignant tumors. Given their rarity, the pathogenesis of these tumors has not been clarified, and there is no standard treatment. CASE PRESENTATION: We present a case of a 45-year-old man with MS to supplement the clinical manifestations and explore the molecular mechanism of MS. The patient underwent amputation surgery to inhibit tumor development and was diagnosed with MS with 1-2 grade giant chondrosarcoma in the left ankle. In addition, the whole exon analysis results revealed isocitrate dehydrogenase 1 (IDH1) R132C mutation in chondrosarcoma lesions but not in blood DNA. CONCLUSIONS: This case report showed MS complicated by giant chondrosarcoma in the left ankle with an IDH1 R132C mutation, which is appropriate to monitor the development of MS pathology and other concomitant lesions.

Acute spontaneous spinal subdural hematoma presenting with Takotsubo cardiomyopathy: a rare case report and literature review.

Spontaneous spinal subdural hematoma (SSDH) is a rare and dangerous intraspinal hematoma that usually occurs in the thoracic vertebra. The influence of early cardiovascular changes secondary to spinal cord injury is an important emergent issue. Herein, we report a case of a middle-aged woman with clinical manifestations of back pain and motion and sensory disturbances below the level of spinal cord compression. During the disease course, she also developed changes indicative of myocardial injury, such as tachycardia, markedly increased concentrations of brain natriuretic peptide and cardiac troponin I, and a decreased left ventricular ejection fraction, which were consistent with the diagnosis of Takotsubo cardiomyopathy (TTC). After the administration of supportive therapies, the symptoms of myocardial injury rapidly resolved. With the absorption of SSDH, the symptoms and clinical signs were alleviated. We also reviewed the literature on cases of concomitant SSDH and TTC. This rare case broadens the symptom spectrum of SSDH and highlights the need for clinicians to be aware of concomitant SSDH and TTC. Initial conservative treatment is a viable option for SSDH with concomitant TTC. However, urgent surgery may be a better option if the SSDH progressively enlarges and causes spinal cord compression.

A novel technique of transpedicular opening-wedge osteotomy for treatment of rigid kyphosis in patients with ankylosing spondylitis.

BACKGROUND: To investigate the effectiveness and feasibility of a novel vertebral osteotomy technique, transpedicular opening-wedge osteotomy (TOWO) was used to correct rigid thoracolumbar kyphotic deformities in patients with ankylosing spondylitis (AS). METHODS: Eighteen AS patients underwent TOWO to correct rigid thoracolumbar kyphosis. Radiographic parameters were compared before surgery, 1 week after surgery and at the last follow-up. The SRS-22 questionnaire was given before surgery and at the last follow-up to evaluate clinical improvement. The operating time, estimated blood loss and complications were analyzed. RESULTS: The mean operating time and estimated blood loss were 236 min and 595 ml, respectively. The mean preoperative sagittal vertical axis (SVA), thoracic kyphosis (TK), pelvic tilt (PT) and thoracolumbar kyphosis (TLK) were 158.97 mm, 51.24 mm, 43.63 mm and 41.74 mm, respectively, and decreased to 66.72 mm, 35.96 mm, 27.21 mm and 8.67 mm at the last follow-up. The mean preoperative lumbar lordosis (LL) and sacral slope (SS) were 8.30 ± 24.43 mm and 19.67 ± 9.40 mm, respectively, which increased to 38.23 mm and 28.13 mm at the last follow-up. The mean height of the anterior column of osteotomized vertebrae increased significantly from 25.17 mm preoperatively to 37.59 mm at the last follow, but the height of the middle column did not change significantly. SRS-22 scores were improved significantly at the last follow-up compared with preoperatively. Solid bone union was achieved in all patients after 12 months of follow-up, and no screw loosening, screw removal or rod breakage was noticed at the last follow-up. CONCLUSIONS: TOWO could achieve satisfactory kyphosis correction by opening the anterior column instead of vertebral body decancellation and posterior column closing, thus simplifying the osteotomy procedure and improving surgical efficacy.