Spermidine attenuates chondrocyte inflammation and cellular pyroptosis through the AhR/NF-κB axis and the NLRP3/caspase-1/GSDMD pathway.

Introduction: Osteoarthritis (OA) is a prevalent chronic degenerative disease, marked by a complex interplay of mechanical stress, inflammation, and metabolic imbalances. Recent studies have highlighted the potential of spermidine (SPD), a naturally occurring polyamine known for its anti-inflammatory and antioxidant properties, as a promising therapeutic agent for OA. This study delves into the therapeutic efficacy and mechanistic pathways of SPD in mitigating OA symptoms. Methods: Forty Sprague-Dawley rats were randomly assigned to four groups, including the CG (sham operation), model (anterior cruciate ligament transection [ACLT], and treatment (ACLT + two different doses of SPD) groups. In vivo, correlations between OA severity and different interventions were assessed by ELISA, X-rays, CT imaging, histological staining, and immunohistochemistry. In vitro, IL-1ß was used to trigger chondrocyte inflammation, and SPD's cytotoxicity was assessed in primary rat chondrocytes. Next, inflammatory markers, extracellular matrix (ECM) proteins, and pathway marker proteins were detected in chondrocytes administered IL-1ß alone, SPD, or aryl hydrocarbon receptor (AhR) silencing, by qRT-PCR, Griess reaction, ELISA, Western blot, and immunofluorescence. Morphological alterations and pyroptosis in chondrocytes were examined by transmission electron microscopy (TEM) and flow cytometry. Results: Our research reveals that SPD exerts significant anti-inflammatory and antipyroptotic effects on IL-1ß-treated chondrocytes and in anterior cruciate ligament transection (ACLT) rat models of OA, primarily through interaction with the Aryl hydrocarbon receptor (AhR). Specifically, SPD's binding to AhR plays a crucial role in modulating the inflammatory response and cellular pyroptosis by inhibiting both the AhR/NF-κB and NLRP3/caspase-1/GSDMD signaling pathways. Furthermore, the knockdown of AhR was found to negate the beneficial effects of SPD, underscoring the centrality of the AhR pathway in SPD's action mechanism. Additionally, SPD was observed to promote the preservation of cartilage integrity and suppress ECM degradation, further supporting its potential as an effective intervention for OA. Discussion: Collectively, our findings propose SPD as a novel therapeutic approach for OA treatment, targeting the AhR pathway to counteract the disease's progression and highlighting the need for further clinical evaluation to fully establish its therapeutic utility.

Diagnosis and treatment of anterior cruciate ligament injuries: Consensus of Chinese experts part II: Graft selection and clinical outcome evaluation.

Background: In the recent decade, there has been substantial progress in the technologies and philosophies associated with diagnosing and treating anterior cruciate ligament (ACL) injuries in China. The therapeutic efficacy of ACL reconstruction in re-establishing the stability of the knee joint has garnered widespread acknowledgment. However, the path toward standardizing diagnostic and treatment protocols remains to be further developed and refined. Objective: In this context, the Chinese Association of Orthopaedic Surgeons (CAOS) and the Chinese Society of Sports Medicine (CSSM) collaboratively developed an expert consensus on diagnosing and treating ACL injury, aiming to enhance medical quality through refining professional standards. Methods: The consensus drafting team invited experts across the Greater China region, including the mainland, Hong Kong, Macau, and Taiwan, to formulate and review the consensus using a modified Delphi method as a standardization approach. As members of the CSSM Lower Limb Study Group and the CAOS Arthroscopy and Sports Medicine Study Group, invited experts concentrated on two pivotal issues: "Graft Selection" and "Clinical Outcome Evaluation" during the second part of the consensus development. Results: This focused discussion ultimately led to a strong consensus on nine specific consensus terms. Conclusion: The consensus clearly states that ACL reconstruction has no definitive "gold standard" graft choice. Autografts have advantages in healing capability but are limited in availability and have potential donor site morbidities; allografts reduce surgical trauma but incur additional costs, and there are concerns about slow healing, quality control issues, and a higher failure rate in young athletes; synthetic ligaments allow for early rehabilitation and fast return to sport, but the surgery is technically demanding and incurs additional costs. When choosing a graft, one should comprehensively consider the graft's characteristics, the doctor's technical ability, and the patient's needs. When evaluating clinical outcomes, it is essential to ensure an adequate sample size and follow-up rate, and the research should include patient subjective scoring, joint function and stability, complications, surgical failure, and the return to sport results. Medium and long-term follow-ups should not overlook the assessment of knee osteoarthritis.

Stair Climbing, Genetic Predisposition, and the Risk of Hip/Knee Osteoarthritis.

BACKGROUND: Few studies have explored the association between stair climbing and osteoarthritis (OA) to determine whether the former is a protective or risk factor for the latter. This study prospectively evaluated the associations among stair climbing, genetic susceptibility, and their interaction with the risk of incident hip/knee OA. METHODS: The cohort analyses included 398,939 participants from the UK Biobank. Stair climbing was assessed using a questionnaire. Genetic risk scores (GRSs) consisting of 70, 83, and 87 single-nucleotide polymorphisms for hip, knee, and hip/knee OA were constructed. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations among stair climbing, genetic predisposition, and hip and/or knee OA risk. RESULTS: After 3,621,735 person-years of follow-up, 31,940 patients developed OA. Stair climbing was positively associated with incident hip/knee (P for trend<0.001) and knee (P for trend<0.0001) OA but not hip OA. After adjustments, compared with no stair climbing, climbing >150 steps/day was associated with a higher risk of hip/knee OA (HR, 1.08; 95% CI, 1.03-1.12) and knee OA (HR, 1.13; 95% CI, 1.06-1.20). Although no significant interaction between stair climbing and the GRS of OA risk was found, the above associations were only significant in participants with middle and high GRSs. CONCLUSION: A higher frequency of stair climbing was positively associated with the risk of knee OA but not hip OA, highlighting the importance of avoiding frequent stair climbing in preventing knee OA, especially in genetically predisposed individuals.

The phosphatase inhibitor BVT-948 can be used to efficiently screen functional sexual development proteins in the malaria parasite Plasmodium berghei.

BACKGROUND: Studying and discovering the molecular mechanism of Plasmodium sexual development is crucial for the development of transmission blocking drugs and malaria eradication. The aim of this study was to investigate the feasibility of using phosphatase inhibitors as a tool for screening proteins essential for Plasmodium sexual development and to discover proteins affecting the sexual development of malaria parasites. METHODS: Differences in protein phosphorylation among Plasmodium gametocytes incubated with BVT-948 under in vitro ookinete culture conditions were evaluated using phosphoproteomic methods. Gene Ontology (GO) analysis was performed to predict the mechanism by which BVT-948 affected gametocyte-ookinete conversion. The functions of 8 putative proteins involved in Plasmodium berghei sexual development were evaluated. Bioinformatic analysis was used to evaluate the possible mechanism of PBANKA_0100800 in gametogenesis and subsequent sexual development. RESULTS: The phosphorylation levels of 265 proteins decreased while those of 67 increased after treatment with BVT-948. Seven of the 8 genes selected for phenotype screening play roles in P. berghei sexual development, and 4 of these were associated with gametocytogenesis. PBANKA_0100800 plays essential roles in gametocyte-ookinete conversion and transmission to mosquitoes. CONCLUSIONS: Seven proteins identified by screening affect P. berghei sexual development, suggesting that phosphatase inhibitors can be used for functional protein screening.

Pectolinarigenin targeting FGFR3 alleviates osteoarthritis progression by regulating the NF-κB/NLRP3 inflammasome pyroptotic pathway.

OBJECTIVE: Osteoarthritis (OA) is a chronic degenerative disease characterized by cartilage degeneration, involving inflammation, pyroptosis, and degeneration of the extracellular matrix (ECM). Pectolinarigenin (PEC) is a natural flavonoid with antioxidant, anti-inflammatory and anti-tumor properties. This study aims to explore the potential of PEC in ameliorating OA progression and its underlying mechanisms. METHODS: Chondrocytes were exposed to 10 ng/mL IL-1ß to simulate OA-like changes. The effect of PEC on IL-1ß-treated chondrocytes was assessed using ELISA, western blot, and immunofluorescence. The mRNA sequencing (mRNA-seq) was employed to explore the possible targets of PEC in delaying OA progression. The OA mouse model was induced through anterior cruciate ligament transection (ACLT) and divided into sham, ACLT, ACLT+5 mg/kg PEC, and ACLT+10 mg/kg PEC groups. Micro-computed tomography and histological analysis were conducted to confirm the beneficial effects of PEC on OA in vivo. RESULTS: PEC mitigated chondrocyte pyroptosis, as evidenced by reduced levels of pyroptosis-related proteins. Additionally, PEC attenuated IL-1ß-mediated chondrocyte ECM degradation and inflammation. Mechanistically, mRNA-seq showed that FGFR3 was a downstream target of PEC. FGFR3 silencing reversed the beneficial effects of PEC on IL-1ß-exposed chondrocytes. PEC exerted anti-pyroptotic, anti-ECM degradative, and anti-inflammatory effects through upregulating FGFR3 to inhibit the NF-κB/NLRP3 pyroptosis-related pathway. Consistently, in vivo experiments demonstrated the chondroprotective effects of PEC in OA mice. CONCLUSION: PEC alleviate OA progression by FGFR3/NF-κB/NLRP3 pathway mediated chondrocyte pyroptosis, ECM degradation and inflammation, suggesting the potential of PEC as a therapeutic agent for OA.

Machine learning-based identification and immune characterization of ferroptosis-related molecular clusters in osteoarthritis and validation.

Osteoarthritis (OA), a degenerative joint disease, involves synovial inflammation, subchondral bone erosion, and cartilage degeneration. Ferroptosis, a regulated non-apoptotic programmed cell death, is associated with various diseases. This study investigates ferroptosis-related molecular subtypes in OA to comprehend underlying mechanisms. The Gene Expression Omnibus datasets GSE206848, GSE55457, GSE55235, GSE77298 and GSE82107 were used utilized. Unsupervised clustering identified the ferroptosis-related gene (FRG) subtypes, and their immune characteristics were assessed. FRG signatures were derived using LASSO and SVM-RFE algorithms, forming models to evaluate OA's ferroptosis-related immune features. Three FRG clusters were found to be immunologically heterogeneous, with cluster 1 displaying robust immune response. Models identified nine key signature genes via algorithms, demonstrating strong diagnostic and prognostic performance. Finally, qRT-PCR and Western blot validated these genes, offering consistent results. In addition, some of these genes may have implications as new therapeutic targets and can be used to guide clinical applications.

Ultra-processed food consumption, genetic susceptibility, and the risk of hip/knee osteoarthritis.

BACKGROUND: The associations between ultra-processed food (UPF) consumption, genetic susceptibility, and the risk of osteoarthritis (OA) remain unknown. This study was to examine the effect of UPF consumption, genetic susceptibility, and their interactions on hip/knee OA. METHODS: Cohort analyses included 163,987 participants from the UK Biobank. Participants' UPF consumption was derived from their 24-h dietary recall using a questionnaire. Genetic risk scores (GRSs) of 70 and 83 single nucleotide polymorphisms (SNPs) for hip and knee OA were constructed. FINDINGS: After 1,461,447 person-years of follow-up, 11,540 patients developed OA. After adjustments, compared to participants in the low quartile of UPF consumption, those in the high quartile had a 10 % (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03-1.18) increased risk of knee OA. No significant association was found between UPF consumption and hip OA. Replacing 20% of UPF diet weight with an equivalent proportion of unprocessed or minimally processed food caused a 6% (HR, 0.94; 95% CI, 0.89-0.98) decreased risk of knee OA, respectively. A significant interaction was found between UPF consumption, genetic predisposition, and the risk of knee OA (P = 0.01). Participants with lower OA-GRS scores experienced higher knee OA risks due to UPF consumption. INTERPRETATION: UPF consumption was associated with a higher risk of knee OA but not hip OA, particularly in those with lower genetic susceptibility. These results highlight the importance of reducing UPF consumption to prevent knee OA.

Exerkines and osteoarthritis.

Osteoarthritis (OA) is the most prevalent chronic joint disease, with physical exercise being a widely endorsed strategy in its management guidelines. Exerkines, defined as cytokines secreted in response to acute and chronic exercise, function through endocrine, paracrine, and/or autocrine pathways. Various tissue-specific exerkines, encompassing exercise-induced myokines (muscle), cardiokines (heart), and adipokines (adipose tissue), have been linked to exercise therapy in OA. Exerkines are derived from these kines, but unlike them, only kines regulated by exercise can be called exerkines. Some of these exerkines serve a therapeutic role in OA, such as irisin, metrnl, lactate, secreted frizzled-related protein (SFRP), neuregulin, and adiponectin. While others may exacerbate the condition, such as IL-6, IL-7, IL-15, IL-33, myostatin, fractalkine, follistatin-like 1 (FSTL1), visfatin, activin A, migration inhibitory factor (MIF), apelin and growth differentiation factor (GDF)-15. They exerts anti-/pro-apoptosis/pyroptosis/inflammation, chondrogenic differentiation and cell senescence effect in chondrocyte, synoviocyte and mesenchymal stem cell. The modulation of adipokine effects on diverse cell types within the intra-articular joint emerges as a promising avenue for future OA interventions. This paper reviews recent findings that underscore the significant role of tissue-specific exerkines in OA, delving into the underlying cellular and molecular mechanisms involved.

RNF125, transcriptionally regulated by NFATC2, alleviates osteoarthritis via inhibiting the Wnt/ß-catenin signaling pathway through degrading TRIM14.

Osteoarthritis (OA) is a chronic joint disease characterized by the progressive degradation of articular cartilage. In this study, as determined by histological staining, the cartilage surface of the OA rats was damaged, defective and broken, and chondrocytes and proteoglycan were reduced. While moderate physical exercise showed protective effects on the cartilage. Besides, RNA-seq was performed to select a target protein and RNF125 (an E3 ubiquitin ligase) was decreased in the cartilage tissues of OA rats and increased after physiological exercise. However, the precise role of RNF125 in OA is still unknown. This work aimed to investigate the involvement and underlying mechanism of RNF125 in OA pathogenesis. Our results defined that adenovirus-mediated overexpression of RNF125 inhibited the degradation of extracellular matrix of chondrocytes induced by IL-1ß, as revealed by increased chondrocyte viability, upregulated COL2A1 and ACAN levels, and downregulated MMP1, MMP13 and ADAMTS5 levels, which was abrogated by NR4A2 knockdown. In vivo, RNF125 relieved OA, manifested as reduced cartilage injury and increased chondrocytes. Mechanically, NFATC2 bound to the RNF125 promoter and directly regulated RNF125 transcription, as illustrated by luciferase reporter, Ch-IP and DNA pull-down assays. Furthermore, RNF125 overexpression inhibited the nuclear translocation of ß-catenin, thus suppressing activation of the Wnt/ß-catenin signaling pathway. Also, RNF125 as E3 ubiquitin ligase led to the ubiquitination and degradation of TRIM14 protein, and TRIM14 overexpression efficiently reversed the effects of RNF125 overexpression on OA progression. Totally, this study provides new insights into OA pathogenesis regulated by RNF125. RNF125 may be a novel biomarker for OA therapy.

Synovium is a sensitive tissue for mapping the negative effects of systemic iron overload in osteoarthritis: identification and validation of two potential targets.

BACKGROUND: The prevention and treatment of osteoarthritis (OA) pose a major challenge in its research. The synovium is a critical tissue in the systematic treatment of OA. The present study aimed to investigate potential target genes and their correlation with iron overload in OA patients. METHODS: The internal datasets for analysis included the microarray datasets GSE46750, GSE55457, and GSE56409, while the external datasets for validation included GSE12021 and GSE55235. The GSE176308 dataset was used to generate single-cell RNA sequencing profiles. To investigate the expression of the target genes in synovial samples, quantitative reverse transcription-PCR, western blotting, and immunohistochemical assay were conducted. ELISA was used to detect the levels of ferritin and Fe2+ in both serum and synovium. RESULTS: JUN and ZFP36 were screened from the differentially expressed genes, and their mRNA were significantly reduced in the OA synovium compared to that in normal synovium. Subsequently, complex and dynamically evolving cellular components were observed in the OA synovium. The mRNA level of JUN and ZFP36 differed across various cell clusters of OA synovium and correlated with immune cell infiltration. Moreover, ferritin and Fe2+ were significantly increased in the serum and synovium of OA patients. Further, we found that JUN elevated and ZFP36 decreased at protein level. CONCLUSIONS: The synovium is a sensitive tissue for mapping the adverse effects of systemic iron overload in OA. JUN and ZFP36 represent potential target genes for attenuating iron overload during OA treatment. Some discrepancies between the transcription and protein levels of JUN suggest that post-transcriptional modifications may be implicated. Future studies should also focus on the roles of JUN and ZFP36 in inducing changes in cellular components in the synovium during OA pathogenesis.

The Bcr-Abl inhibitor DCC-2036 inhibits necroptosis and ameliorates osteoarthritis by targeting RIPK1 and RIPK3 kinases.

Osteoarthritis (OA) is a chronic progressive degenerative joint disease. Owing to its complex pathogenesis, OA treatment is typically challenging. Necroptosis is a form of programmed cell death mainly mediated by the serine/threonine kinases, RIPK1 and RIPK3, and mixed lineage kinase-like domain (MLKL). In this study, we found that the multi-targeted kinase inhibitor DCC-2036 can inhibit TSZ (TNF-α, Smac mimetic, and z-VAD-FMK)-induced necroptosis of chondrocytes and synovial fibroblast cells (SFs). In addition, we found that oral DCC-2036 inhibited chondrocyte damage in a rat model of OA induced by intra-articular injection of monosodium iodoacetate (MIA). A mechanistic study showed that DCC-2036 directly inhibited the activities of RIPK1 and RIPK3 kinases to block necroptosis, inhibiting the inflammatory response and protecting chondrocytes. In summary, our research suggests that DCC-2036, a new necroptosis inhibitor targeting RIPK1 and RIPK3 kinase activity, may be useful for the clinical treatment of OA and provides a new direction for the research and treatment of OA.

Chitosan targets PI3K/Akt/FoxO3a axis to up-regulate FAM172A and suppress MAPK/ERK pathway to exert anti-tumor effect in osteosarcoma.

Osteosarcoma (OS) is a serve and the most frequent primary malignant tumor of bone. Chitosan was reported to have anti-tumor effect on human cancers including OS. However, the molecular mechanism by which chitosan suppresses tumor growth is not fully illustrated. In this study, human OS cell lines, including both Saos-2 and U2OS cells, were used to dissect the underlying mechanisms. RNA sequencing results show that a candidate biomarker family with sequence similarity 172 member A (FAM172A) was up-regulated in both of the two cell lines treated with chitosan. We observed that the mitogen-activated protein kinase (MAPK) signaling pathway could be inactivated by chitosan, and the MAPK inhibition caused by chitosan was reversed by FAM172A knockdown. Moreover, we uncovered a direct interaction between C-terminal domain of FAM172A (311-415) and mitogen-activated protein kinase kinase 1 (MEK1) (270-307) by immunoprecipitation assay. Finally, we also found that chitosan could bind with subunit p85 of PI3K to further inactivate the PI3K/Akt pathway. Taken together, our study demonstrates that chitosan binds with PI3K p85 subunit to suppress the activity of PI3K/Akt pathway to up-regulate the expression of FAM172A, and which exerts its function by suppressing phosphorylation of MEK1/2 and blocking the activity of MAPK/ERK signaling pathway. Taken together, our study deepens the understanding of the molecular mechanism of MAPK/ERK pathway inhibition induced by chitosan, and provides insights into the development of new targets to enhance the pharmacological effect of chitosan against OS.

Exercise induced meteorin-like protects chondrocytes against inflammation and pyroptosis in osteoarthritis by inhibiting PI3K/Akt/NF-κB and NLRP3/caspase-1/GSDMD signaling.

The production of metrnl, a novel adipomyokine, is induced upon exercise in adipose tissue and skeletal muscle. In this study, we investigated the anti-inflammatory and antipyroptotic effects of exercise-induced metrnl producted in rats in vitro and in vivo. Forty Sprague-Dawley rats were divided randomly into five groups: control (CG), osteoarthritis (OA) with sedentary lifestyle (OAG), OA with low intensity exercise (OAL), OA with moderate intensity exercise (OAM), and OA with high intensity exercise (OAH). The correlation between the level of metrnl and OA degree was detected using ELISA, X-ray imaging, histology, and immunohistochemistry in vivo. Primary chondrocytes were preincubated with recombinant metrnl before interleukin-1ß administration to verify the anti-inflammatory and antipyroptotic effects of metrnl. Western blotting and quantitative reverse transcription (qRT)-PCR were used to evaluate the differences in protein and mRNA expression between groups, respectively. Reactive oxygen species (ROS) assay, immunofluorescence, transmission electron microscopy (TEM), and flow cytometry were used to evaluate morphological changes and pyroptosis in chondrocytes. In the moderate-intensity treadmill exercise group, the severity of OA showed maximum relief and the metrnl levels had the most significant increase. Metrnl exerted its anti-inflammatory effect through the suppression of the PI3K/Akt/NF-κB pathway in IL-1ß-induced OA chondrocytes, which was accompanied with the recovery of collagen II expression and the attenuation of MMP13 and ADAMTS5. Moreover, metrnl ameliorated chondrocyte pyroptosis by inhibiting the activation of the nod-like receptor protein-3/caspase-1/gasdermin D cascade. In conclusion, moderate-intensity exercise improves inflammation and pyroptosis by increasing metrnl release, which inhibits the PI3K/Akt/NF-κB and further NLRP3/caspase-1/GSDMD signaling pathways.

Senomorphic agent pterostilbene ameliorates osteoarthritis through the PI3K/AKT/NF-κB axis: an in vitro and in vivo study.

OBJECTIVES: Osteoarthritis (OA) is the most common joint disease in the world. Among the many risk factors for OA, aging is one of the most critical factors. The treatment with senop-associated secretory phenotype (SASP) is one of the important, promising anti-aging strategies at present. Pterostilbene (PTE) is a trans-stilbene compound with anti-tumor, anti-oxidation, anti-inflammatory, and anti-aging pharmacologic activities. The purpose of this study is to explore the therapeutic effects of PTE on articular chondrocyte senescence and OA and its related mechanisms. METHODS: Male Sprague-Dawley rats were operated on with transection of the anterior cruciate ligament (ACLT) and a destabilized medial meniscus (DMM) surgery to establish the OA model and then injected intraperitoneally with PTE (20 mg/kg) for 5 weeks. Finally, rats were sacrificed and knee joints were collected for histologic analysis. Rat chondrocytes were stimulated with interleukin-1ß (IL-1ß) with or without PTE treatment. The therapeutic effects of PTE and related mechanisms were investigated by examining and analyzing relative markers through senescence-associated ß-galactosidase (SA-ß-Gal) assay, cell cycle, qRT-PCR, western blot, bioinformatic analysis, immunofluorescence, and molecular modeling. RESULTS: With in vivo experiments, PTE can significantly reduce the Mankin scores and OARSI scores of the knee joint in ACLT+DMM OA model rats and reduce the interleukin-6 (IL-6) level in the knee lavage fluid. Immunohistochemical staining showed that compared to the OA group, the PTE treatment group had significantly increased expression of collagen type II in articular cartilage, and significantly decreased matrix metalloproteinase 13 (MMP-13) and IL-6, the main SASP proteins, and had expression of p16 and p21, markers of aging in chondrocytes. In vitro, PTE reduced the ratio of SA-ß-Gal positive chondrocytes and G0-G1 phase chondrocytes in IL-1ß-induced rat chondrocytes. PTE significantly inhibited the expression of MMP-13, IL-6, thrombospondin motif 5 (ADAMTS5), p16, and p21, and significantly increased the expression of collagen type II. Bioassay and subsequent western blot showed that PTE significantly inhibited the activation of PI3K/AKT and NF-κB signaling pathways. The results of molecular docking experiments showed that PTE could bind closely to the sites of PI3K protein, thereby inhibiting the phosphorylation of PI3K. CONCLUSIONS: The experimental results indicate that PTE plays an anti-chondrocyte senescence role in the treatment of OA by inhibiting the PI3K/AKT/NF-κB signaling pathway and reducing expression of SASP.

Role of adiponectin in osteoarthritis.

Osteoarthritis (OA) is a widespread and most common joint disease which leads to social cost increasing accompany with aging population. Surgery is often the final treatment option. The major progression of OA includes cartilage degradation caused by chondrocytes metabolism imbalance. So, the molecular mechanisms of action in chondrocytes may provide insights into treatment methods for OA. Adiponectin is an adipokine with many biological functions in the cell metabolism. Numerous studies have illustrated that adiponectin has diverse biological effects, such as inhibition of cell apoptosis. It regulates various functions in different organs, including muscle, adipose tissue, brain, and bone, and regulates skeletal homeostasis. However, the relationship between adiponectin and cell death in the progression of OA needs further investigation. We elaborate the structure and function and the effect of adiponectin and state the correlation and intersection between adiponectin, autophagy, inflammation, and OA. From the perspective of oxidative stress, apoptosis, pyroptosis, and autophagy, we discuss the possible association between adiponectin, chondrocyte metabolism, and inflammatory factor efforts in OA. What's more, we summarize the possible treatment methods, including the use of adiponectin as a drug target, and highlight the potential future mechanistic research. In this review, we summarize the molecular pathways and mechanisms of action of adiponectin in chondrocyte inflammation and death and the pathogenesis of OA. We also review the research on adiponectin as a target for treating OA. These studies provide a novel perspective to explore more effective treatment options considering the complex interrelationship between inflammation and metabolism in OA.

Mechanical stress protects against chondrocyte pyroptosis through lipoxin A4 via synovial macrophage M2 subtype polarization in an osteoarthritis model.

Our previous study found that lipoxin A4 (LXA4) exerts therapeutic effects on osteoarthritis (OA). In this study, we evaluated the effects of LXA4 via synovial macrophage M1/M2 subtype polarization on chondrocyte pyroptosis and corresponding mechanisms during mechanical stimulation. Synovial macrophages were subjected to various LXA4 concentrations and cyclic tensile strain (CTS) conditions to determine optimal co-culture conditions. The effects of LXA4 on chondrocyte pyroptosis, as represented by macrophage M1/M2 subtype polarization, were detected by western blot, immunofluorescence, and flow cytometry analyses. Forty male Sprague-Dawley rats were randomly divided into four groups (n = 10): control (CG), OA (OAG), OA with moderate-intensity treadmill exercise (OAE), and OAE + BOC-2 (an LXA4 antagonist). All rats were evaluated using histology, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot analyses. We found that with increasing Kellgren-Lawrence grade, LXA4 expression was downregulated in articular fluid and that CD86 and Arg1 expression was upregulated in the synovium of patients. In vitro, CTS and LXA4 both promoted M2 subtype polarization of synovial macrophages, which inhibited the nuclear translocation of NF-κB p65 and formation of NLRP3 in chondrocytes. In vivo, the OAE treatment exerted protective effects on articular cartilage and facilitated M2 polarization of synovial macrophages. These effects were suppressed by BOC-2 treatment. We concluded that moderate CTS enhances therapeutic effects of LXA4 by inhibiting the nuclear translocation of NF-κB p65 and NLRP3. Furthermore, the therapeutic effects of LXA4 during treadmill exercise in monoiodoacetate-induced OA were driven by promotion of synovial macrophage M2 subtype polarization.

Primary Repair for Treating Acute Proximal Anterior Cruciate Ligament Tears: A Histological Analysis and Prospective Clinical Trial.

Reconstruction surgery for acute proximal anterior cruciate ligament (ACL) tears remains controversial. Recently, ACL primary repair has received increasing attention in ACL treatment. This study aimed to explore the histological characteristics of ACL healing in primary repair and compare its therapeutic and prognostic results with the reconstruction of acute proximal ACL tears. Histological experiments using rabbits and a prospective clinical trial were conducted. We established a rabbit model of ACL primary repair, and histological changes were observed using haematoxylin and eosin (HE) and toluidine blue staining. We performed immunohistochemical analysis of CD34 and S-100 and measured the expression of collagen I and II using qRT-PCR, Western blotting, and immunohistochemistry. The prospective clinical trial involved performing ACL primary repair and reconstruction in patients with acute proximal ACL tears to detect proprioception and evaluate the function of joints. We discovered that primary repair promoted cell proliferation in the tendon-bone transition and ligament portions, reduced osteoarthritis-like pathological changes, and maintained blood vessels and proprioceptors within the ACL. In the clinical trial, primary repair achieved similar therapeutic outcomes, including recovery of knee function and proprioception, in the follow-up period as ACL reconstruction. However, the primary repair had a significantly shorter operative time and lower cost than reconstruction. Therefore, doctors should consider the benefit of primary repair in treating acute proximal ACL tears.

Curcumin exerts chondroprotective effects against osteoarthritis by promoting AMPK/PINK1/Parkin-mediated mitophagy.

Osteoarthritis (OA), a chronic degenerative disease with heterogeneous properties, is difficult to cure due to its complex pathogenesis. Curcumin possesses excellent anti-inflammatory and antioxidant properties and may have potential therapeutic value in OA. In this study, we investigated the action targets of curcumin and identified potential anti-OA targets for curcumin. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analyses were performed to evaluate these targets. Furthermore, we established a sodium monoiodoacetate-induced rat knee OA model and IL-1ß induced OA chondrocyte model to verify the effect and mechanism of curcumin against OA. The GO and KEGG analyses screened seven hub genes involved in metabolic processes and the AMPK signaling pathway. Curcumin can significantly attenuate OA characteristics according to Osteoarthritis Research Society International (OARSI) and Mankin scores in OA rats. Additionally, curcumin is notably employed as an activator of mitophagy in maintaining mitochondrial homeostasis (ROS, Ca2+, ATP production, and mitochondrial membrane potential). The expression levels of mitophagy-related proteins were increased not only in articular cartilage but also in chondrocytes with curcumin intervention. Combining validation experiments and network pharmacology, we identified the importance of mitophagy in the curcumin treatment of OA. The chondroprotective effects of curcumin against OA are mediated by the AMPK/PINK1/Parkin pathway, and curcumin may serve as a potential novel drug for OA management.

Mechanical Stimulation Protects Against Chondrocyte Pyroptosis Through Irisin-Induced Suppression of PI3K/Akt/NF-κB Signal Pathway in Osteoarthritis.

Irisin, a myokine secreted by muscle during physical exercise, is known to have biological activities in different cell types. Chondrocyte inflammation and pyroptosis have been shown to play important roles in osteoarthritis (OA). In this study, we investigated the effects of exercise-induced irisin during different intensities of treadmill exercise in a rat OA model and the anti-inflammatory and antipyroptosis mechanism of irisin in OA chondrocytes. Forty-eight SD rats (n = 8) were randomly assigned to control (CG), OA (OAG), OA groups under different intensities of treadmill exercise (OAL, OAM, and OAH), OAM + irisin neutralizing antibodies group (OAM + irisin (NA)). The levels of irisin and the severity of OA between groups were detected using ELISA, histology, immunohistochemistry, X-ray and computed tomography and magnetic resonance imaging. The anti-inflammatory and antipyroptosis mechanisms of irisin were investigated in vitro in OA chondrocytes preincubated with recombinant irisin (0, 5, or 10 ng/ml) for 1 h before treatment with interleukin-1ß (IL-1ß) for 24 h mRNA and protein expression levels were determined using quantitative reverse transcription polymerase chain reaction, and western blot analyses. Morphological changes and cell death associated with pyroptosis were examined using transmission electron microscopy, flow cytometry and immunofluorescence. Moderate-intensity treadmill exercise increased the levels of irisin, exhibiting the best therapeutic effects on OA which could be suppressed by irisin neutralizing antibodies. Irisin not only recovered the expression of collagen II and attenuated that of MMP-13 and ADAMTS-5 in IL-1ß-induced OA chondrocytes by inhibiting the PI3K/Akt/NF-κB signaling pathway, but also inhibited the activity of nod-like receptor protein-3 (NLRP3)/caspase-1, thus ameliorating pyroptosis in chondrocytes. In conclusion, moderate mechanical stimulation protects against chondrocyte pyroptosis through irisin-induced suppression of PI3K/Akt/NF-κB signal pathway in osteoarthritis.