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1.
Nat Commun ; 15(1): 3225, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622181

RESUMO

Osteoarthritis (OA) is a painful, incurable disease affecting over 500 million people. Recent clinical trials of the nerve growth factor (NGF) inhibitors in OA patients have suggested adverse effects of NGF inhibition on joint structure. Here we report that nerve growth factor receptor (NGFR) is upregulated in skeletal cells during OA and plays an essential role in the remodeling and repair of osteoarthritic joints. Specifically, NGFR is expressed in osteochondral cells but not in skeletal progenitor cells and induced by TNFα to attenuate NF-κB activation, maintaining proper BMP-SMAD1 signaling and suppressing RANKL expression in mice. NGFR deficiency hyper-activates NF-κB in murine osteoarthritic joints, which impairs bone formation and enhances bone resorption as exemplified by a reduction in subchondral bone and osteophytes. In human OA cartilage, NGFR is also negatively associated with NF-κB activation. Together, this study suggests a role of NGFR in limiting inflammation for repair of diseased skeletal tissues.


Assuntos
Cartilagem Articular , Osteoartrite , Humanos , Camundongos , Animais , Receptor de Fator de Crescimento Neural , NF-kappa B , Fator de Crescimento Neural/metabolismo , Receptores de Fator de Crescimento Neural , Inflamação , Cartilagem Articular/metabolismo , Articulações/metabolismo
2.
PLoS One ; 19(4): e0298575, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38593124

RESUMO

Osteoarthritis (OA) is a widespread chronic, progressive, degenerative joint disease that causes pain and disability. Current treatments for OA have limited effectiveness and new biomarkers need to be identified. Bioinformatics analysis was conducted to explore differentially expressed genes and DNA repair/recombination protein 54 L (RAD54L) was selected. We firstly overexpressed RAD54L in interleukin-1ß (IL-1ß)-induced human articular chondrocytes or in OA rats to investigate its effect on OA. Chondrocyte viability and apoptotic rate were measured by Cell Counting Kit-8 and flow cytometry, respectively. Then we evaluated OA severity in vivo by Hematoxylin-eosin staining and Osteoarthritis Research Society International standards. The expression of inflammatory mediators was tested by enzyme-linked immunosorbent assay. Finally, western blot was performed to determine the relative expression level of hypoxia-inducible factors 1α (HIF-1α) and vascular endothelial growth factor (VEGF). Overexpression of RAD54L promoted cell viability and attenuated apoptosis in IL-1ß-induced human chondrocytes. A lower Osteoarthritis Research Society International score and a remarkable alleviation of chondrocyte disordering and infiltration of inflammatory cells were found in cartilage tissues of OA rats after overexpressing RAD54L. The inflammatory response induced by OA was decreased by RAD54L overexpression in vitro and in vivo. In addition, RAD54L overexpression decreased the relative expression level of HIF-1α and VEGF. Overexpression of RAD54L could attenuate OA by suppressing the HIF-1α/VEGF signaling pathway, indicating that RAD54L may be a potential treatment target for OA.


Assuntos
Cartilagem Articular , Osteoartrite , Ratos , Humanos , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Interleucina-1beta/metabolismo , Transdução de Sinais , Condrócitos/metabolismo , Cartilagem Articular/metabolismo , Apoptose , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo
3.
BMC Musculoskelet Disord ; 25(1): 253, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561728

RESUMO

BACKGROUND: The characteristics and therapeutic potential of subtypes of bone marrow mesenchymal stem cells (BMSCs) are largely unknown. Also, the application of subpopulations of BMSCs in cartilage regeneration remains poorly characterized. The aim of this study was to explore the regenerative capacity of CD146-positive subpopulations of BMSCs for repairing cartilage defects. METHODS: CD146-positive BMSCs (CD146 + BMSCs) were sorted by self-developed CD146-specific lipid magnetic spheres (CD146-LMS). Cell surface markers, viability, and proliferation were evaluated in vitro. CD146 + BMSCs were subjected to in vitro chondrogenic induction and evaluated for chondrogenic properties by detecting mRNA and protein expression. The role of the CD146 subpopulation of BMSCs in cartilage damage repair was assessed by injecting CD146 + BMSCs complexed with sodium alginate gel in the joints of a mouse cartilage defect model. RESULTS: The prepared CD146-LMS had an average particle size of 193.7 ± 5.24 nm, an average potential of 41.9 ± 6.21 mv, and a saturation magnetization intensity of 27.2 Am2/kg, which showed good stability and low cytotoxicity. The sorted CD146 + BMSCs highly expressed stem cell and pericyte markers with good cellular activity and cellular value-added capacity. Cartilage markers Sox9, Collagen II, and Aggrecan were expressed at both protein and mRNA levels in CD146 + BMSCs cells after chondrogenic induction in vitro. In a mouse cartilage injury model, CD146 + BMSCs showed better function in promoting the repair of articular cartilage injury. CONCLUSION: The prepared CD146-LMS was able to sort out CD146 + BMSCs efficiently, and the sorted subpopulation of CD146 + BMSCs had good chondrogenic differentiation potential, which could efficiently promote the repair of articular cartilage injury, suggesting that the sorted CD146 + BMSCs subpopulation is a promising seed cell for cartilage tissue engineering.


Assuntos
Cartilagem Articular , Células-Tronco Mesenquimais , Animais , Camundongos , Cartilagem Articular/metabolismo , Antígeno CD146/metabolismo , Diferenciação Celular , Células Cultivadas , Células-Tronco Mesenquimais/metabolismo , Células da Medula Óssea/metabolismo , Condrogênese , RNA Mensageiro/metabolismo , Fenômenos Magnéticos , Lipídeos
4.
Immun Inflamm Dis ; 12(4): e1211, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38602270

RESUMO

BACKGROUND: Traumatic cartilage injury is an important cause of osteoarthritis (OA) and limb disability, and toll-like receptors (TLRs) mediated innate immune response has been confirmed to play a crucial role in cartilage injury. In the previous study, we found that the activation of TLR8 molecules in injured articular cartilage was more obvious than other TLRs by establishing an animal model of knee impact injury in rabbits, and the changes of TLR8 molecules could significantly affect the process of articular cartilage injury and repair. OBJECTIVE: To verify how mir-99a-5p regulates TLR8 receptor mediated innate immune response to treat traumatic cartilage injury. METHODS: The impact of a heavy object on the medial condyle of the rabbit's knee joint caused damage to the medial condylar cartilage. Through pathological and imaging analysis, it was demonstrated whether the establishment of an animal model of traumatic cartilage injury was successful. Establishing a cell model by virus transfection of chondrocytes to demonstrate the role of TLR8 in the innate immune response to impact cartilage injury. Through transcriptome sequencing, potential targets of TLR8, mir-99a-5p, were predicted, and basic experiments were conducted to demonstrate how they interact with innate immune responses to impact cartilage damage. RESULTS: TLR8 is a receptor protein of the immune system, which is widely expressed in immune cells. In our study, we found that TLR8 expression is localized in lysosomes and endosomes. Mir-99a-5p can negatively regulate TLR8 to activate PI3K-AKT molecular pathway and aggravate cartilage damage. Inhibiting TLR8 expression can effectively reduce the incidence of articular cartilage damage. CONCLUSION: Based on the results from this study, mir-99a-5p may be an effective molecular marker for predicting traumatic cartilage injury and targeting TLR8 is a novel and promising approach for the prevention or early treatment of cartilage damage.


Assuntos
Cartilagem Articular , MicroRNAs , Animais , Coelhos , MicroRNAs/genética , Receptor 8 Toll-Like/metabolismo , Fosfatidilinositol 3-Quinases , Articulação do Joelho/metabolismo , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia
5.
ACS Appl Bio Mater ; 7(4): 2594-2603, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38523342

RESUMO

Repairing articular cartilage damage is challenging due to its low regenerative capacity. In vitro, cartilage regeneration is a potential strategy for the functional reconstruction of cartilage defects. A hydrogel is an advanced material for mimicking the extracellular matrix (ECM) due to its hydrophilicity and biocompatibility, which is known as an ideal scaffold for cartilage regeneration. However, chondrocyte culture in vitro tends to dedifferentiate, leading to fibrosis and reduced mechanical properties of the newly formed cartilage tissue. Therefore, it is necessary to understand the mechanism of modulating the chondrocytes' morphology. In this study, we synthesize photo-cross-linkable bovine serum albumin-glycidyl methacrylate (BSA-GMA) with 65% methacrylation. The scaffolds are found to be suitable for chondrocyte growth, which are fabricated by homemade femtosecond laser maskless optical projection lithography (FL-MOPL). The large-area chondrocyte scaffolds have holes with interior angles of triangle (T), quadrilateral (Q), pentagon (P), hexagonal (H), and round (R). The FL-MOPL polymerization mechanism, swelling, degradation, and biocompatibility of the BSA-GMA hydrogel have been investigated. Furthermore, cytoskeleton and nucleus staining reveals that the R-scaffold with larger interior angle is more effective in maintaining chondrocyte morphology and preventing dedifferentiation. The scaffold's ability to maintain the chondrocytes' morphology improves as its shape matches that of the chondrocytes. These results suggest that the BSA-GMA scaffold is a suitable candidate for preventing chondrocyte differentiation and supporting cartilage tissue repair and regeneration. The proposed method for chondrocyte in vitro culture by developing biocompatible materials and flexible fabrication techniques would broaden the potential application of chondrocyte transplants as a viable treatment for cartilage-related diseases.


Assuntos
Cartilagem Articular , Condrócitos , Compostos de Epóxi , Metacrilatos , Condrócitos/metabolismo , Soroalbumina Bovina/farmacologia , Soroalbumina Bovina/metabolismo , Tecidos Suporte , Hidrogéis/farmacologia , Hidrogéis/metabolismo , Cartilagem Articular/metabolismo
6.
Acta Biochim Biophys Sin (Shanghai) ; 56(4): 499-512, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38439665

RESUMO

Osteoarthritis (OA) is the most common joint disease, and good therapeutic results are often difficult to obtain due to its complex pathogenesis and diverse causative factors. After decades of research and exploration of OA, it has been progressively found that subchondral bone is essential for its pathogenesis, and pathological changes in subchondral bone can be observed even before cartilage lesions develop. Osteoclasts, the main cells regulating bone resorption, play a crucial role in the pathogenesis of subchondral bone. Subchondral osteoclasts regulate the homeostasis of subchondral bone through the secretion of degradative enzymes, immunomodulation, and cell signaling pathways. In OA, osteoclasts are overactivated by autophagy, ncRNAs, and Rankl/Rank/OPG signaling pathways. Excessive bone resorption disrupts the balance of bone remodeling, leading to increased subchondral bone loss, decreased bone mineral density and consequent structural damage to articular cartilage and joint pain. With increased understanding of bone biology and targeted therapies, researchers have found that the activity and function of subchondral osteoclasts are affected by multiple pathways. In this review, we summarize the roles and mechanisms of subchondral osteoclasts in OA, enumerate the latest advances in subchondral osteoclast-targeted therapy for OA, and look forward to the future trends of subchondral osteoclast-targeted therapies in clinical applications to fill the gaps in the current knowledge of OA treatment and to develop new therapeutic strategies.


Assuntos
Reabsorção Óssea , Cartilagem Articular , Osteoartrite , Humanos , Osteoclastos/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Reabsorção Óssea/metabolismo , Remodelação Óssea/fisiologia , Cartilagem Articular/metabolismo
7.
Ageing Res Rev ; 96: 102275, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38494091

RESUMO

Osteoarthritis (OA), a chronic joint disease affecting millions of people aged over 65 years, is the main musculoskeletal cause of diminished joint mobility in the elderly. It is characterized by lingering pain and increasing deterioration of articular cartilage. Aging and accumulation of senescent cells (SCs) in the joints are frequently associated with OA. Apoptosis resistance; irreversible cell cycle arrest; increased p16INK4a expression, secretion of senescence-associated secretory phenotype factors, senescence-associated ß-galactosidase levels, secretion of extracellular vesicles, and levels of reactive oxygen and reactive nitrogen species; and mitochondrial dysregulation are some common changes in cellular senescence in joint tissues. Development of OA correlates with an increase in the density of SCs in joint tissues. Senescence-associated secretory phenotype has been linked to OA and cartilage breakdown. Senolytics and therapeutic pharmaceuticals are being focused upon for OA management. SCs can be selectively eliminated or killed by senolytics to halt the pathogenesis and progression of OA. Comprehensive understanding of how aging affects joint dysfunction will benefit OA patients. Here, we discuss age-related mechanisms associated with OA pathogenesis and senolytics as an emerging modality in the management of age-related SCs and pathogenesis of OA in preclinical and clinical studies.


Assuntos
Cartilagem Articular , Osteoartrite , Idoso , Humanos , Senoterapia , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Envelhecimento/fisiologia , Senescência Celular/fisiologia , Cartilagem Articular/metabolismo
8.
J Zhejiang Univ Sci B ; 25(3): 197-211, 2024 Mar 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38453635

RESUMO

Osteoarthritis (OA), characterized by cartilage degeneration, synovial inflammation, and subchondral bone remodeling, is among the most common musculoskeletal disorders globally in people over 60 years of age. The initiation and progression of OA involves the abnormal metabolism of chondrocytes as an important pathogenic process. Cartilage degeneration features mitochondrial dysfunction as one of the important causative factors of abnormal chondrocyte metabolism. Therefore, maintaining mitochondrial homeostasis is an important strategy to mitigate OA. Mitophagy is a vital process for autophagosomes to target, engulf, and remove damaged and dysfunctional mitochondria, thereby maintaining mitochondrial homeostasis. Cumulative studies have revealed a strong association between mitophagy and OA, suggesting that the regulation of mitophagy may be a novel therapeutic direction for OA. By reviewing the literature on mitophagy and OA published in recent years, this paper elaborates the potential mechanism of mitophagy regulating OA, thus providing a theoretical basis for studies related to mitophagy to develop new treatment options for OA.


Assuntos
Cartilagem Articular , Osteoartrite , Humanos , Pessoa de Meia-Idade , Idoso , Mitofagia , Inflamação/metabolismo , Condrócitos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia
9.
Int J Mol Sci ; 25(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38473759

RESUMO

Osteoarthritis (OA) causes joint pain and disability due to the abnormal production of inflammatory cytokines and reactive oxygen species (ROS) in chondrocytes, leading to cell death and cartilage matrix destruction. Selenium (Se) intake can protect cells against oxidative damage. It is still unknown whether Se supplementation is beneficial for OA. This study investigated the effects of Se on sodium iodoacetate (MIA)-imitated OA progress in human chondrocyte cell line (SW1353 cells) and rats. The results showed that 0.3 µM of Se treatment could protect SW1353 cells from MIA-induced damage by the Nrf2 pathway by promoting the gene expression of glutathione-synthesis-related enzymes such as the glutamate-cysteine ligase catalytic subunit, the glutamate-cysteine ligase modifier subunit, and glutathione synthetase. In addition, glutathione, superoxide dismutase, glutathione peroxidase, and glutathione reductase expressions are also elevated to eliminate excessive ROS production. Moreover, Se could downregulate NF-κB, leading to a decrease in cytokines, matrix proteases, and glycosaminoglycans. In the rats, MIA-induced cartilage loss was lessened after 2 weeks of Se supplementation by oral gavage; meanwhile, glutathione synthesis was increased, and the expressions of pro-inflammatory cytokines were decreased. These results suggest that Se intake is beneficial for OA due to its effects of decreasing cartilage loss by enhancing antioxidant capacity and reducing inflammation.


Assuntos
Cartilagem Articular , Osteoartrite , Selênio , Humanos , Ratos , Animais , NF-kappa B/metabolismo , Condrócitos/metabolismo , Selênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Glutamato-Cisteína Ligase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Osteoartrite/metabolismo , Estresse Oxidativo , Citocinas/metabolismo , Glutationa/metabolismo , Cartilagem Articular/metabolismo
10.
Elife ; 122024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38466626

RESUMO

This study aimed to investigate the glycan structural changes that occur before histological degeneration in osteoarthritis (OA) and to determine the mechanism by which these glycan conformational changes affect cartilage degeneration. An OA model was established in rabbits using mannosidase injection, which reduced high-mannose type N-glycans and led to cartilage degeneration. Further analysis of glycome in human OA cartilage identified specific corefucosylated N-glycan expression patterns. Inhibition of N-glycan corefucosylation in mice resulted in unrecoverable cartilage degeneration, while cartilage-specific blocking of corefucosylation led to accelerated development of aging-associated and instability-induced OA models. We conclude that α1,6 fucosyltransferase is required postnatally to prevent preosteoarthritic deterioration of articular cartilage. These findings provide a novel definition of early OA and identify glyco-phenotypes of OA cartilage, which may distinguish individuals at higher risk of progression.


Assuntos
Cartilagem Articular , Osteoartrite , Resiliência Psicológica , Humanos , Coelhos , Animais , Camundongos , Cartilagem Articular/metabolismo , Osteoartrite/metabolismo , Envelhecimento , Polissacarídeos/metabolismo , Modelos Animais de Doenças
11.
Cell Commun Signal ; 22(1): 189, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38519981

RESUMO

The proinflammatory cytokines and arachidonic acid (AA)-derived eicosanoids play a key role in cartilage degeneration in osteoarthritis (OA). The lysophosphatidylcholine acyltransferase 3 (LPCAT3) preferentially incorporates AA into the membranes. Our recent studies showed that MALT1 [mucosa-associated lymphoid tissue lymphoma translocation protein 1]) plays a crucial role in propagating inflammatory signaling triggered by IL-1ß and other inflammatory mediators in endothelial cells. The present study shows that LPCAT3 expression was up-regulated in both human and mice articular cartilage of OA, and correlated with severity of OA. The IL-1ß-induces cell death via upregulation of LPCAT3, MMP3, ADAMTS5, and eicosanoids via MALT1. Gene silencing or pharmacological inhibition of LPCAT3 or MALT1 in chondrocytes and human cartilage explants notably suppressed the IL-1ß-induced cartilage catabolism through inhibition of expression of MMP3, ADAMTS5, and also secretion of cytokines and eicosanoids. Mechanistically, overexpression of MALT1 in chondrocytes significantly upregulated the expression of LPCAT3 along with MMP3 and ADAMTS5 via c-Myc. Inhibition of c-Myc suppressed the IL-1ß-MALT1-dependent upregulation of LPCAT3, MMP3 and ADAMTS5. Consistent with the in vitro data, pharmacological inhibition of MALT1 or gene silencing of LPCAT3 using siRNA-lipid nanoparticles suppressed the synovial articular cartilage erosion, pro-inflammatory cytokines, and eicosanoids such as PGE2, LTB4, and attenuated osteoarthritis induced by the destabilization of the medial meniscus in mice. Overall, our data reveal a previously unrecognized role of the MALT1-LPCAT3 axis in osteoarthritis. Targeting the MALT1-LPCAT3 pathway with MALT1 inhibitors or siRNA-liposomes of LPCAT3 may become an effective strategy to treat OA by suppressing eicosanoids, matrix-degrading enzymes, and proinflammatory cytokines.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Humanos , Camundongos , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferase/farmacologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/metabolismo , Citocinas/metabolismo , Eicosanoides/metabolismo , Eicosanoides/farmacologia , Eicosanoides/uso terapêutico , Células Endoteliais/metabolismo , Interleucina-1beta/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/farmacologia , Metaloproteinase 3 da Matriz/uso terapêutico , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Osteoartrite/metabolismo , RNA Interferente Pequeno/metabolismo
12.
J Orthop Surg Res ; 19(1): 197, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528611

RESUMO

BACKGROUND: Patellofemoral osteoarthritis (PFJOA) is a subtype of knee OA, which is one of the main causes of anterior knee pain. The current study found an increased prevalence of OA in postmenopausal women, called postmenopausal OA. Therefore, we designed the ovariectomized rat model of patella baja-induced PFJOA. Alendronate (ALN) inhibits osteoclast-mediated bone loss, and has been reported the favorable result of a potential intervention option of OA treatment. However, the potential effects of ALN treatment on PFJOA in the ovariectomized rat model are unknown and need further investigation prior to exploration in the clinical research setting. In this study, the effects of ALN on articular cartilage degradation and subchondral bone microstructure were assessed in the ovariectomized PFJOA rat model for 10 weeks. METHODS: Patella baja and estrogen withdrawal were induced by patellar ligament shortening (PLS) and bilateral ovariectmomy surgeries in 3-month-old female Sprague-Dawley rats, respectively. Rats were randomly divided into five groups (n = 8): Sham + V; OVX + V, Sham + PLS + V, OVX + PLS + V, OVX + PLS + ALN (ALN: 70 µg/kg/week). Radiography was performed to evaluate patellar height ratios, and the progression of PFJOA was assessed by macroscopic and microscopic analyses, immunohistochemistry and micro-computed tomography (micro-CT). RESULTS: Our results found that the patella baja model prepared by PLS can successfully cause degeneration of articular cartilage and subchondral bone, resulting in changes of PFJOA. OVX caused a decrease in estrogen levels in rats, which aggravated the joint degeneration caused by PFJOA. Early application of ALN can delay the degenerative changes of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent, improve and maintain the micrometabolism and structural changes of cartilage and subchondral bone. CONCLUSION: The early application of ALN can delay the destruction of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent.


Assuntos
Reabsorção Óssea , Cartilagem Articular , Osteoartrite do Joelho , Humanos , Ratos , Feminino , Animais , Lactente , Alendronato/farmacologia , Ratos Sprague-Dawley , Patela/diagnóstico por imagem , Microtomografia por Raio-X , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/metabolismo , Cartilagem Articular/metabolismo , Reabsorção Óssea/tratamento farmacológico , Modelos Animais de Doenças , Estrogênios
13.
Int J Mol Sci ; 25(6)2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38542192

RESUMO

Osteoarthritis is a widespread chronic degenerative disease marked by the deterioration of articular cartilage, modifications in subchondral bone, and a spectrum of symptoms, including pain, stiffness, and disability. Ultimately, this condition impairs the patient's quality of life. This study aimed to evaluate the therapeutic efficacy of standardized Boswellia serrata gum resin extract (BSRE) in a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis. A total of 60 rats were allocated into six groups: normal control group (NC), osteoarthritis control (injected with MIA, OC), O + B50 (injected with MIA and treated with 50 mg/kg body weight (BW) BSRE), O + B75 (injected with MIA and treated with 75 mg/kg BW BSRE), O + B100 (injected with MIA and treated with 100 mg/kg BW BSRE), and O + M (injected with MIA and treated with 150 mg/kg BW methyl sulfonyl methane). Several parameters, including knee joint swelling, histopathological changes, and the expression of collagen type II alpha 1 (COL2A1) and aggrecan, were comprehensively assessed. Concurrently, the serum levels and mRNA expression of inflammatory mediators, cytokines, and matrix metalloproteinases (MMPs) were analyzed in both the serum and knee joint synovium. The results demonstrated that BSRE significantly mitigated knee joint swelling, cartilage destruction, and tissue deformation. Notably, BSRE administration markedly upregulated the expression of COL2A1 and aggrecan while concurrently reducing levels of nitric oxide, prostaglandin E2, leukotriene B4, interleukin (IL)-6, and tumor necrosis factor (TNF)-α. Furthermore, a substantial decrease was observed in the mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, 5-lipoxygenase, IL-6, TNF-α and MMP-3 and -13, thereby indicating promising therapeutic implications for osteoarthritis. In conclusion, BSRE exhibited anti-inflammatory properties and inhibited cartilage matrix degradation in a rat model of MIA-induced osteoarthritis, with the O + B100 group showing significant reductions in swelling and notable improvements in joint cartilage damage. These findings illuminate the preventive and therapeutic potential of BSRE for osteoarthritis treatment, emphasizing the criticality of exhaustive evaluation of novel compounds.


Assuntos
Boswellia , Cartilagem Articular , Osteoartrite , Ratos , Humanos , Animais , Boswellia/metabolismo , Agrecanas/metabolismo , Qualidade de Vida , Modelos Animais de Doenças , Osteoartrite/metabolismo , Inflamação/metabolismo , Articulação do Joelho/patologia , Ácido Iodoacético/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , RNA Mensageiro/metabolismo , Cartilagem Articular/metabolismo
14.
J Orthop Surg Res ; 19(1): 178, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468339

RESUMO

BACKGROUND: Osteoarthritis (OA) is a common degenerative joint disease characterized by persistent articular cartilage degeneration and synovitis. Oxymatrine (OMT) is a quinzolazine alkaloid extracted from the traditional Chinese medicine, matrine, and possesses anti-inflammatory properties that may help regulate the pathogenesis of OA; however, its mechanism has not been elucidated. This study aimed to investigate the effects of OMT on interleukin-1ß (IL-1ß)-induced damage and the potential mechanisms of action. METHODS: Chondrocytes were isolated from Sprague-Dawley rats. Toluidine blue and Collagen II immunofluorescence staining were used to determine the purity of the chondrocytes. Thereafter, the chondrocytes were subjected to IL-1ß stimulation, both in the presence and absence of OMT, or the autophagy inhibitor 3-methyladenine (3-MA). Cell viability was assessed using the MTT assay and SYTOX Green staining. Additionally, flow cytometry was used to determine cell apoptosis rate and reactive oxygen species (ROS) levels. The protein levels of AKT, mTOR, LC3, P62, matrix metalloproteinase-13, and collagen II were quantitatively analyzed using western blotting. Immunofluorescence was used to assess LC3 expression. RESULTS: OMT alleviated IL-1ß-induced damage in chondrocytes, by increasing the survival rate, reducing the apoptosis rates of chondrocytes, and preventing the degradation of the cartilage matrix. In addition, OMT decreased the ROS levels and inhibited the AKT/mTOR signaling pathway while promoting autophagy in IL-1ß treated chondrocytes. However, the effectiveness of OMT in improving chondrocyte viability under IL-1ß treatment was limited when autophagy was inhibited by 3-MA. CONCLUSIONS: OMT decreases oxidative stress and inhibits the AKT/mTOR signaling pathway to enhance autophagy, thus inhibiting IL-1ß-induced damage. Therefore, OMT may be a novel and effective therapeutic agent for the clinical treatment of OA.


Assuntos
Alcaloides , Cartilagem Articular , Matrinas , Osteoartrite , Ratos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Condrócitos/metabolismo , Interleucina-1beta/toxicidade , Interleucina-1beta/metabolismo , Osteoartrite/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Cartilagem Articular/metabolismo , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Alcaloides/metabolismo , Autofagia , Colágeno/metabolismo , Apoptose
15.
Acta Cir Bras ; 39: e390924, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38324802

RESUMO

PURPOSE: Osteoarthritis (OA) is a degenerative joint disease which is categorized via destruction of joint cartilage and it also affects the various joints, especially knees and hips. Sinomenine active phytoconstituents isolated from the stem of Sinomenium acutum and already proof anti-inflammatory effect against the arthritis model of rodent. In this experimental protocol, we scrutinized the anti-osteoarthritis effect of sinomenine against monosodium iodoacetate (MIA) induced OA in rats. METHODS: MIA (3 mg/50 µL) was used for inducing the OA in the rats, and rats received the oral administration of sinomenine (2.5, 5 and 7.5 mg/kg body weight) up to the end of the experimental study (four weeks). The body and organs weight were estimated. Aggrecan, C-terminal cross-linked telopeptide of type II collagen (CTX-II), glycosaminoglycans (GCGs), monocyte chemoattractant protein-1 (MCP-1), Interferon gamma (IFN-γ), antioxidant, inflammatory cytokines, inflammatory mediators and matrix metalloproteinases (MMP) were analyzed. RESULTS: Sinomenine significantly (P < 0.001) boosted the body weight and reduced the heart weight, but the weight of spleen and kidney remain unchanged. Sinomenine significantly (P < 0.001) reduced the level of nitric oxide, MCP-1 and improved the level of aggrecan, IFN-γ and GCGs. Sinomenine remarkably upregulated the level of glutathione, superoxide dismutase and suppressed the level of malonaldehyde. It effectually modulated the level of inflammatory cytokines and inflammatory mediators and significantly (P < 0.001) reduced the level of MMPs, like MMP-1, 2, 3, 9 and 13. CONCLUSIONS: Sinomenine is a beneficial active agent for the treatment of OA disease.


Assuntos
Cartilagem Articular , Morfinanos , Osteoartrite , Ratos , Animais , Ácido Iodoacético/metabolismo , Ácido Iodoacético/farmacologia , Osteoartrite/metabolismo , Agrecanas/metabolismo , Agrecanas/farmacologia , Modelos Animais de Doenças , Cartilagem Articular/metabolismo , Metaloproteinases da Matriz/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Peso Corporal
16.
Sci Transl Med ; 16(735): eadh9751, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38381849

RESUMO

Osteoarthritis (OA) is a chronic joint disease characterized by progressive degeneration of articular cartilage. A challenge in the development of disease-modifying drugs is effective delivery to chondrocytes. The unique structure of the joint promotes rapid clearance of drugs through synovial fluid, and the dense and avascular cartilage extracellular matrix (ECM) limits drug penetration. Here, we show that poly(lactide-co-glycolic acid) nanoparticles coated in chondrocyte membranes (CM-NPs) were preferentially taken up by rat chondrocytes ex vivo compared with uncoated nanoparticles. Internalization of the CM-NPs was mediated primarily by E-cadherin, clathrin-mediated endocytosis, and micropinocytosis. These CM-NPs adhered to the cartilage ECM in rat knee joints in vivo and penetrated deeply into the cartilage matrix with a residence time of more than 34 days. Simulated synovial fluid clearance studies showed that CM-NPs loaded with a Wnt pathway inhibitor, adavivint (CM-NPs-Ada), delayed the catabolic metabolism of rat and human chondrocytes and cartilage explants under inflammatory conditions. In a surgical model of rat OA, drug-loaded CM-NPs effectively restored gait, attenuated periarticular bone remodeling, and provided chondroprotection against cartilage degeneration. OA progression was also mitigated by CM-NPs-Ada in a canine model of anterior cruciate ligament transection. These results demonstrate the feasibility of using chondrocyte membrane-coated nanoparticles to improve the pharmacokinetics and efficacy of anti-OA drugs.


Assuntos
Cartilagem Articular , Nanopartículas , Osteoartrite , Ratos , Animais , Cães , Humanos , Condrócitos/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Articulação do Joelho , Cartilagem Articular/metabolismo
17.
Int J Mol Sci ; 25(3)2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38338721

RESUMO

We investigated the effects of a Tankyrase (TNKS-1/2) inhibitor on mechanical stress-induced gene expression in human chondrocytes and examined TNKS-1/2 expression in human osteoarthritis (OA) cartilage. Cells were seeded onto stretch chambers and incubated with or without a TNKS-1/2 inhibitor (XAV939) for 12 h. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 8% elongation, 30 min) was applied and the gene expression of type II collagen a1 chain (COL2A1), aggrecan (ACAN), SRY-box9 (SOX9), TNKS-1/2, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and matrix metalloproteinase-13 (MMP-13) were examined by real-time PCR. The expression of ADAMTS-5, MMP-13, nuclear translocation of nuclear factor-κB (NF-κB), and ß-catenin were examined by immunocytochemistry and Western blotting. The concentration of IL-1ß in the supernatant was examined by enzyme-linked immunosorbent assay (ELISA). TNKS-1/2 expression was assessed by immunohistochemistry in human OA cartilage obtained at the total knee arthroplasty. TNKS-1/2 expression was increased after CTS. The expression of anabolic factors were decreased by CTS, however, these declines were abrogated by XAV939. XAV939 suppressed the CTS-induced expression of catabolic factors, the release of IL-1ß, as well as the nuclear translocation of NF-κB and ß-catenin. TNKS-1/2 expression increased in mild and moderate OA cartilage. Our results demonstrated that XAV939 suppressed mechanical stress-induced expression of catabolic proteases by the inhibition of NF-κB and activation of ß-catenin, indicating that TNKS-1/2 expression might be associated with OA pathogenesis.


Assuntos
Cartilagem Articular , Osteoartrite , Tanquirases , Humanos , beta Catenina/metabolismo , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Interleucina-1beta/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Peptídeo Hidrolases/efeitos dos fármacos , Peptídeo Hidrolases/metabolismo , Estresse Mecânico , Tanquirases/antagonistas & inibidores
18.
Arthritis Res Ther ; 26(1): 53, 2024 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-38368390

RESUMO

BACKGROUND: Understanding of pain in osteoarthritis, its genesis, and perception is still in its early stages. Identification of precise ligand-receptor pairs that transduce pain and the cells and tissues in which they reside will elucidate new therapeutic approaches for pain management. Our recent studies had identified an inflammation-amplifying (Inf-A) cell population that is expanded in human OA cartilage and is distinctive in the expression of both IL1R1 and TNF-R2 receptors and active Jnk signaling cascade. METHODS: In this study, we have tested the function of the cartilage-resident IL1R1+TNF-R2+ Inf-A cells in OA. We have identified that the IL1R1+TNF-R2+ Inf-A cells expand in aged mice as well as after anterior cruciate ligament tear upon tibia loading and OA initiation in mice. We targeted and modulated the Jnk signaling cascade in InfA through competitive inhibition of Jnk signaling in mice and human OA explants and tested the effects on joint structure and gait in mice. RESULTS: Modulation of Jnk signaling led to attenuation of inflammatory cytokines CCL2 and CCL7 without showing any structural improvements in the joint architecture. Interestingly, Jnk inhibition and lowered CCL2 and 7 are sufficient to significantly improve the gait parameters in treated PTOA mice demonstrating reduced OA-associated pain. Consistent with the mice data, treatment with JNK inhibitor did not improve human OA cartilage explants. CONCLUSION: These studies demonstrate that Inf-A, an articular-cartilage resident cell population, contributes to pain in OA via secretion of CCL2 and 7 and can be targeted via inhibition of Jnk signaling.


Assuntos
Cartilagem Articular , Osteoartrite , Humanos , Camundongos , Animais , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/farmacologia , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Modelos Animais de Doenças , Osteoartrite/metabolismo , Cartilagem Articular/metabolismo , Dor/etiologia , Dor/metabolismo , Inflamação/metabolismo
19.
Int J Mol Sci ; 25(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38339087

RESUMO

Osteoarthritis (OA) is the most prevalent form of arthritis and a major cause of pain and disability. The pathology of OA involves the whole joint in an inflammatory and degenerative process, especially in articular cartilage. OA may be divided into distinguishable phenotypes including one associated with the metabolic syndrome (MetS) of which dyslipidemia and hyperglycemia have been individually linked to OA. Since their combined role in OA pathogenesis remains to be elucidated, we investigated the chondrocyte response to these metabolic stresses, and determined whether a n-3 polyunsaturated fatty acid (PUFA), i.e., eicosapentaenoic acid (EPA), may preserve chondrocyte functions. Rat chondrocytes were cultured with palmitic acid (PA) and/or EPA in normal or high glucose conditions. The expression of genes encoding proteins found in cartilage matrix (type 2 collagen and aggrecan) or involved in degenerative (metalloproteinases, MMPs) or in inflammatory (cyclooxygenase-2, COX-2 and microsomal prostaglandin E synthase, mPGES) processes was analyzed by qPCR. Prostaglandin E2 (PGE2) release was also evaluated by an enzyme-linked immunosorbent assay. Our data indicated that PA dose-dependently up-regulated the mRNA expression of MMP-3 and -13. PA also induced the expression of COX-2 and mPGES and promoted the synthesis of PGE2. Glucose at high concentrations further increased the chondrocyte response to PA. Interestingly, EPA suppressed the inflammatory effects of PA and glucose, and strongly reduced MMP-13 expression. Among the free fatty acid receptors (FFARs), FFAR4 partly mediated the EPA effects and the activation of FFAR1 markedly reduced the inflammatory effects of PA in high glucose conditions. Our findings demonstrate that dyslipidemia associated with hyperglycemia may contribute to OA pathogenesis and explains why an excess of saturated fatty acids and a low level in n-3 PUFAs may disrupt cartilage homeostasis.


Assuntos
Cartilagem Articular , Dislipidemias , Hiperglicemia , Osteoartrite , Ratos , Animais , Condrócitos/metabolismo , Ácido Eicosapentaenoico/farmacologia , Ácido Eicosapentaenoico/metabolismo , Ciclo-Oxigenase 2/metabolismo , Palmitatos/metabolismo , Células Cultivadas , Osteoartrite/metabolismo , Cartilagem Articular/metabolismo , Dinoprostona/metabolismo , Hiperglicemia/metabolismo , Glucose/farmacologia , Glucose/metabolismo , Dislipidemias/metabolismo
20.
J Orthop Surg Res ; 19(1): 111, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308324

RESUMO

The 5'-HOXD genes are important for chondrogenesis in vertebrates, but their roles in osteoarthritis (OA) are still ambiguous. In our study, 5'-HOXD genes involvement contributing to cartilage degradation and OA was investigated. In bioinformatics analysis of 5'-HOXD genes, we obtained the GSE169077 data set related to OA in the GEO and analyzed DEGs using the GEO2R tool attached to the GEO. Then, we screened the mRNA levels of 5'-HOXD genes by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). We discovered that OA chondrocyte proliferation was inhibited, and apoptosis was increased. Moreover, it was discovered that SOX9 and COL2A1 were downregulated at mRNA and protein levels, while matrix metalloproteinases (MMPs) and a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTSs) were upregulated. According to the results of differentially expressed genes (DEGs) and qRT-PCR, we evaluated the protein level of HOXD11 and found that the expression of HOXD11 was downregulated, reversed to MMPs and ADAMTSs but consistent with the cartilage-specific factors, SOX9 and COL2A1. In the lentivirus transfection experiments, HOXD11 overexpression reversed the effects in OA chondrocytes. In human OA articular cartilage, aberrant subchondral bone was formed in hematoxylin-eosin (H&E) and Safranin O and fast green (SOFG) staining results. Furthermore, according to immunohistochemistry findings, SOX9 and HOXD11 expression was inhibited. The results of this study established that HOXD11 was downregulated in OA cartilage and that overexpression of HOXD11 could prevent cartilage degradation in OA.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Humanos , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Metaloproteinases da Matriz/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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