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AbstractOsteoarthritis (OA) is a chronic degenerative disease caused by various factors such as aging, obesity, trauma, and genetics. It is a challenging condition faced by orthopedic doctors in clinical practice and places a heavy burden on patients and their families. Currently, the treatment of OA primarily focuses on symptomatic relief and lacks ideal therapeutic methods. Resveratrol is a natural polyphenolic compound with anti-inflammatory and antioxidant properties, and in recent years, it has gained attention as a candidate drug for OA treatment. This article provides an overview of the research status on the role and mechanisms of resveratrol in treating OA. It has been found that resveratrol can prevent the development of OA by inhibiting inflammatory responses, protecting chondrocytes, maintaining cartilage homeostasis, promoting autophagy, and has shown certain therapeutic effects. This process may be related to the regulation of signaling pathways such as nuclear factor-kappa B (NF-κB), Toll-like receptor 4 (TLR4), and silent information regulator 1 (SIRT1). We summarize the current molecular mechanisms of resveratrol in treating OA, hoping to provide a reference for further research and application of resveratrol in OA treatment. [ABSTRACT FROM AUTHOR]

To perform non-invasive Electroarthrography (EAG) on live horses and establish relationships between EAG and direct measurements of cartilage streaming potentials in weight bearing areas of the equine metacarpophalangeal joint. EAG was performed bilaterally on the metacarpophalangeal joints of live horses (n = 3). Separate experiments used metacarpophalangeal joint explants (n = 11) to measure EAG obtained during simulated loading followed by direct measurements of cartilage streaming potentials on joint surfaces using the Arthro-BST probe. Joints were assigned to relatively normal (n = 5) and mildly degraded (n = 6) groups based on histological scoring of Safranin-O/Fast Green stained sections. EAG, involving application of electrodes to skin surrounding the joint and repeated weight shifting, was well-tolerated in live horses. One pair of distal forelimbs were available for analogous ex vivo EAG testing and measurements were strongly correlated to in vivo EAG measurements obtained on the same joints (r = 0.804, p = 0.016, n = 8). Both indirect (EAG) and direct (Arthro-BST) measurements of cartilage streaming potentials distinguished between normal and mildly degraded cartilage with statistically significant differences at 5 of 6 and 4 of 6 electrodes during simulated standing and walking, respectively. Strong and moderate correlations for weight bearing regions on the dorsal phalanx and central metacarpus were detected during both standing and walking. At the metacarpus/sesamoid interface a moderate correlation occurred during walking. Non-invasive EAG was used successfully in a clinical scenario and correlated to direct measurements of streaming potentials in weight bearing cartilage. These data support the potential of EAG to contribute to the diagnosis and treatment of degenerative joint diseases. [ABSTRACT FROM AUTHOR]

BACKGROUND: Studies have shown that hesperetin exerts protective effects on chondrocytes through a variety of mechanisms or signaling pathways, but the protective mechanisms have not been fully elucidated. OBJECTIVE: To investigate the effect of hesperetin on lipopolysaccharide-induced inflammatory degeneration of chondrocytes. METHODS: Knee joint chondrocytes from suckling Sprague-Dawley rats were isolated and cultured in vitro, and identified by Safranine O staining. The cytotoxicity of hesperetin on chondrocytes was determined by the MTT assay to ensure the optimal concentration of hesperetin. Chondrocytes were randomly divided into three groups, including the control group, model group, and experimental group. The cellular model of osteoarthritis was established in the latter two groups by simulating chondrocytes with lipopolysaccharide. Chondrocytes in the experimental group was then intervened with hesperetin for 24 hours. Calcein-AM/EthD-I staining was used to detect cell viability. Immunohistochemical staining was performed to determine the expression of type II collagen in chondrocytes. Intracellular reactive oxygen species level was detected by a reactive oxygen species detection kit. Total glutathione level was detected by ELISA. Real-time fluorescent PCR was employed to detect the expression of interleukin 1β, interleukin 6, tumor necrosis factor α and type II collagen. RESULTS AND CONCLUSION: Safranine O staining results showed that the cells extracted were chondrocytes. Cytotoxicity test results showed 0.5 μmol/L hesperetin had the most significant effect on chondrocyte vitality. Compared with the control group, the model group showed a decrease in chondrocyte proliferation ability, an increase in reactive oxygen species levels, a decrease in total glutathione levels, an increase in type II collagen degradation, an increase in the levels of interleukin 1β, interleukin 6, and tumor necrosis factor α, and a decrease in the expression of type II collagen (P < 0.05). Compared with the model group, in the experimental group, the proliferation ability of chondrocytes increased, reactive oxygen species levels decreased, total glutathione levels increased, and type II collagen degradation decreased, levels of interleukin 1β, interleukin 6, and tumor necrosis factor α downregulated, and the expression of type II collagen upregulated (P < 0.05). To conclude, hesperetin has a protective effect on lipopolysaccharide-induced inflammatory degeneration of osteoarthritic chondrocytes, and the mechanism may be associated with inhibition of reactive oxygen species-mediated oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Studies comparing the effectiveness of arthroscopic knee surgery and conservative treatment on knee osteoarthritis (OA) came up with inconsistent results. Systematic review on this topic still is still lacking. This systematic review and meta-analysis aimed to evaluate the effectiveness of arthroscopic knee surgery on knee OA, compared to conservative treatments. Materials and methods: Literature searches were performed in PubMed, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) published before on 1st July 2024. Studies comparing the effectiveness of arthroscopy and conservative treatments only on knee OA were included. Quality of included studies was evaluated by risk of bias 2 (ROB2). Long-term results in terms of pain relief, functional recovery and patients reported satisfaction were meta-analyzed to evaluate the therapeutic effectiveness. Results: Ten studies were included in this review, among which only 1 was considered as low risk of bias. Five studies were involved in meta-analyses and no difference was found in therapeutic effectiveness of arthroscopic surgery and conservative treatment on knee OA, in the evaluation of VAS (p = 0.63), WOMAC (p = 0.38), SF-36 (p = 0.74) and patient satisfaction (p = 0.07). Conclusion: The evidence does not support the effectiveness of arthroscopic knee surgery compared to conservative treatments in knee OA. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis is a prevalent joint disorder characterized by cartilage degeneration, pain, and impaired physical function. Vitamin D might be implicated in the management of knee osteoarthritis through its effects on bone health, cartilage preservation, inflammation modulation, and muscle function. Objectives: This literature review aims to synthesize the current state of literature to provide information about the correlation between vitamin D and knee osteoarthritis. Methods: We conducted a comprehensive literature search in databases such as PubMed, Web of Science, Scopus, and Google Scholar to identify studies published in the last ten years investigating the association between vitamin D and knee osteoarthritis. Results: Vitamin D deficiency has been linked to cartilage degeneration and more severe symptomatology of knee osteoarthritis. Conclusions: The evidence supports an association between vitamin D levels and knee osteoarthritis, but with some studies showing mixed results, there is a need for further research. [ABSTRACT FROM AUTHOR]

Cartilage, a critical tissue for joint function, often degenerates due to osteoarthritis (OA), rheumatoid arthritis (RA), and trauma. Recent research underscores necroptosis, a regulated form of necrosis, as a key player in cartilage degradation. Unlike apoptosis, necroptosis triggers robust inflammatory responses, exacerbating tissue damage. Key mediators such as receptor-interacting serine/threonine-protein kinase-1 (RIPK1), receptor-interacting serine/threonine-protein kinase-3(RIPK3), and mixed lineage kinase domain-like (MLKL) are pivotal in this process. Studies reveal necroptosis contributes significantly to OA and RA pathophysiology, where elevated RIPK3 and associated proteins drive cartilage degradation. Targeting necroptotic pathways shows promise; inhibitors like Necrostatin-1 (Nec-1), GSK'872, and Necrosulfonamide (NSA) reduce necroptotic cell death, offering potential therapeutic avenues. Additionally, autophagy's role in mitigating necroptosis-induced damage highlights the need for comprehensive strategies addressing multiple pathways. Despite these insights, further research is essential to fully understand necroptosis' mechanisms and develop effective treatments. This review synthesizes current knowledge on necroptosis in cartilage degeneration, aiming to inform novel therapeutic approaches for OA, RA, and trauma. [ABSTRACT FROM AUTHOR]

During surgery for osteochondral lesions of the talus (OLT), preservation or excision of the osteochondral fragment is chosen based on the cartilage condition which influences the indication and clinical outcomes of surgical treatments. However, it is difficult to predict arthroscopic and histological findings of the cartilage on osteochondral fragments by radiographic evaluation. We focused on osteoarthritis (OA) changes on plain radiographs to predict the cartilage condition of the OLT. This study aimed to evaluate whether OA changes, including osteophyte and joint space narrowing, could predict arthroscopic and histological findings of the cartilage in OLT. Seventy ankles with OLT were included in this study. Osteophytes and joint space narrowing were scored on plain radiographs. Lesion sizes were measured on computed tomography images. The cartilage surfaces of fragments were arthroscopically assessed using the International Cartilage Repair Society (ICRS) grade. Biopsy specimens from 32 ankles were histologically analyzed using the Mankin score. The relationships between OA scores, lesion size, ICRS grades, and Mankin score were analyzed. OA changes were frequently observed with increasing ICRS grades, especially in the medial tibiotalar joint. OA scores in patients with ICRS grade 1 were significantly lower than those in ICRS grades 2,3, and 4. The lesion sizes in patients with ICRS grade 3 and 4 were significantly smaller than those in patients with ICRS grade 1 and 2. Histological analysis showed increasing Mankin scores as the ICRS grade worsened. A mild correlation existed between the OA and Mankin scores (rs = 0.494). OA changes, such as osteophyte formation and joint space narrowing, are associated with arthroscopic findings of the articular surface and cartilage degeneration in osteochondral fragment in OLT. Articular cartilage conditions can be predicted by OA changes on plain radiographs, which is useful for choosing the appropriate treatment for patients with OLT. Level Ⅳ, case series. [ABSTRACT FROM AUTHOR]

Abstract Background Studies comparing the effectiveness of arthroscopic knee surgery and conservative treatment on knee osteoarthritis (OA) came up with inconsistent results. Systematic review on this topic still is still lacking. This systematic review and meta-analysis aimed to evaluate the effectiveness of arthroscopic knee surgery on knee OA, compared to conservative treatments. Materials and methods Literature searches were performed in PubMed, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) published before on 1st July 2024. Studies comparing the effectiveness of arthroscopy and conservative treatments only on knee OA were included. Quality of included studies was evaluated by risk of bias 2 (ROB2). Long-term results in terms of pain relief, functional recovery and patients reported satisfaction were meta-analyzed to evaluate the therapeutic effectiveness. Results Ten studies were included in this review, among which only 1 was considered as low risk of bias. Five studies were involved in meta-analyses and no difference was found in therapeutic effectiveness of arthroscopic surgery and conservative treatment on knee OA, in the evaluation of VAS (p = 0.63), WOMAC (p = 0.38), SF-36 (p = 0.74) and patient satisfaction (p = 0.07). Conclusion The evidence does not support the effectiveness of arthroscopic knee surgery compared to conservative treatments in knee OA.

Temporomandibular joint osteoarthritis (TMJOA) is characterized by progressive cartilage degeneration, subchondral bone remodeling, chronic inflammation in the synovial tissue and osteophyte formation. Chondrocyte apoptosis is one of the main factors of cartilage degeneration. Prevention and treatment of TMJOA can be achieved by inhibiting premature or excessive chondrocyte apoptosis. Primary cilia protruding from the surface of chondrocytes can sense mechanical stimulation and induce chondrocyte differentiation. Studying the role of primary cilia in TMJOA will help us understand the pathogenesis of TMJOA and construct a reasonable and effective treatment strategy.

Abstract Objectives To explore the feasibility of Ultra-short echo time (UTE) – MRI quantitative imaging in detecting early cartilage degeneration in vivo and underlying pathological and biochemical basis. Methods Twenty volunteers with osteoarthritis (OA) planning for total knee arthroplasty (TKA) were prospectively recruited. UTE-MRI sequences and conventional sequences were performed preoperatively. Regions of interests (ROIs) were manually drawn on the tibial plateau and lateral femoral condyle images to calculate MRI values. Cartilage samples were collected during TKA according to the preset positions corresponding to MR images. Pathological and biochemical components of the corresponding ROI, including histological grading, glycosaminoglycan (GAG) content, collagen integrity, and water content were obtained. Results 91 ROIs from volunteers of 7 males (age range: 68 to 78 years; 74 ± 3 years) and 13 females (age range: 57 to 79 years; 67 ± 6 years) were evaluated. UTE-MTR (r = −0.619, p

The objective of this study was to assess the osteoarthritis (OA) disease severity in 47 temporomandibular joints (TMJs) using a validated scale for gross signs of OA while noting the specific sites for profound disease on the donor condyle and fossa. A disease severity score of Grade 0–4, representing absent to severe disease, was awarded to each specimen’s condyle and fossa by two blinded investigators who have demonstrated interrater reliability. The mandibular fossa was more pathological compared to the mandibular condyle (* p = 0.001). When the deepest focal lesions were qualitatively assessed, it was demonstrated that the mandibular fossa was more severely degenerated than the articular eminence in 58% of donors. In this subpopulation, 74% of the severe mandibular fossa pathology was seen on the deep articular surface. When the articular eminence was the most severely degenerated region of the fossa, it was equivalently likely to see severe focal lesions on the lateral eminence (35%) or equally distributed across the entire eminence (35%). The greatest disease severity was discovered in sites of overloading, which may be associated with paranormal mandibular movements and potentially bruxism. Patients with bruxism produce significant translational movements (grinding) in the upper joint compartment and heavy vertical loading (clenching). Theoretically, this amplifies pressure and inflammation on the lateral articular surfaces and in the deep fossa.

Abstract Objective Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative joint disorder characterized by extracellular matrix degeneration and inflammatory response of condylar cartilage. β-arrestin2 is an important regulator of inflammation response, while its role in TMJOA remains unknown. The objective of this study was to investigate the role of β-arrestin2 in the development of TMJOA at the early stage and the underlying mechanism. Methods A unilateral anterior crossbite (UAC) model was established on eight-week-old wild-type (WT) and β-arrestin2 deficiency mice to simulate the progression of TMJOA. Hematoxylin-eosin (HE) staining and microcomputed tomography (micro-CT) analysis were used for histological and radiographic assessment. Immunohistochemistry was performed to detect the expression of inflammatory and degradative cytokines, as well as autophagy related factors. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay was carried out to assess chondrocyte apoptosis. Results The loss of β-arrestin2 aggravated cartilage degeneration and subchondral bone destruction in the model of TMJOA at the early stage. Furthermore, in UAC groups, the expressions of degradative (Col-X) and inflammatory (TNF-α and IL-1β) factors in condylar cartilage were increased in β-arrestin2 null mice compared with WT mice. Moreover, the loss of β-arrestin2 promoted apoptosis and autophagic process of chondrocytes at the early stage of TMJOA. Conclusion In conclusion, we demonstrated for the first time that β-arrestin2 plays a protective role in the development of TMJOA at the early stage, probably by inhibiting apoptosis and autophagic process of chondrocytes. Therefore, β-arrestin2 might be a potential therapeutic target for TMJOA, providing a new insight for the treatment of TMJOA at the early stage.

Background: Osteoarthritis is a chronic disorder that affects the synovial joints by the progressive loss of articular cartilage. In the hip, the largest weight-bearing joint, the deterioration of articular cartilage and acetabular labrum can cause pain, diminishing the quality of life for patients. This study presents changes in reported pain scales from patients who received Wharton's jelly applications to cartilage deterioration in the hip from the observational retrospective repository at Regenative Labs. Methods: Sixty-nine patients were selected based on inclusion criteria with patient-reported pain scales, including the Numeric Pain Rating Scale and the Western Ontario and McMaster University Osteoarthritis Index, collected at the initial application, 30, and 90-day follow-up visits. Thirteen patients received a second allograft application and had additional follow-up visits at 120 and 180 days. Results: Five of the six scales used showed a statistically significant improvement in average scores across the cohort. The greatest improvements were observed in the NPRS with a 31.36% improvement after 90 days and a 44.64% improvement for patients with two applications after 180 days. The minimal clinically important difference (MCID) was also calculated to determine the perceived value of care for each patient with 44.9% of patients exceeding the MCID and 78.3% reporting at least one level of improvement. Conclusions: The positive outcomes for the patients in this cohort suggest WJ to be a promising alternative care option for patients with structural tissue degeneration in the hip refractory to the current standard of care. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate the relationship between the joint line convergence angle (JLCA) and the severity of medial knee osteoarthritis (OA). We hypothesise that JLCA is the most associated factor with the severity of medial knee OA. Methods: This retrospective study included a total of 202 knees that underwent either high tibial osteotomy or medial meniscus repair/partial resection. Kellgren–Lawrence grade and hip–knee–ankle angle (HKAA), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA) and JLCA were assessed from preoperative radiographs. Medial meniscus extrusion (MME) was measured using preoperative magnetic resonance imaging. The International Cartilage Research Society (ICRS) grade on the medial femoral condyle and medial tibial plateau were also assessed. The relationships between JLCA and Kellgren–Lawrence grades and MME and ICRS grades were analysed using Spearman's correlation test and regression analysis. Results: The JLCA was correlated with the Kellgren–Lawrence grade (R = 0.765, p < 0.001), MME (R = 0.638, p < 0.001), ICRS grade on the MFC (R = 0.586, p < 0.001) and the MTP (R = 0.586, p < 0.001). Regression analysis showed that age (p = 0.002) and JLCA (p < 0.001) were associated with Kellgren–Lawrence grade. Furthermore, JLCA was related to ICRS grade on the MFC (p < 0.001) and MTP (p < 0.001). Conclusion: The JLCA, reflecting radiological severity, meniscus status, and cartilage lesion, was the most associated alignment parameter in the severity of medial knee OA. The JLCA may be beneficial for quantitative assessment of medial knee OA. Level of Evidence: Level III, retrospective cohort study. [ABSTRACT FROM AUTHOR]

Objectives: To explore the feasibility of Ultra-short echo time (UTE) – MRI quantitative imaging in detecting early cartilage degeneration in vivo and underlying pathological and biochemical basis. Methods: Twenty volunteers with osteoarthritis (OA) planning for total knee arthroplasty (TKA) were prospectively recruited. UTE-MRI sequences and conventional sequences were performed preoperatively. Regions of interests (ROIs) were manually drawn on the tibial plateau and lateral femoral condyle images to calculate MRI values. Cartilage samples were collected during TKA according to the preset positions corresponding to MR images. Pathological and biochemical components of the corresponding ROI, including histological grading, glycosaminoglycan (GAG) content, collagen integrity, and water content were obtained. Results: 91 ROIs from volunteers of 7 males (age range: 68 to 78 years; 74 ± 3 years) and 13 females (age range: 57 to 79 years; 67 ± 6 years) were evaluated. UTE-MTR (r = −0.619, p < 0.001), UTE-AdiabT1ρ (r = 0.568, p < 0.001), and UTE-T2* values (r = −0.495, p < 0.001) showed higher correlation with Mankin scores than T2 (r = 0.287, p = 0.006) and T1ρ (r = 0.435, p < 0.001) values. Of them, UTE-MTR had the highest diagnostic performance (AUC = 0.824, p < 0.001). UTE-MTR, UTE-AdiabT1ρ and UTE-T2* value was mainly related to collagen structural integrity, PG content and water content, respectively (r = 0.536, −0.652, −0.518, p < 0.001, respectively). Conclusion: UTE-MRI have shown greater in vivo diagnostic value for early cartilage degeneration compared to conventional T2 and T1ρ values. Of them, UTE-MTR has the highest diagnostic efficiency. UTE-MTR, UTE-AdiabT1ρ, and UTE-T2* value mainly reflect different aspects of cartilage degeneration--integrity of collagen structure, PG content, and water content, respectively. Critical relevance statement: Ultra-short echo time (UTE)-MRI has the potential to be a novel image biomarkers for detecting early cartilage degeneration in vivo and was correlated with biochemical changes of early cartilage degeneration. Key Points: Conventional MR may miss some early cartilage changes due to relatively long echo times. Ultra-short echo time (UTE)-MRI showed the ability in identifying early cartilage degeneration in vivo. UTE-MT, UTE-AdiabT1ρ, and UTE-T2* mapping mainly reflect different aspects of cartilage degeneration. [ABSTRACT FROM AUTHOR]

BACKGROUND: Currently, there have been studies on the regulatory mechanism of lncRNA\miRNA\mRNA co-expression network on the occurrence and development of osteoarthritis. Our research group has screened qualified NONHSAT248596.1 and miR-146a-5p through the database in the previous stage, but the corresponding in vivo experiments to verify the above regulatory mechanisms are still lacking. OBJECTIVE: To explore the role of NONHSAT248596.1 in regulating competitive endogenous RNA of miR-146a-5p in cartilage degeneration mediated by stromal cell derived factor type 1/chemokine receptor 4 axis in vivo. METHODS: The models of osteoarthritis were established in 36 New Zealand rabbits by injecting stromal cell derived factor 1 solution into the knee joint of the right hind limb. According to the random number table method, they were divided into four groups. lncRNA group, miRNA group, ceRNA group and control group were injected with lentivirus vector overexpressing NONHSAT248596.1, lentivirus vector overexpressing miR-146a-5p, lentivirus vector overexpressing miR-146a-5p+NONHSAT248596.1 and empty lentivirus vector into the molded knee joint, respectively. At 4, 8 and 12 weeks of modeling, cartilage tissues and subchondral bone tissues of the knee joint were taken for relevant detection. RESULTS AND CONCLUSION: Hematoxylin-eosin staining and safranin fast green staining showed different degrees of degeneration in the four groups. At 4 weeks, the cartilage tissue of the lncRNA group showed swelling of chondrocytes, loss of cell polarity, destruction of extracellular matrix, surface erosion, fracture formation and partial or full layer loss of cartilage tissue. The degree of cartilage injury was gradually aggravated with time. The progression of articular cartilage inflammation in the miRNA group was the slowest among the four groups. qRT-PCR showed that at the same time point, mRNA expression levels of NONHSAT248596.1, chemokine receptor 4, matrix metalloproteinase 3, matrix metalloproteinase 9 and matrix metalloproteinase 13 in cartilage tissue of the lncRNA group were higher than those of the other three groups (P < 0.05). The mRNA expression levels of miR-146a-5p, aggrecan and type II collagen were lower than those of the other three groups (P < 0.05). The mRNA expression levels of NONHSAT248596.1, chemokine receptor 4, matrix metalloproteinase 3, matrix metalloproteinase 9 and matrix metalloproteinase 13 in the miRNA group were lower than those in the ceRNA group and control group at 8 and 12 weeks after the model construction (P < 0.05). The mRNA expressions of miR-146a-5p, aggrecan and type II collagen were higher than those of the ceRNA group and control group (P < 0.05). Western blot assay showed that at the same time point, the expression levels of aggrecan and type II collagen in cartilage tissue of the lncRNA group were always lower than those of the other three groups (P < 0.05). The expression levels of aggrecan and type II collagen in cartilage tissue of the miRNA group at 8 and 12 weeks after modeling were higher than those of the ceRNA group and control group (P < 0.05). The results showed that miR-146a-5p, as the target of NONHSAT248596.1, could be inhibited by the effect of its ceRNA. After acting on miR-146a-5p, NONHSAT248596.1 regulates the stromal cell derived factor type 1/chemokine receptor 4 axis to affect the expression of matrix metalloprotein, type II collagen, and aggrecan in osteoarthritis chondrocytes, resulting in the degradation of extracellular matrix and the loss of proteoglycan. [ABSTRACT FROM AUTHOR]

Objective: Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative joint disorder characterized by extracellular matrix degeneration and inflammatory response of condylar cartilage. β-arrestin2 is an important regulator of inflammation response, while its role in TMJOA remains unknown. The objective of this study was to investigate the role of β-arrestin2 in the development of TMJOA at the early stage and the underlying mechanism. Methods: A unilateral anterior crossbite (UAC) model was established on eight-week-old wild-type (WT) and β-arrestin2 deficiency mice to simulate the progression of TMJOA. Hematoxylin-eosin (HE) staining and microcomputed tomography (micro-CT) analysis were used for histological and radiographic assessment. Immunohistochemistry was performed to detect the expression of inflammatory and degradative cytokines, as well as autophagy related factors. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay was carried out to assess chondrocyte apoptosis. Results: The loss of β-arrestin2 aggravated cartilage degeneration and subchondral bone destruction in the model of TMJOA at the early stage. Furthermore, in UAC groups, the expressions of degradative (Col-X) and inflammatory (TNF-α and IL-1β) factors in condylar cartilage were increased in β-arrestin2 null mice compared with WT mice. Moreover, the loss of β-arrestin2 promoted apoptosis and autophagic process of chondrocytes at the early stage of TMJOA. Conclusion: In conclusion, we demonstrated for the first time that β-arrestin2 plays a protective role in the development of TMJOA at the early stage, probably by inhibiting apoptosis and autophagic process of chondrocytes. Therefore, β-arrestin2 might be a potential therapeutic target for TMJOA, providing a new insight for the treatment of TMJOA at the early stage. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the osteoarthritis (OA) disease severity in 47 temporomandibular joints (TMJs) using a validated scale for gross signs of OA while noting the specific sites for profound disease on the donor condyle and fossa. A disease severity score of Grade 0–4, representing absent to severe disease, was awarded to each specimen's condyle and fossa by two blinded investigators who have demonstrated interrater reliability. The mandibular fossa was more pathological compared to the mandibular condyle (* p = 0.001). When the deepest focal lesions were qualitatively assessed, it was demonstrated that the mandibular fossa was more severely degenerated than the articular eminence in 58% of donors. In this subpopulation, 74% of the severe mandibular fossa pathology was seen on the deep articular surface. When the articular eminence was the most severely degenerated region of the fossa, it was equivalently likely to see severe focal lesions on the lateral eminence (35%) or equally distributed across the entire eminence (35%). The greatest disease severity was discovered in sites of overloading, which may be associated with paranormal mandibular movements and potentially bruxism. Patients with bruxism produce significant translational movements (grinding) in the upper joint compartment and heavy vertical loading (clenching). Theoretically, this amplifies pressure and inflammation on the lateral articular surfaces and in the deep fossa. [ABSTRACT FROM AUTHOR]

Lang Liu,1,&ast; Binghua Zhang,1,&ast; Zhenwei Zhou,2 Jie Yang,1 Ailin Li,1 Yongji Wu,1 Zeyu Peng,1 Xiangyan Li,2 Zhonghua Liu,3 Xiangyang Leng,1 Changwei Zhao,4 Haisi Dong,2 Wenhai Zhao4 1College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 2Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 3Department of Orthopaedics, The Third Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 4Affiliated Hospital of Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haisi Dong, Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, People’s Republic of China, Tel/Fax +86 431-18604361976, Email adonghaisi@163.com Wenhai Zhao, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130021, People’s Republic of China, Tel/Fax +86 431-86177836, Email zwh9899@163.comBackground: Knee osteoarthritis (KOA) is a persistent degenerative condition characterized by the deterioration of cartilage. The Chinese herbal formula Radix Rehmanniae Praeparata- Angelica Sinensis-Radix Achyranthis Bidentatae (RAR) has often been used in effective prescriptions for KOA as the main functional drug, but its underlying mechanism remains unclear. Therefore, network pharmacology and verification experiments were employed to investigate the impact and mode of action of RAR in the treatment of KOA.Methods: The destabilization of the medial meniscus model (DMM) was utilized to assess the anti-KOA effect of RAR by using gait analysis, micro-computed tomography (Micro-CT), and histology. Primary chondrocytes were extracted from the rib cartilage of a newborn mouse. The protective effects of RAR on OA cells were evaluated using a CCK‐8 assay. The antioxidative effect of RAR was determined by measuring reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione (GSH) production. Furthermore, network pharmacology and molecular docking were utilized to propose possible RAR targets for KOA, which were further verified through experiments.Results: In vivo, RAR significantly ameliorated DMM-induced KOA characteristics, such as subchondral bone sclerosis, cartilage deterioration, gait abnormalities, and the degree of knee swelling. In vitro, RAR stimulated chondrocyte proliferation and the expression of Col2a1, Comp, and Acan. Moreover, RAR treatment significantly reduced ROS accumulation in an OA cell model induced by IL-1β and increased the activity of antioxidant enzymes (SOD and GSH). Network pharmacology analysis combined with molecular docking showed that Mapk1 might be a key therapeutic target. Subsequent research showed that RAR could downregulate Mapk1 mRNA levels in IL-1β-induced chondrocytes and DMM-induced rats.Conclusion: RAR inhibited extracellular matrix (ECM) degradation and oxidative stress response via the MAPK signaling pathway in KOA, and Mapk1 may be a core target.Keywords: knee osteoarthritis, RAR, cartilage degeneration, network pharmacology, Mapk1

The presence of healthy cartilage in the knee joint, featuring smooth articular surfaces, is crucial for normal physiological knee function. However, noninvasive in-vivo assessment of cartilage quality in the knee remains challenging and has not been thoroughly investigated. We aimed to illustrate two clinical cases, a 62-year-old male and a 67-year-old male, presented to the orthopaedic outpatient clinic with severe knee complaints. The novel combination of sodium fluoride-18 positron emission tomography/computed tomography and intra-articular injection of a contrast agent (Na[18F]F-PET/CT arthrography) was performed to evaluate cartilage defects of the knee as part of a prospective patient study. The lesion size observed on the Na[18F]F-PET was substantially larger compared to the findings on CT. This might indicate that Na[18F]F-PET/CT arthrography was able to image osseous and chondral pathological changes in an early stage and in a single procedure. Na[18F]F-PET/CT arthrography is a promising imaging technique and might extend the diagnostic potential of nuclear and radiological imaging in the evaluation of cartilage defects.

Natural macromolecules like alginate and gelatin are employed to create medication delivery systems that are both safe and effective. Zirconium nanoparticles (ZrO2 NPs) have been proposed as a means of enhancing the alginate-gelatin hydrogel's physical and biological properties. This study combines the synthesis of the biopolymers gelatin and alginate nanofibers with nanoparticles of zirconium oxide (GA/NF– ZrO2 NPs). UV, XRD, FTIR, and SEM were used to characterize the synthesized nanofibers. The expression of osteogenic genes was analyzed by western blotting and qualitative real-time polymerase chain reaction (qRT-PCR). Based on our findings, MC3T3-E1 cells are performed for cell viability, apoptosis and reactive oxygen species production by GA/NF– ZrO2 NPs through the Wnt/β-catenin signaling pathway. Cell migration was accelerated at 75 μg/mL concentration after 24 h of damage in a scratch wound healing assay. Proliferation of the MC3T3-E1 cell line was also detected. GA/NF–ZrO2 NPs influenced the osteogenic variation of MC3T3-E1 cells by inducing autophagy. Furthermore, the impact of obstruction on the temporomandibular joint (TMJ) is a subject of ongoing discussion and analysis within the context of animal models. Coordinated GA/NF–ZrO2 NPs on biomaterial nanofibers could be used to introduce physical signals for modifying MC3T3-E1 responds for orthodontic engineering constructs.

Context: Osteoarthritis (OA) is a degenerative joint disease characterized by an inflammatory reaction and cartilage degradation. Artocarpus altilis is a well-known traditional medicine with various phenolic and flavonoid content. Several pharmacological properties of A. altilis extract (AAE) have been reported, but its effectiveness in osteoarthritis is unknown. Aims: To investigate the potential of AAE as an anti-osteoarthritis. Methods: The Wistar rats induced OA with mono-iodoacetate (MIA). The OA model rats were treated with AAE with three dose levels (100, 200, and 400 mg/kg) for 28 days. As a positive control used Na-diclofenac (20 mg/kg). Serum IL-1β, IL-10, MMP-3, and MMP-13 levels and histopathological profiles were compared to the MIA group and normal control (5% Na-CMC). Results: The experimental results showed that AAE could significantly suppress the production of inflammatory mediator factor IL-1β, matrix-degrading proteinase MMP-3, MMP-13, and cartilage degeneration. In addition, AAE increased the production of the anti-inflammatory mediator IL-10, improved synovial inflammation, and increased cartilage thickness. Conclusions: A. altilis extract has the potential to be developed as an anti-osteoarthritis therapeutic agent from natural medicine.

Background: Diagnosing knee osteoarthritis (KOA) often relies on limited routine methods. This study investigates the efficacy of T2 mapping and Apparent Diffusion Coefficient (ADC) values in MRI for enhanced assessment of cartilage damage in KOA, focusing on their correlation with pain severity. Materials and Methods: A total of 52 KOA patients (74 knee joints) and 50 healthy individuals (100 knee joints) were assessed from May 2022 to June 2023. Both groups underwent MRI with Diffusion Weighted Imaging (DWI) sequence and T2 mapping to analyze ADC and T2 mapping values across femoral condyle, tibial plateau, and patellar joint surfaces, and their correlation with pain levels. Results: The KOA group showed significantly higher ADC and T2 mapping values in all examined areas compared to the control group (P<0.05). These values were also higher in advanced stages of cartilage degeneration and correlated positively with increased pain scores (P<0.05). Conclusion: MRI utilizing DWI and T2 mapping provides a quantitative reflection of knee joint cartilage degeneration in KOA. These methods show a positive correlation with pain severity, suggesting their potential for more accurate KOA diagnostics and assessment. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) of the temporomandibular joint (TMJ) occurs spontaneously in humans and various animal species, including horses. In humans, obtaining tissue samples is challenging and clinical symptoms appear late in the disease progression. Therefore, genetically modified, induced, and naturally occurring animal models play a crucial role in understanding the pathogenesis and evaluating potential therapeutic interventions for TMJ OA. Among the naturally occurring models, the equine TMJ OA model is characterized by slow, age-related progression, a wide range of clinical examinations, and imaging modalities that can be performed on horses, as well as easy tissue and synovial fluid collection. The morphological and functional similarities of TMJ structures in both species make the equine model of TMJ OA an excellent opportunity to track disease progression and response to treatment. However, much work remains to be carried out to determine the utility of human TMJ OA biomarkers in horses. Among the main TMJ OA biomarkers, IL-1, IL-6, TGF-β, TNF-α, and PGE2 have been recently investigated in the equine model. However, the majority of biomarkers for cartilage degradation, chondrocyte hypertrophy, angiogenesis, and TMJ overload—as well as any of the main signaling pathways—have not been studied so far. Therefore, it would be advisable to focus further research on equine specimens, considering both mediators and signaling. [ABSTRACT FROM AUTHOR]

Abstract Purpose The purpose of this study was to evaluate the relationship between the joint line convergence angle (JLCA) and the severity of medial knee osteoarthritis (OA). We hypothesise that JLCA is the most associated factor with the severity of medial knee OA. Methods This retrospective study included a total of 202 knees that underwent either high tibial osteotomy or medial meniscus repair/partial resection. Kellgren–Lawrence grade and hip–knee–ankle angle (HKAA), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA) and JLCA were assessed from preoperative radiographs. Medial meniscus extrusion (MME) was measured using preoperative magnetic resonance imaging. The International Cartilage Research Society (ICRS) grade on the medial femoral condyle and medial tibial plateau were also assessed. The relationships between JLCA and Kellgren–Lawrence grades and MME and ICRS grades were analysed using Spearman's correlation test and regression analysis. Results The JLCA was correlated with the Kellgren–Lawrence grade (R = 0.765, p

Background: Osteoarthritis (OA) is the most common age-related musculoskeletal disease. However, there is still a lack of therapy that can modify OA progression due to the complex pathogenic mechanisms. The aim of the study was to explore the role and mechanism of XJB-5-131 inhibiting chondrocytes ferroptosis to alleviate OA progression. Methods: We treated tert-butyl hydroperoxide (TBHP)-induced ferroptosis of mouse primary chondrocytes with XJB-5-131 in vitro. The intracellular ferroptotic hallmarks, cartilage anabolic and catabolic markers, ferroptosis regulatory genes and proteins were detected. Then we established a mouse OA model via destabilization of the medial meniscus (DMM) surgery. The OA mice were treated with intra-articular injection of XJB-5-131 regularly (2 μM, 3 times per week). After 4 and 8 weeks, we performed micro-CT and histological examination to evaluate the protection role of XJB-5-131 in mouse OA subjects. RNA sequencing analysis was performed to unveil the key downstream gene of XJB-5-131 exerting the anti-ferroptotic effect in OA. Results: XJB-5-131 significantly suppressed TBHP-induced increases of ferroptotic hallmarks (ROS, lipid peroxidation, and Fe2+ accumulation), ferroptotic drivers (Ptgs2, Pgd, Tfrc, Atf3, Cdo1), while restored the expression of ferroptotic suppressors (Gpx4, Fth1). XJB-5-131 evidently promoted the expression of cartilage anabolic and decreased the expression of cartilage catabolic markers. Moreover, intra-articular injection of XJB-5-131 significantly inhibited the expression of Cox2 and Mmp13, while promoted the expression of Col2a1, Gpx4 and Fth1 in DMM-induced mouse articular cartilage. Further, we identified Pebp1 as a potential target of XJB-5-131 by RNA sequencing analysis. The anti-ferroptosis and chondroprotective effects of XJB-5-131 were significantly diminished by Locostatin, a specific antagonist of Pebp1. Conclusion: XJB-5-131 significantly protects chondrocytes from ferroptosis in TBHP-induced mouse primary chondrocytes and DMM surgery-induced OA mice model via restoring the expression of Pebp1. XJB-5-131 is a potential therapeutic drug in the management of OA progression.

Knee osteoarthritis is a prevalent joint disorder characterized by cartilage degeneration, pain, and impaired physical function. Vitamin D might be implicated in the management of knee osteoarthritis through its effects on bone health, cartilage preservation, inflammation modulation, and muscle function. This literature review aims to synthesize the current state of literature to provide information about the correlation between vitamin D and knee osteoarthritis. Methods: We conducted a comprehensive literature search in databases such as PubMed, Web of Science, Scopus, and Google Scholar to identify studies published in the last ten years investigating the association between vitamin D and knee osteoarthritis. Vitamin D deficiency has been linked to cartilage degeneration and more severe symptomatology of knee osteoarthritis. The evidence supports an association between vitamin D levels and knee osteoarthritis, but with some studies showing mixed results, there is a need for further research.

Cartilage, a critical tissue for joint function, often degenerates due to osteoarthritis (OA), rheumatoid arthritis (RA), and trauma. Recent research underscores necroptosis, a regulated form of necrosis, as a key player in cartilage degradation. Unlike apoptosis, necroptosis triggers robust inflammatory responses, exacerbating tissue damage. Key mediators such as receptor-interacting serine/threonine-protein kinase-1 (RIPK1), receptor-interacting serine/threonine-protein kinase-3(RIPK3), and mixed lineage kinase domain-like (MLKL) are pivotal in this process. Studies reveal necroptosis contributes significantly to OA and RA pathophysiology, where elevated RIPK3 and associated proteins drive cartilage degradation. Targeting necroptotic pathways shows promise; inhibitors like Necrostatin-1 (Nec-1), GSK’872, and Necrosulfonamide (NSA) reduce necroptotic cell death, offering potential therapeutic avenues. Additionally, autophagy’s role in mitigating necroptosis-induced damage highlights the need for comprehensive strategies addressing multiple pathways. Despite these insights, further research is essential to fully understand necroptosis’ mechanisms and develop effective treatments. This review synthesizes current knowledge on necroptosis in cartilage degeneration, aiming to inform novel therapeutic approaches for OA, RA, and trauma.

This study aimed to evaluate the effects of general control non-derepressible 2 (GCN2) on osteoarthritis (OA) in vivo and in vitro. First, anterior cruciate ligament transection (ACLT)-induced rat model and interleukin (IL)-1β-induced ATDC5 chondrocyte were established. Hematoxylin and eosin staining and safranin O/fast green staining were employed for analyzing the histological changes in the rat cartilage. In addition, immunohistochemistry, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, western blot, and immunofluorescence staining were employed for examining cartilage degeneration-, inflammation-, autophagy-, and NLR family pyrin domain containing 3 (NLRP3) inflammasome-associated genes expression. Moreover, 2,7-dichlorodihydrofluorescein acetoacetic acid probe was utilized for examining the intracellular reactive oxygen species. In addition, 5-ethynyl-2′-deoxyuridine assay and flow cytometry were applied for detecting chondrocyte proliferation and apoptosis IL-1β-treated ATDC5 chondrocytes. GCN2 overexpression ameliorated articular cartilage degeneration and inflammation but promoted chondrocyte autophagy in ACLT-induced OA rats. Similarly, we demonstrated that the upregulation of GCN2 could promote chondrocyte proliferation, suppress chondrocyte apoptosis, attenuate chondrocyte inflammation and extracellular matrix degradation, and promote chondrocyte autophagy. Moreover, GCN2 overexpression could inhibit the activation of NLRP3 inflammasome in IL-1β-induced ATDC5 chondrocyte. Furthermore, 3-methyladenine neutralized the protective and autophagy-promoting effects of GCN2 overexpression on ATDC5 chondrocytes. GCN2 could attenuate inflammation and cartilage degeneration, promote chondrocyte autophagy, and inhibit NLRP3 inflammasome activation in OA. [ABSTRACT FROM AUTHOR]

Cartilage plays a crucial role in the human body by forming long bones during development and growth to bear loads on joints and intervertebral discs. However, the increasing prevalence of cartilage degenerative disorders is a growing public health concern, especially due to the poor innate regenerative capacity of cartilage. Chondrocytes are a source of several inflammatory mediators that play vital roles in the pathogenesis of cartilage disorders. Among these mediators, chemokines have been explored as potential contributors to cartilage degeneration and regeneration. Our review focuses on the progress made during the last ten years in identifying the regulators and roles of chemokines and their receptors in different mechanisms related to chondrocytes and cartilage. Recent findings have demonstrated that chemokines influence cartilage both positively and negatively. Their induction and involvement in either process depends on the local molecular environment and is both site- and time-dependent. One of the challenges in defining the role of chemokines in cartilage pathology or regeneration is the apparent redundancy in the interaction of chemokines with their receptors. Hence, it is crucial to determine, for each situation, whether targeting specific chemokines or their receptors will help in developing effective therapeutic strategies for cartilage repair. [ABSTRACT FROM AUTHOR]

The knee is the joint most frequently involved in osteoarthritis, a common joint disorder in the adult population that is associated with significant chronic joint pain, reduced mobility and quality of life. Recent studies have established an association between obesity and the development of knee osteoarthritis that goes beyond the increased mechanical load on the knees as weight-bearing joints. This link is based on the maintenance of a chronic low-grade inflammation, altered secretion of adipokines by the adipose tissue and development of sarcopenia. Major adipokines involved in the pathogenesis of obesity-related knee osteoarthritis include adiponectin, which appears to have a protective effect, as well as leptin, resistin and visfatin, which are associated with higher pain scores and more severe structural damage. Joint pain in knee osteoarthritis may be both nociceptive and neuropathic and is the result of complex mechanisms driven by nerve growth factor, calcitonin gene-related peptide and pro-inflammatory cytokines. The role of endogenous cannabinoids and gut microbiota in common mechanisms between obesity and knee pain has recently been studied. The aim of the present review is to highlight major pathogenic mechanisms in obesity-related knee osteoarthritis with special attention on pain and to comment on possible therapeutic approaches. [ABSTRACT FROM AUTHOR]

Recurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N=5) and osteoarthritis (OA) (N=5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss of Tnxb in F8-/- mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss. Tnxb knockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects following Tnxb knockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.

BackgroundThe quantitative MR techniques developed rapidly, vary MR-biomarkers have shown the ability to assess the quality of articular cartilage. This study aimed to investigate the diagnostic efficacy of multi-parametric quantitative ultrashort echo time (UTE)-based MRI for evaluating human cartilage degeneration.MethodsTwenty fresh anterolateral femoral condyle samples were obtained from 20 patients (age, 58.8±6.6 years; 6 females) who underwent total knee arthroplasty due to primary osteoarthritis (OA). The samples were imaged using UTE-based magnetization transfer (UTE-MT), UTE-based adiabatic T1ρ (UTE-AdiabT1ρ), UTE-based T2* (UTE-T2*), and CubeQuant-T2 sequences. Cartilage degeneration was classified based on the OA Research Society International grade and polarized light microscopy (PLM) collagen organization score. Spearman's correlation analysis was used to determine the relationships between quantitative MRI biomarkers [UTE-MT ratio (UTE-MTR), UTE-AdiabT1ρ, UTE-T2*, and CubeQuant-T2], OA Research Society International grade, and PLM collagen organization score. The diagnostic efficacy of each MRI biomarker for the detection of mild cartilage degeneration was assessed using the area under the receiver operating characteristic (ROC) curve (AUC).ResultsOf the quantitative MRI biomarkers, UTE-MTR had the strongest correlation with both OA Research Society International grade (r=-0.709, P

Abstract Background Knee osteoarthritis (KOA) is an age-related degenerative disease characterized by abrasion of articular cartilage. Tongbi Huoluo Decoction (TBHLD) has been transformed from the famous traditional Chinese medicine Duhuo Jisheng Decoction, which can effectively alleviate pain symptoms in KOA. However, the active components and mechanisms of TBHLD in treating KOA have not yet been elucidated. The purpose of the study was to demonstrate the molecular mechanism of TBHLD in treating KOA. Methods The components and targets of TBHLD and KOA were collected from multiple databases, and the protein to protein interaction (PPI) network was constructed. Next, we performed topological calculation and enrichment analysis. Besides, we performed virtual screening for molecular docking and molecular dynamics simulation (MDS). Furthermore, the vitro and vivo experiments were performed to evaluate the validity and mechanism of TBHLD. Results 206 active components and 187 potential targets were screened from Tongbi Huoluo Decoction. A total of 50 intersecting genes were identified between TBHLD and KOA, 20 core targets were calculated by network topology analysis. The core targets were enriched in the ECM interaction pathways. The results of virtual screening for molecular docking and MDS showed that the active components of TBHLD had steady binding conformations with core genes. Moreover, we identified 32 differential serum components in TBHLD-containing serum using LC–MS, including 22 upregulated and 10 downregulated serum components. TBHLD improved the proliferation activity of OA chondrocytes, decreased the expression of Col1a1, Col1a2, Mmp2, Mmp13 in OA chondrocytes, ameliorated the cartilage lesions and restored the cartilage abrasion. Conclusion TBHLD inhibited degradation of cartilage ECM by regulating the expression of type I collagens and Mmps to ameliorate cartilage degeneration in KOA.

Osteoarthritis (OA) is a chronic debilitating joint disease, characterized by degeneration of the cartilage and loss of the cartilage matrix, and it is clinically manifested as joint pain. Osteopontin (OPN) is a glycoprotein that is abnormally expressed in the bone and cartilage tissues and plays a vital role in various pathological processes such as the osteoarthritic inflammatory response and endochondral ossification. The focus of our study is to investigate the therapeutic potential and specific role of OPN in OA. Using morphological comparisons, we found that the cartilage was severely worn-out and there was a significant loss of the cartilage matrix in OA. OPN, CD44, and hyaluronic acid (HA) synthase 1 (HAS1) were highly expressed, and the anabolism of HA was significantly higher in the OA chondrocytes than in the control chondrocytes. Additionally, we treated the OA chondrocytes with small interfering RNA (siRNA) targeting OPN, recombinant human OPN (rhOPN), and a combination of rhOPN and anti-CD44 antibodies. Furthermore, in vivo experiments were performed in mice. We found that OPN upregulated the expression of downstream HAS1 and increased the anabolism of HA through CD44 protein expression in OA mice compared with those in control mice. Moreover, intra-articular injection of OPN in mice with OA significantly inhibited OA progression. In summary, OPN initiates an intracellular cascade via CD44 which results in an anabolic increase in HA levels, thereby inhibiting OA progression. Therefore, OPN is a promising therapeutic agent in precision treatment of OA.

Recent molecular biology studies have revealed the process of nasal capsule determination. We aimed to create a fate map showing the association between the adult and embryonic components of the nasal wall and nasal capsule derivatives. We examined paraffin‐embedded histological sections between 15 mid‐term (9–16 weeks) and 12 near‐term (27–40 weeks) foetuses. Until 15 weeks, membranous ossification occurred 'along' the capsular cartilage, contributing to the formation of the vomer, maxilla and bony nasal septum as well as the nasal, frontal and lacrimal bones. After 15 weeks, a wide lateral part of the capsule became thin and fragmented, and degenerative cartilage was observed near the lacrimal bone, in the three conchae, and at the inferolateral end of the capsule sandwiched between the maxilla and palatine bone. The disappearing cartilages appeared to be replaced by nearby membranous bones. This type of membranous ossification did not appear to use the capsular cartilage as a 'mould', although the perichondrium may have a role in inducing ossification. Calcified cartilage indicated endochondral ossification in the inferior concha until 15 weeks and, later, at the bases of three conchae and around the future sphenoid sinus (i.e. the concha sphenoidalis). The capsular cartilage extended antero‐superiorly over the frontal bone and inserted into the nasal bone. At 40 weeks, the capsular cartilage remained in the cribriform plate and at the inferolateral end along the palatine bone. Consequently, less guidance from the nasal capsule seemed to provide great individual variation in the shape of the wide anterolateral wall of the nasal cavity. [ABSTRACT FROM AUTHOR]

MicroRNAs play a crucial role in regulating cartilage extracellular matrix (ECM) metabolism and are being explored as potential therapeutic targets for osteoarthritis (OA). The present study indicated that microRNA-224-5p (miR-224-5p) could balance the homeostasis of OA via regulating cartilage degradation and synovium inflammatory simultaneously. Multifunctional polyamidoamine dendrimer with amino acids used as efficient vector to deliver miR-224-5p. The vector could condense miR-224-5p into transfected nanoparticles, which showed higher cellular uptake and transfection efficiency compared to lipofectamine 3000, and also protected miR-224-5p from RNase degradation. After treatment with the nanoparticles, the chondrocytes showed an increase in autophagy rate and ECM anabolic components, as evidenced by the upregulation of autophagy-related proteins and OA-related anabolic mediators. This led to a corresponding inhibition of cell apoptosis and ECM catabolic proteases, ultimately resulting in the alleviation of ECM degradation. In addition, miR-224-5p also inhibited human umbilical vein endothelial cells angiogenesis and fibroblast-like synoviocytes inflammatory hyperplasia. Integrating the above synergistic effects of miR-224-5p in regulating homeostasis, intra-articular injection of nanoparticles performed outstanding therapeutic effect by reducing articular space width narrowing, osteophyte formation, subchondral bone sclerosis and inhibiting synovial hypertrophy and proliferation in the established mouse OA model. The present study provides a new therapy target and an efficient intra-articular delivery method for improving OA therapy. Osteoarthritis (OA) is the most prevalent joint disease worldwide. Gene therapy, which involves delivering microRNAs, has the potential to treat OA. In this study, we demonstrated that miR-224-5p can simultaneously regulate cartilage degradation and synovium inflammation, thereby restoring homeostasis in OA gene therapy. Moreover, compared to traditional transfection reagents such as lipofectamine 3000, G5-AHP showed better efficacy in both microRNA transfection and protection against degradation due to its specific surface structure. In summary, G5-AHP/miR-224-5p was developed to meet the clinical needs of OA patients and the high requirement of gene transfection efficiency, providing a promising paradigm for the future application and development of gene therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a prevalent articular disease mainly characterized by extracellular matrix degradation, apoptosis, and inflammation, which lead to cartilage destruction and abnormal bone metabolism. With undesirable side effects, current limited symptomatic treatments are aimed at relieving pain and improving joint mobility in patients with OA. Intra-articular (IA) hyaluronic acid (HA) injection, as a nonsurgical therapy, is commonly used in the clinical management of knee OA, but the efficacy of this therapeutic option remains controversial. Ebselen has tremendous pharmacological importance for some diseases due to its antioxidant, antiapoptotic, and anti-inflammatory features. However, there is no research examining the therapeutic effect of Ebselen in OA using the rat OA model. Therefore, we aimed to investigate the therapeutic effect of Ebselen on cartilage degeneration and its role in bone morphogenetic protein 2 (BMP2) and nuclear factor kappa B (NF-κB) signaling in the molecular pathogenesis of OA. We induced a knee OA model in rats with an IA injection of monosodium-iodoacetate (MIA). After the treatment of Ebselen, we evaluated its chondroprotective effects by morphological, histopathological, and immunohistochemical methods and an enzyme-linked immunosorbent assay. We report for the first time that Ebselen treatment alleviated articular cartilage degeneration in the rat knee OA model and reduced MIA-induced BMP2 and NF-κB expressions. In addition, our results unveiled that Ebselen decreased IL-β and IL-6 levels but did not affect COMP levels in the rat serum. Ebselen could be a promising therapeutic drug for the prevention and treatment of OA by alleviating cartilage degeneration and regulating BMP2 and NF-κB expressions. [ABSTRACT FROM AUTHOR]

Osteoarthritis, a chronic degenerative cartilage disease, is the leading cause of movement disorders among humans. Although the specific pathogenesis and associated mechanisms remain unclear, oxidative stress‐induced metabolic imbalance in chondrocytes plays a crucial role in the occurrence and development of osteoarthritis. In this study, a trimanganese tetroxide (Mn3O4) nanozyme with superoxide dismutase (SOD)‐like and catalase (CAT)‐like activities is designed to reduce oxidative stress‐induced damage and its therapeutic effect is investigated. In vitro, Mn3O4 nanozymes are confirmed to reprogram both the imbalance of metabolism in chondrocytes and the uncontrolled inflammatory response stimulated by hydrogen peroxide. In vivo, a cross‐linked chondroitin sulfate (CS) hydrogel is designed as a substrate for Mn3O4 nanozymes to treat osteoarthritis in mouse models. As a result, even in the early stage of OA (4 weeks), the therapeutic effect of the Mn3O4@CS hydrogel is observed in both cartilage metabolism and inflammation. Moreover, the Mn3O4@CS hydrogel maintained its therapeutic effects for at least 7 days, thus revealing a broad scope for future clinical applications. In conclusion, these results suggest that the Mn3O4@CS hydrogel is a potentially effective therapeutic treatment for osteoarthritis, and a novel therapeutic strategy for osteoarthritis based on nanozymes is proposed. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a painful and debilitating disease characterized by the chronic and progressive degradation of articular cartilage. Post-traumatic OA (PTOA) is a secondary form of OA that develops in ~50% of cases of severe articular injury. Inflammation and re-occurring injury have been implicated as contributing to the progression of PTOA after the initial injury. However, there is very little known about external factors prior to injury that could affect the risk of PTOA development. To examine how the gut microbiome affects PTOA development we used a chronic antibiotic treatment regimen starting at weaning for six weeks prior to ACL rupture, in mice. A six-weeks post-injury histological examination showed more robust cartilage staining on the antibiotic (AB)-treated mice than the untreated controls (VEH), suggesting slower disease progression in AB cohorts. Injured joints also showed an increase in the presence of anti-inflammatory M2 macrophages in the AB group. Molecularly, the phenotype correlated with a significantly lower expression of inflammatory genes Tlr5, Ccl8, Cxcl13, and Foxo6 in the injured joints of AB-treated animals. Our results indicate that a reduced state of inflammation at the time of injury and a lower expression of Wnt signaling modulatory protein, Rspo1, caused by AB treatment can slow down or improve PTOA outcomes.

Aging and injury are two major risk factors for osteoarthritis (OA). Yet, very little is known about how aging and injury interact and contribute to OA pathogenesis. In the present study, we examined age- and injury-related molecular changes in mouse knee joints that could contribute to OA. Using RNA-seq, first we profiled the knee joint transcriptome of 10-week-old, 62-week-old, and 95-week-old mice and found that the expression of several inflammatory-response related genes increased as a result of aging, whereas the expression of several genes involved in cartilage metabolism decreased with age. To determine how aging impacts post-traumatic arthritis (PTOA) development, the right knee joints of 10-week-old and 62-week-old mice were injured using a non-invasive tibial compression injury model and injury-induced structural and molecular changes were assessed. At six-week post-injury, 62-week-old mice displayed significantly more cartilage degeneration and osteophyte formation compared with young mice. Although both age groups elicited similar transcriptional responses to injury, 62-week-old mice had higher activation of inflammatory cytokines than 10-week-old mice, whereas cartilage/bone metabolism genes had higher expression in 10-week-old mice, suggesting that the differential expression of these genes might contribute to the differences in PTOA severity observed between these age groups.

Pinger Wang,1– 3,&ast; Jianbo Xu,1,&ast; Qi Sun,4,&ast; Qinwen Ge,2,3 Min Qiu,1 Kaiao Zou,2,3 Jun Ying,3,5 Wenhua Yuan,2,3 Jiali Chen,2,3 Qinghe Zeng,2,3 Qi Cui,1 Hongting Jin,2,3 Chunchun Zhang,1 Fanzhu Li1 1College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 4Department of Orthopedic Joint Surgery, Hangzhou Fuyang Hospital of TCM Orthopaedics and Traumatology, Hangzhou, People’s Republic of China; 5Department of Orthopedic Surgery, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunchun Zhang, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China, Tel/Fax +86 571-86613684, Email 20081026@zcmu.edu.cn Fanzhu Li, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China, Tel/Fax +86 571-86613684, Email lifanzhu@zcmu.edu.cnBackground: Knee osteoarthritis (KOA) is the primary prevalent disabling joint disorder among osteoarthritis (OA), and there is no particularly effective treatment at the clinic. Traditional Chinese medicine (TCM) herbs, such as Eucommia ulmoides Oliv. and Glycyrrhiza uralensis Fisch. (E.G.) couplet medicines, have been reported to exhibit beneficial health effects on KOA, exact mechanism of E.G. nevertheless is not fully elucidated.Purpose: We assess the therapeutic effects of E.G. on KOA and explore its underlying molecular mechanism.Methods: UPLC-Q-TOF/MS technique was used to analyze the active chemical constituents of E.G. The destabilization of the medial meniscus model (DMM) was employed to evaluate the chondroprotective action of E.G. in KOA mice using histomorphometry, μCT, behavioral testing and immunohistochemical staining. Additionally, network pharmacology and molecular docking were used to predict potential targets for anti-KOA activities of E.G., which was further verified through in vitro experiments.Results: In vivo studies have shown that E.G. could significantly ameliorate DMM-induced KOA phenotypes including subchondral bone sclerosis, cartilage degradation, gait abnormality and thermal pain reaction sensibility. E.G. treatment could also promote extracellular matrix synthesis to protect articular chondrocytes, which was indicated by Col2 and Aggrecan expressions, as well as reducing matrix degradation by inhibiting MMP13 expression. Interestingly, network pharmacologic analysis showed that PPARG might be a therapeutic center. Further study proved that E.G.-containing serum (EGS) could up-regulate PPARG mRNA level in IL-1β-induced chondrocytes. Notably, significant effects of EGS on the increment of anabolic gene expressions (Col2, Aggrecan) and the decrement of catabolic gene expressions (MMP13, Adamts5) in KOA chondrocytes were abolished due to the silence of PPARG.Conclusion: E.G. played a chondroprotective role in anti-KOA by inhibiting extracellular matrix degradation, which might be related to PPARG.Graphical Abstract: Keywords: couplet medicines, UPLC-Q-TOF/MS, network pharmacology, cartilage degeneration, knee osteoarthritis, PPARG

Abstract Background Osteoarthritis (OA) is a common joint disorder worldwide which causes great health and economic burden. However, there remains an unmet goal to develop an effective therapeutic method to prevent or delay OA. Chondrocytes, as the major cells involved in OA progression, may serve as a promising therapeutic target. Results A kind of carbon dots (CDs) with excellent biocompatibility was fabricated from folic acid via hydrothermal method and could effectively attenuate osteoarthritis. It was demonstrated that CDs treatment could rescue IL1β-induced proinflammatory responses, oxidative stress, cartilage degeneration and extracellular matrix degradation. Moreover, CDs reprogrammed lipopolysaccharide (LPS)-induced macrophage inflammation and polarization. Conditioned medium (CM) from CDs-treated macrophages could attenuate IL1β-induced chondrocyte injury. Also, CM from CDs-treated chondrocytes had immunoregulatory functions on macrophages. Mechanistically, CDs inhibited the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways in IL1β-stimulated chondrocytes. In vivo, anterior cruciate ligament transection (ACLT) mice model was adopted and it was indicated that intra-articular injection of CDs effectively delays OA pathogenesis. Conclusions Taken together, these findings indicated CDs could mediate OA via promoting cartilage repair and immunomodulating macrophages within local microenvironment, which may provide evidences for utilizing CDs as a novel nanomaterial for OA treatment.

The contribution of the NLRP3 inflammasome in osteoarthritis (OA) pathogenesis has been uncovered in recent years. Holomycin (HL) has recently been identified as a novel NLRP3 inflammasome inhibitor. Herein, we aimed to explore the benefits of HL for OA. A chondrocyte-macrophage co-culture system and the destabilization of the medial meniscus (DMM) mouse model were established to study the effect of HL on OA in vitro and in vivo. ECM degradation-related proteins (MMP-13, aggrecan, and Collagen II) were detected by Western blot (WB) and immunohistochemistry (IHC). The chondrocyte senescence was determined by cell cycle, p16 and p21 expressions, and SA-β-Gal staining. The cartilage degeneration was evaluated by OARSI score and Safranin O and H&E staining. Inflammation and NLRP3 inflammasome activation were investigated via RT-PCR, ELISA, WB, and IHC. In vitro studies showed that IL-1β stimulation caused a significant increase of MMP13, p16, p21, and β-galactosidase expressions, a G1-phase arrest, and a down-regulation of aggrecan and Collagen II in chondrocytes, and the increased expressions of IL-6, CXCL-1, IL-1β, NLRP3, and Caspase 1 p20 in both chondrocyte and macrophage. Meanwhile, HL administration could partly reverse these effects induced by IL-1β. In DMM mouse models, intra-articular administration of HL alleviated cartilage degeneration and inflammation, as evidenced by the decrease of OARSI score and MMP13, p16, p21, Collagen II, IL-6, and CXCL-1 expressions and the restoration of chondrocyte number, proteoglycan, and MMP13 expression in cartilage tissues. This study identified HL as a promising agent for OA. • IL-1β stimulation caused ECM degradation and senescence of chondrocytes in vitro. • IL-1β activated NLRP3 inflammasome in both chondrocytes and macrophages. • Holomycin (HL) partly reversed the deleterious effects of IL-1β on chondrocytes. • HL attenuated cartilage degeneration and inflammation in osteoarthritis mice. [ABSTRACT FROM AUTHOR]

Abstract Osteoarthritis, a chronic degenerative cartilage disease, is the leading cause of movement disorders among humans. Although the specific pathogenesis and associated mechanisms remain unclear, oxidative stress‐induced metabolic imbalance in chondrocytes plays a crucial role in the occurrence and development of osteoarthritis. In this study, a trimanganese tetroxide (Mn3O4) nanozyme with superoxide dismutase (SOD)‐like and catalase (CAT)‐like activities is designed to reduce oxidative stress‐induced damage and its therapeutic effect is investigated. In vitro, Mn3O4 nanozymes are confirmed to reprogram both the imbalance of metabolism in chondrocytes and the uncontrolled inflammatory response stimulated by hydrogen peroxide. In vivo, a cross‐linked chondroitin sulfate (CS) hydrogel is designed as a substrate for Mn3O4 nanozymes to treat osteoarthritis in mouse models. As a result, even in the early stage of OA (4 weeks), the therapeutic effect of the Mn3O4@CS hydrogel is observed in both cartilage metabolism and inflammation. Moreover, the Mn3O4@CS hydrogel maintained its therapeutic effects for at least 7 days, thus revealing a broad scope for future clinical applications. In conclusion, these results suggest that the Mn3O4@CS hydrogel is a potentially effective therapeutic treatment for osteoarthritis, and a novel therapeutic strategy for osteoarthritis based on nanozymes is proposed.

Osteoarthritis (OA) of the temporomandibular joint (TMJ) occurs spontaneously in humans and various animal species, including horses. In humans, obtaining tissue samples is challenging and clinical symptoms appear late in the disease progression. Therefore, genetically modified, induced, and naturally occurring animal models play a crucial role in understanding the pathogenesis and evaluating potential therapeutic interventions for TMJ OA. Among the naturally occurring models, the equine TMJ OA model is characterized by slow, age-related progression, a wide range of clinical examinations, and imaging modalities that can be performed on horses, as well as easy tissue and synovial fluid collection. The morphological and functional similarities of TMJ structures in both species make the equine model of TMJ OA an excellent opportunity to track disease progression and response to treatment. However, much work remains to be carried out to determine the utility of human TMJ OA biomarkers in horses. Among the main TMJ OA biomarkers, IL-1, IL-6, TGF-β, TNF-α, and PGE2 have been recently investigated in the equine model. However, the majority of biomarkers for cartilage degradation, chondrocyte hypertrophy, angiogenesis, and TMJ overload—as well as any of the main signaling pathways—have not been studied so far. Therefore, it would be advisable to focus further research on equine specimens, considering both mediators and signaling.

Cartilage plays a crucial role in the human body by forming long bones during development and growth to bear loads on joints and intervertebral discs. However, the increasing prevalence of cartilage degenerative disorders is a growing public health concern, especially due to the poor innate regenerative capacity of cartilage. Chondrocytes are a source of several inflammatory mediators that play vital roles in the pathogenesis of cartilage disorders. Among these mediators, chemokines have been explored as potential contributors to cartilage degeneration and regeneration. Our review focuses on the progress made during the last ten years in identifying the regulators and roles of chemokines and their receptors in different mechanisms related to chondrocytes and cartilage. Recent findings have demonstrated that chemokines influence cartilage both positively and negatively. Their induction and involvement in either process depends on the local molecular environment and is both site- and time-dependent. One of the challenges in defining the role of chemokines in cartilage pathology or regeneration is the apparent redundancy in the interaction of chemokines with their receptors. Hence, it is crucial to determine, for each situation, whether targeting specific chemokines or their receptors will help in developing effective therapeutic strategies for cartilage repair.

The knee is the joint most frequently involved in osteoarthritis, a common joint disorder in the adult population that is associated with significant chronic joint pain, reduced mobility and quality of life. Recent studies have established an association between obesity and the development of knee osteoarthritis that goes beyond the increased mechanical load on the knees as weight-bearing joints. This link is based on the maintenance of a chronic low-grade inflammation, altered secretion of adipokines by the adipose tissue and development of sarcopenia. Major adipokines involved in the pathogenesis of obesity-related knee osteoarthritis include adiponectin, which appears to have a protective effect, as well as leptin, resistin and visfatin, which are associated with higher pain scores and more severe structural damage. Joint pain in knee osteoarthritis may be both nociceptive and neuropathic and is the result of complex mechanisms driven by nerve growth factor, calcitonin gene-related peptide and pro-inflammatory cytokines. The role of endogenous cannabinoids and gut microbiota in common mechanisms between obesity and knee pain has recently been studied. The aim of the present review is to highlight major pathogenic mechanisms in obesity-related knee osteoarthritis with special attention on pain and to comment on possible therapeutic approaches.

AimsTo evaluate inducing osteoarthritis (OA) by surgical destabilization of the medial meniscus (DMM) in mice with and without a stereomicroscope.MethodsBased on sample size calculation, 70 male C57BL/6 mice were randomly assigned to three surgery groups: DMM aided by a stereomicroscope; DMM by naked eye; or sham surgery. The group information was blinded to researchers. Mice underwent static weightbearing, von Frey test, and gait analysis at two-week intervals from eight to 16 weeks after surgery. Histological grade of OA was determined with the Osteoarthritis Research Society International (OARSI) scoring system.ResultsSurgical DMM with or without stereomicroscope led to decrease in the mean of weightbearing percentages (-20.64% vs -21.44%, p = 0.792) and paw withdrawal response thresholds (-21.35% vs -24.65%, p = 0.327) of the hind limbs. However, the coefficient of variation (CV) of weight-bearing percentages and paw withdrawal response thresholds in naked-eye group were significantly greater than that in the microscope group (19.82% vs 6.94%, p < 0.001; 21.85% vs 9.86%, p < 0.001). The gait analysis showed a similar pattern. Cartilage degeneration was observed in both DMM-surgery groups, evidenced by increased OARSI scores (summed score: 11.23 vs 11.43, p = 0.842), but the microscope group showed less variation in OARSI score than the naked-eye group (CV: 21.03% vs 32.44%; p = 0.032).ConclusionAlthough surgical DMM aided by stereomicroscope is technically difficult, it produces a relatively more homogeneous OA model in terms of the discrete degree of pain behaviours and histopathological grading when compared with surgical DMM without stereomicroscope.Cite this article: Bone Joint Res 2022;11(8):518–527.