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1.
Arthritis Res Ther ; 24(1): 221, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-36096945

RESUMO

Osteoarthritis (OA) is a degenerative disease associated with cartilage degradation, osteophyte formation, and fibrillation. Autologous Protein Solution (APS), a type of autologous anti-inflammatory orthobiologic, is used for pain management and treatment of OA. Various compositions of autologous PRP formulations are in clinical use for musculoskeletal pathologies, by nature of their minimal processing and source of bioactive molecules. Currently, there is no consensus on the optimal composition of the complex mixture. In this study, we focused on elucidating the immune cell subtypes and phenotypes in APS. We identified the immune cell types in APS from healthy donors and investigated phenotypic changes in the immune cells after APS processing. Based on flow cytometric analysis, we found that neutrophils and T cells are the most abundant immune cell types in APS, while monocytes experience the largest fold change in concentration compared to WBCs. Gene expression profiling revealed that APS processing results in differential gene expression changes dependent on immune cell type, with the most significantly differentially regulated genes occurring in the monocytes. Our results demonstrate that the mechanical processing of blood, whose main purpose is enrichment and separation, can alter its protein and cellular composition, as well as cellular phenotypes in the final product.


Assuntos
Osteoartrite , Anti-Inflamatórios/uso terapêutico , Expressão Gênica , Humanos , Leucócitos , Monócitos , Osteoartrite/patologia
2.
Arthritis Res Ther ; 24(1): 223, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115996

RESUMO

BACKGROUND: Subchondral bone plays an important role in the pathogenesis of radiographic osteoarthritis (OA). However, the bony changes that occur in hand OA (HOA) are much less understood. This study aimed to describe the association between radiographic HOA and high-resolution peripheral quantitative computed tomography (HRpQCT) measures of the hand and radius in a population-based sample. METHODS: A total of 201 participants (mean age 72, 46% female) from the Tasmanian Older Adult Cohort (TASOAC) study underwent HRpQCT assessment of the 2nd distal and proximal interphalangeal (DIP, PIP), 1st carpometacarpal (CMC) joint, and distal radius. Radiographic HOA was assessed at the 2nd DIP, PIP joints, and the 1st CMC joint using the OARSI atlas. RESULTS: Proximal osteophyte and joint space narrowing (JSN) scores were consistently more strongly associated with HRpQCT measures compared to the distal site with positive associations for indices of bone size (total and trabecular bone area and cortical perimeter but inconsistent for cortical area) and negative associations for volumetric bone mineral density (vBMD). There was a decrease in trabecular number and bone volume fraction with increasing osteophyte and JSN score as well as an increase in trabecular separation and inhomogeneity. Osteophyte and JSN scores in the hand were not associated with HRpQCT measures at the distal radius. CONCLUSIONS: This hypothesis generating data suggests that bone size and trabecular disorganization increase with both osteophyte formation and JSN (proximal more than distal), while local vBMD decreases. This process appears to be primarily at the site of pathology rather than nearby unaffected bone.


Assuntos
Articulação da Mão , Osteoartrite , Osteófito , Idoso , Compostos de Anilina , Osso e Ossos/patologia , Feminino , Articulação da Mão/diagnóstico por imagem , Articulação da Mão/patologia , Humanos , Masculino , Osteoartrite/diagnóstico por imagem , Osteoartrite/patologia , Osteófito/diagnóstico por imagem , Osteófito/patologia
3.
J Orthop Surg Res ; 17(1): 406, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064420

RESUMO

PURPOSE: Osteoarthritis (OA) is a common joint disease characterized by cartilage degeneration, synovial inflammation, osteophytes, and subchondral osteosclerosis. This study investigated the effects of resveratrol (RES) on extracellular matrix (ECM), autophagy, and apoptosis in OA pathogenesis via the SIRT1/FOXO1 pathway. METHODS: The microenvironment of OA chondrocytes was stimulated in vitro by adding 10 ng/mL of IL-1ß to primary Wistar rat chondrocyte. Western blotting, immunofluorescence, quantitative real-time PCR, and transmission electron microscopy (TEM) were used for analysis. RESULTS: In the presence of IL-1ß, RES increased the expression of silent information regulator (SIR) 1 protein and the phosphorylation level of forkhead transcription factor (FOXO) 1. It also promoted chondrocyte autophagy, increased the expression of SOX9 and aggrecan, inhibited chondrocyte apoptosis and matrix breakdown, and protected chondrocytes from IL-1ß damage. After a SIRT1 inhibitor or FOXO1 inhibitor was added, the protective effect of RES on chondrocytes was significantly weakened. Our results suggest that RES regulates the ECM metabolism, autophagy, and apoptosis of OA chondrocytes through the SIRT1/FOXO1 pathway to ameliorate IL-1ß-induced chondrocyte injury. CONCLUSION: RES protects chondrocytes from IL-1ß-induced damage by activating SIRT1/FOXO1 signaling and holds potential in OA treatment.


Assuntos
Condrócitos , Osteoartrite , Animais , Condrócitos/metabolismo , Interleucina-1beta , Proteínas do Tecido Nervoso/metabolismo , Osteoartrite/patologia , Ratos , Ratos Wistar , Resveratrol/farmacologia , Transdução de Sinais , Sirtuína 1/metabolismo
4.
Front Immunol ; 13: 901555, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059477

RESUMO

Background: Pyruvate kinase M2 (PKM2) is an enzyme that regulates the final process of glycolysis and exists in tetrameric and dimeric forms. The dimeric form of PKM2, also known as tumour M2-PK, increases when aerobic glycolysis is augmented, a feature observed in rheumatoid arthritis (RA). We investigated whether plasma tumour M2-PK is elevated in patients with RA and whether its levels correlate with disease activity. Methods: Plasma levels of tumour M2-PK were measured for patients with RA (n=151), those with osteoarthritis (OA) (n=37), and controls (n=37). We evaluated the association between plasma tumour M2-PK and continuous variables using Pearson's correlation analysis, and multivariate logistic regression analysis to determine the association between plasma tumour M2-PK and disease activity status. Knee synovial tissue blocks from patients with RA and OA were subjected to real-time quantitative PCR (qPCR) using two different primers for PKM2 and tumour M2-PK immunohistochemical (IHC) staining. Results: The tumour M2-PK level significantly correlated with the disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) (r=0.546, p<0.001) and DAS28-C-reactive protein (CRP) (r=0.589, p<0.001). Moreover, repeat testing of tumour M2-PK levels in 20 patients revealed a significant decline in tumour M2-PK levels after reduction in inflammation (p<0.001). Area under the receiver operating characteristic curve (AUROC) analysis demonstrated that upon incorporation of tumour M2-PK, ESR, and CRP, the area under the curve was 0.962 for distinguishing moderate/high from remission/low disease activity. Adjusted logistic regression also revealed that a tumour M2-PK >43.9 U/mL (OR 3.672, p=0.042) independently predicted moderate/high disease activity status. Furthermore, tumour M2-PK levels in patients with RA were significantly higher than in those with OA and controls (all p<0.001). However, no differences were found in PKM2 expression in RA and OA synovial tissues as assessed by qPCR, and IHC analysis revealed negligible tumour M2-PK expression in the synovial tissues. Conclusion: Circulating plasma tumour M2-PK levels may be a clinically useful indicator for evaluating disease activity and RA diagnosis.


Assuntos
Artrite Reumatoide , Osteoartrite , Piruvato Quinase , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/patologia , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Humanos , Neoplasias/diagnóstico , Neoplasias/patologia , Osteoartrite/diagnóstico , Osteoartrite/metabolismo , Osteoartrite/patologia , Membrana Sinovial/patologia
5.
Cartilage ; 13(3): 19476035221111503, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072990

RESUMO

OBJECTIVE: In the early stages of cartilage damage, diagnostic methods focusing on the mechanism of maintaining the hydrostatic pressure of cartilage are thought to be useful. 17O-labeled water, which is a stable isotope of oxygen, has the advantage of no radiation exposure or allergic reactions and can be detected by magnetic resonance imaging (MRI). This study aimed to evaluate MRI images using 17O-labeled water in a rabbit model. DESIGN: Contrast MRI with 17O-labeled water and macroscopic and histological evaluations were performed 4 and 8 weeks after anterior cruciate ligament transection surgery in rabbits. A total of 18 T2-weighted images were acquired, and 17O-labeled water was manually administered on the third scan. The 17O concentration in each phase was calculated from the signal intensity at the articular cartilage. Macroscopic and histological grades were evaluated and compared with the 17O concentration. RESULTS: An increase in 17O concentration in the macroscopic and histologically injured areas was observed by MRI. Macroscopic evaluation showed that the 17O concentration significantly increased in the damaged site group. Histological evaluations also showed that 17O concentrations significantly increased at 36 minutes 30 seconds after initiating MRI scanning in the Osteoarthritis Research Society International (OARSI) grade 3 (0.493 in grade 0, 0.659 in grade 1, 0.4651 in grade 2, and 0.9964 in grade 3, P < 0.05). CONCLUSION: 17O-labeled water could visualize earlier articular cartilage damage, which is difficult to detect by conventional methods.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Imageamento por Ressonância Magnética/métodos , Osteoartrite/patologia , Coelhos , Água
6.
Stem Cell Res Ther ; 13(1): 457, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064441

RESUMO

BACKGROUND: Synovial membrane-derived mesenchymal progenitor cells (SM-MPCs) are a promising candidate for the cell-based treatment of osteoarthritis (OA) considering their in vitro and in vivo capacity for cartilage repair. However, the OA environment may adversely impact their regenerative capacity. There are no studies for canine (c)SM-MPCs that compare normal to OA SM-MPCs, even though dogs are considered a relevant animal model for OA. Therefore, this study compared cSM-MPCs from normal and OA synovial membrane tissue to elucidate the effect of the OA environment on MPC numbers, indicated by CD marker profile and colony-forming unit (CFU) capacity, and the impact of the OA niche on tri-lineage differentiation. METHODS: Normal and OA synovial membrane were collected from the knee joints of healthy dogs and dogs with rupture of the cruciate ligaments. The synovium was assessed by histopathological OARSI scoring and by RT-qPCR for inflammation/synovitis-related markers. The presence of cSM-MPCs in the native tissue was further characterized with flow cytometry, RT-qPCR, and immunohistochemistry, using the MPC markers; CD90, CD73, CD44, CD271, and CD34. Furthermore, cells isolated upon enzymatic digestion were characterized by CFU capacity, and a population doublings assay. cSM-MPCs were selected based on plastic adherence, expanded to passage 2, and evaluated for the expression of MPC-related surface markers and tri-lineage differentiation capacity. RESULTS: Synovial tissue collected from the OA joints had a significantly higher OARSI score compared to normal joints, and significantly upregulated inflammation/synovitis markers S100A8/9, IL6, IL8, and CCL2. Both normal and OA synovial membrane contained cells displaying MPC properties, including a fibroblast-like morphology, CFU capacity, and maintained MPC marker expression over time during expansion. However, OA cSM-MPCs were unable to differentiate towards the chondrogenic lineage and had low adipogenic capacity in contrast to normal cSM-MPCs, whereas they possessed a higher osteogenic capacity. Furthermore, the OA synovial membrane contained significantly lower percentages of CD90+, CD44+, CD34+, and CD271+ cells. CONCLUSIONS: The OA environment had adverse effects on the regenerative potential of cSM-MPCs, corroborated by decreased CFU, population doubling, and chondrogenic capacity compared to normal cSM-MPCs. OA cSM-MPCs may be a less optimal candidate for the cell-based treatment of OA than normal cSM-MPCs.


Assuntos
Células-Tronco Mesenquimais , Osteoartrite , Sinovite , Adapaleno/metabolismo , Animais , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular , Células Cultivadas , Cães , Inflamação/patologia , Células-Tronco Mesenquimais/metabolismo , Osteoartrite/patologia , Membrana Sinovial , Sinovite/metabolismo , Sinovite/patologia , Antígenos Thy-1/metabolismo
7.
BMC Musculoskelet Disord ; 23(1): 872, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127685

RESUMO

BACKGROUND: Our previous study identified miR-99a as a negative regulator of early chondrogenic differentiation. However, the functional role of miR-99a in the pathogenesis of osteoarthritis (OA) remains unclear. METHODS: We examined the levels of miR-99a and Frizzled 8 (FZD8) expression in tissue specimens. Human SW1353 chondrosarcoma cells were stimulated with IL-6 and TNF-α to construct an in vitro OA environment. A luciferase reporter assay was performed to analyze the relationship between miR-99a and FZD8. CCK-8 assays, flow cytometry, and ELISA assays were used to assess cell viability, apoptosis, and inflammatory molecule expression, respectively. Percutaneous intra-spinal injections of papain mixed solution were performed to create an OA Sprague-Dawley rat model. Alcian Blue staining, Safranin O Fast Green staining, and Toluidine Blue O staining were performed to detect the degrees of cartilage injury. RESULTS: MiR-99a expression was downregulated in the severe spine OA patients when compared with the mild spine OA patients, and was also decreased in the experimentally induced in vitro OA environment when compared with the control environment. Functionally, overexpression of miR-99a significantly suppressed cell apoptosis and extracellular matrix degradation stimulated by IL-6 and TNF-α. FZD8 was identified as a target gene of miR-99a. Furthermore, the suppressive effects of miR-99a on cell injury induced by IL-6 and TNF-α were reversed by FZD8 overexpression. Moreover, the levels of miR-99a expression were also reduced in the induced OA model rats, and miR-99a agomir injection relieved the cartilage damage. At the molecular level, miR-99a overexpression downregulated the levels of MMP13, ß-catenin, Bax, and caspase-3 protein expression and upregulated the levels of COL2A1 and Bcl-2 protein expression in the in vitro OA-like chondrocyte model and also in the experimental OA model rats. CONCLUSIONS: Our data showed that miR-99a alleviated apoptosis and extracellular matrix degradation by targeting FZD8, and thereby suppressed the development and progression of experimentally induced spine osteoarthritis.


Assuntos
MicroRNAs , Osteoartrite da Coluna Vertebral , Osteoartrite , Azul Alciano/metabolismo , Azul Alciano/farmacologia , Animais , Apoptose/genética , Caspase 3/metabolismo , Matriz Extracelular/patologia , Humanos , Interleucina-6/metabolismo , Luciferases/metabolismo , Luciferases/farmacologia , Metaloproteinase 13 da Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite/patologia , Osteoartrite da Coluna Vertebral/metabolismo , Papaína/metabolismo , Papaína/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular , Sincalida/metabolismo , Sincalida/farmacologia , Cloreto de Tolônio/metabolismo , Cloreto de Tolônio/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , beta Catenina/metabolismo , beta Catenina/farmacologia
8.
J Biomech ; 142: 111233, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36007353

RESUMO

In Post Traumatic Osteoarthritis (PTOA), hypomineralization and increased remodeling of the Subchondral bone (SB) are the first stages of tissue alterations. Although these alterations are well depicted and one of the main targets in OA intervention, the link between SB compositional and mechanical properties alterations during OA progression remains scarce in the literature. Here, we hypothesized that SB shows - right after the first sign of gait pattern changes - a decrease in SB tissue formation depicted by (i) a decrease in thickness, (ii) a lower nanoscopic stiffness, and (iii) a decrease in mineral and collagen maturity. To test our hypothesis, we investigated PTOA in female C57Bl6 mice's right knee (n = 13 control group [CL] and n = 27 PTOA group) by using Gait Analysis, Histomorphometry, Nanoindentation, and Raman Spectroscopy (RS). We showed (i) an increased OA histological grade, (ii) a decrease in Cartilage and SB thickness, and (ii) an increase of stance time and stride length on both limbs. The lateral condyle - where the main forces were applied - of mice with PTOA decreased in the degree of mineralization and crystal size and presented a lower Modulus of Elasticity (E). However, while no difference was observed regarding collagen or mineral-related compositional RS properties, we depicted higher crystallinity in the medial condyle than the lateral condyle in the PTOA group, which we did not observe in the control group. Our study depicts an early onset of intermediate PTOA where SB nanoscopic stiffness decreases while the degree of mineralization is not severely altered yet.


Assuntos
Cartilagem Articular , Epífises , Osteoartrite , Animais , Cartilagem Articular/patologia , Colágeno , Modelos Animais de Doenças , Epífises/lesões , Epífises/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Minerais , Osteoartrite/patologia
9.
Sci Adv ; 8(34): eabn3106, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-36026443

RESUMO

Articular cartilage has low regenerative capacity despite permanent stress. Irreversible cartilage lesions characterize osteoarthritis (OA); this is not followed by tissue repair. Lin28a, an RNA binding protein, is detected in damaged cartilage in humans and mice. We investigated the role of LIN28a in cartilage physiology and in osteoarthritis. Lin28a-inducible conditional cartilage deletion up-regulated Mmp13 in intact mice and exacerbated the cartilage destruction in OA mice. Lin28a-specific cartilage overexpression protected mice against cartilage breakdown, stimulated chondrocyte proliferation and the expression of Prg4 and Sox9, and down-regulated Mmp13. Lin28a overexpression inhibited Let-7b and Let-7c miRNA levels while RNA-sequencing analysis revealed five genes of transcriptional factors regulated by Let-7. Moreover, Lin28a overexpression up-regulated HMGA2 and activated SOX9 transcription, a factor required for chondrocyte reprogramming. HMGA2 siRNA knockdown inhibited the cartilage protective effect of Lin28a overexpression. This study provides insights into a new pathway including the Lin28a-Let7 axis, thus promoting chondrocyte anabolism in injured cartilage in mice.


Assuntos
Cartilagem Articular , Osteoartrite , Proteínas de Ligação a RNA , Fatores de Transcrição SOX9 , Animais , Cartilagem Articular/patologia , Reprogramação Celular , Condrócitos , Metaloproteinase 13 da Matriz , Camundongos , Osteoartrite/patologia , Proteínas de Ligação a RNA/genética , Fatores de Transcrição SOX9/genética
10.
J Int Med Res ; 50(8): 3000605221104764, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36000146

RESUMO

OBJECTIVE: Inflammation plays a crucial part in osteoarthritis (OA) development. This work aimed to explore loganin's role and molecular mechanism in inflammation and clarify its anti-inflammatory effects in OA treatment. METHODS: Chondrocytes were stimulated using interleukin (IL)-1ß and loganin at two concentrations (1 µM and 10 µM). Nitric oxide (NO) and prostaglandin E2 (PGE2) expression was assessed. Real-time polymerase chain reaction was used to evaluate inducible NO synthase (iNOS), cyclooxygenase (COX)-2, IL-6, and tumor necrosis factor (TNF)-α mRNA levels. Western blot was used to investigate TLR4, MyD88, p-p65, and IκB-α expression. p65 nuclear translocation, synovial inflammatory response, and cartilage degeneration were also assessed. RESULTS: Loganin significantly reduced IL-1ß-mediated PGE2, NO, iNOS, and COX-2 expression compared with that of the IL-1ß stimulation group. The TLR4/MyD88/NF-κB pathway was suppressed by loganin, which decreased inflammatory cytokine (TNF-α and IL-6) levels compared with those of the IL-1ß stimulation group. Loganin inhibited IL-1ß-mediated NF-κB p65 nuclear translocation compared with that of the IL-1ß stimulation group. Loganin partially suppressed cartilage degeneration and the synovial inflammatory response in vivo. CONCLUSION: This work demonstrated that loganin inhibited IL-1ß-mediated inflammation in rat chondrocytes through TLR4/MyD88/NF-κB pathway regulation, thereby reducing rat cartilage degeneration and the synovial inflammatory response.


Assuntos
NF-kappa B , Osteoartrite , Animais , Cartilagem/patologia , Condrócitos/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/farmacologia , Dinoprostona , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Iridoides , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/farmacologia , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Osteoartrite/patologia , Ratos , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Int Immunopharmacol ; 110: 108996, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35978501

RESUMO

BACKGROUND: Previous evidence has suggested that circular RNA (circRNA) is abnormally expressed in osteoarthritis (OA). However, the underlying mechanism of circRNA in OA progression remains unclear. The study aims to reveal the mechanism of circ_0128846 regulating OA. METHODS: Human chondrocytes (C28/I2 cells) were treated with interleukin-1ß (IL-1ß) to mimic an OA cell model. The expression levels of circ_0128846, miR-940 and protein tyrosine phosphatase 12 (PTPN12) were detected by qRT-PCR. Protein expression was checked by Western blotting. Cell viability, proliferation, and apoptosis were analyzed by a cell counting kit-8 assay, 5-Ethynyl-2'-deoxyuridine (EdU) assay and flow cytometry analysis, respectively. The production of tumor necrosis factor-α (TNF-α) and IL-6 was determined by an enzyme-linked immunosorbent assay (ELISA). The binding relationship between miR-940 and circ_0128846 or PTPN12 was identified by dual-luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: Circ_0128846 and PTPN12 expression were significantly upregulated, whereas miR-940 was downregulated in the cartilage tissues of OA patients and IL-1ß-treated C28/I2 cells compared with controls. IL-1ß treatment inhibited C28/I2 cell proliferation and induced cell apoptosis and the production of inflammatory factors, TNF-α and IL-6; however, these effects were partly reversed after circ_0128846 depletion. In terms of mechanism, circ_0128846 acted as a miR-940 sponge, and miR-940 combined with PTPN12. Also, circ_0128846 depletion partly ameliorated IL-1ß-induced C28/I2 cell disorders through miR-940. PTPN12 overexpression also partly relieved miR-940-mediated effects in IL-1ß-treated C28/I2 cells. Further, circ_0128846 induced PTPN12 expression by interacting with miR-940. CONCLUSION: Circ_0128846 regulated human chondrocyte proliferation, apoptosis and inflammation through the miR-940/PTPN12 pathway in OA.


Assuntos
Condrócitos/metabolismo , MicroRNAs , Osteoartrite , Apoptose , Humanos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 12/metabolismo , RNA Circular/genética , Fator de Necrose Tumoral alfa/metabolismo
12.
Front Immunol ; 13: 938075, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967299

RESUMO

Osteoarthritis (OA) is the most common joint disease, affecting over 300 million people world-wide. Accumulating evidence attests to the important roles of the immune system in OA pathogenesis. Understanding the role of various immune cells in joint degeneration or joint repair after injury is vital for improving therapeutic strategies for treating OA. Post-traumatic osteoarthritis (PTOA) develops in ~50% of individuals who have experienced an articular trauma like an anterior cruciate ligament (ACL) rupture. Here, using the high resolution of single-cell RNA sequencing, we delineated the temporal dynamics of immune cell accumulation in the mouse knee joint after ACL rupture. Our study identified multiple immune cell types in the joint including neutrophils, monocytes, macrophages, B cells, T cells, NK cells and dendritic cells. Monocytes and macrophage populations showed the most dramatic changes after injury. Further characterization of monocytes and macrophages reveled 9 major subtypes with unique transcriptomics signatures, including a tissue resident Lyve1hiFolr2hi macrophage population and Trem2hiFcrls+ recruited macrophages, both showing enrichment for phagocytic genes and growth factors such as Igf1, Pdgfa and Pdgfc. We also identified several genes induced or repressed after ACL injury in a cell type-specific manner. This study provides new insight into PTOA-associated changes in the immune microenvironment and highlights macrophage subtypes that may play a role in joint repair after injury.


Assuntos
Lesões do Ligamento Cruzado Anterior , Receptor 2 de Folato , Osteoartrite , Animais , Lesões do Ligamento Cruzado Anterior/complicações , Lesões do Ligamento Cruzado Anterior/genética , Humanos , Articulação do Joelho/patologia , Glicoproteínas de Membrana , Camundongos , Osteoartrite/genética , Osteoartrite/patologia , RNA-Seq , Receptores Imunológicos
13.
Contrast Media Mol Imaging ; 2022: 7614497, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35992546

RESUMO

Osteoarthritis (OA) is a rheumatic disease and its pathogenesis involves the dysregulation of noncoding RNAs. Therefore, the regulatory mechanism of circular RNA MELK (circMELK) was specified in this work. OA human cartilage tissue was collected, and circMELK, miR-497-5p, and myeloid differentiation factor 88 (MYD88) expression were examined. Human chondrocytes were stimulated with interleukin- (IL-) 1ß and interfered with vectors altering circMELK, miR-497-5p, and MyD88 expression to observe their effects on cell viability, cell cycle and apoptosis, autophagy, and inflammation. The binding relationship between RNAs was verified. The data presented that OA cartilage tissues presented raised circMELK and MYD88 and inhibited miR-497-5p expression. IL-1ß suppressed cell viability, prevented cell cycle, and induced apoptosis, autophagy, and inflammation of chondrocytes. Functionally, IL-1ß-induced changes of chondrocytes could be attenuated by suppressing circMELK or overexpressing miR-497-5p. circMELK acted as a sponge of miR-497-5p while miR-497-5p was a regulator of MYD88. MYD88 restricted the effect of overexpressing miR-497-5p on IL-1ß-stimulated chondrocytes. MYD88 triggered nuclear factor-kappaB (NF-κB) pathway activation. Shortly, CircMELK promotes chondrocyte apoptosis and inhibits autophagy in OA by regulating MYD88/NF-κB signaling axis through miR-497-5p. Our study proposes a new molecular mechanism for the development of OA.


Assuntos
MicroRNAs , Fator 88 de Diferenciação Mieloide , NF-kappa B , Osteoartrite , Proteínas Serina-Treonina Quinases , RNA Circular , Apoptose/genética , Apoptose/fisiologia , Autofagia/genética , Autofagia/fisiologia , Condrócitos/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Circular/genética , RNA Circular/metabolismo
14.
JBJS Rev ; 10(7)2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35922395

RESUMO

➢: Pathologic meniscal extrusion can compromise meniscal function, leading to increased contact forces in the tibiofemoral compartment and the acceleration of osteoarthritic changes. ➢: Extrusion is typically defined as radial displacement of ≥3 mm outside the tibial border and is best diagnosed via magnetic resonance imaging, although ultrasonography has also demonstrated encouraging diagnostic utility. ➢: Surgical management of meniscal extrusion is based on the underlying etiology, the patient's symptom profile, the preexisting health of the articular surface, and the risk of future chondral injury and osteoarthritis.


Assuntos
Osteoartrite , Lesões do Menisco Tibial , Humanos , Imageamento por Ressonância Magnética/métodos , Meniscos Tibiais/diagnóstico por imagem , Meniscos Tibiais/cirurgia , Osteoartrite/patologia , Lesões do Menisco Tibial/diagnóstico por imagem , Lesões do Menisco Tibial/cirurgia
15.
J Orthop Surg Res ; 17(1): 400, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36045373

RESUMO

OBJECTIVE: Osteoarthritis (OA) presents cartilage damage in addition to chronic inflammation. However, self-recovery of damaged cartilage in an inflammatory environment is not possible. Mesenchymal stem cells (MSCs) in the bone marrow are a source of regenerative repair of damaged cartilage. To date, whether intra-luminal administration of the bone marrow can delay the progression of OA is still unknown. This study, therefore, aimed to explore the role of intra-bone marrow injection of Magnesium isoglycyrrhizinate (MgIG) in delaying the OA progression and to investigate the underlying mechanism. METHODS: Rabbit OA models were established using the anterior cruciate ligament transection method while a catheter was implanted into the bone marrow cavity. 1 week after surgery, MgIG treatment was started once a week for 4 weeks. The cartilage degradation was analyzed using hematoxylin-eosin staining, Masson's trichrome staining and Alcian blue staining. Additionally, the pro-inflammatory factors and cartilage regeneration genes involved in the cartilage degeneration and the underlying mechanisms in OA were detected using enzyme-linked immunosorbent assay, quantitative real-time PCR (qRT-PCR) and Western blotting. RESULTS: The results of histological staining revealed that intra-bone marrow injection of MgIG reduced degeneration and erosion of articular cartilage, substantially reducing the Osteoarthritis Research Society International scores. Furthermore, the productions of inflammatory cytokines in the bone marrow cavity and articular cavity such as interleukin-1ß(IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) were inhibited upon the treatment of MgIG. At the same time, the expression of alkaline phosphate, tartrate-resistant acid phosphatase-5b (TRAP-5b) and C-telopeptides of type II collagen (CTX-II) in the blood also decreased and was positively correlated. On the contrary, cartilage-related genes in the bone marrow cavity such as type II collagen (Col II), Aggrecan (AGN), and SRY-box 9 (SOX9) were up-regulated, while matrix metalloproteinase-3 (MMP-3) was down-regulated. Mechanistically, MgIG was found to exert an anti-inflammatory effect and impart protection to the cartilage by inhibiting the NF-κB pathway. CONCLUSION: Intra-bone marrow injection of MgIG might inhibit the activation of the NF-κB pathway in the progression of OA to exert an anti-inflammatory effect in the bone marrow cavity and articular cavity, thereby promoting cartilage regeneration of MSCs in the bone marrow, making it a potential new therapeutic intervention for the treatment of OA.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Anti-Inflamatórios/farmacologia , Medula Óssea , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Colágeno Tipo II/metabolismo , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/prevenção & controle , Interleucina-1beta/metabolismo , Magnésio/metabolismo , NF-kappa B/metabolismo , Osteoartrite/patologia , Coelhos
16.
Int J Mol Sci ; 23(15)2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35955514

RESUMO

Chronic inflammation is implicated in numerous human pathologies. In particular, low-grade inflammation is currently recognized as an important mechanism of osteoarthritis (OA), at least in some patients. Among the signs of the inflammatory process are elevated macrophage numbers detected in the OA synovium compared to healthy controls. High macrophage counts also correlate with clinical symptoms of the disease. Macrophages are central players in the development of chronic inflammation, pain, cartilage destruction, and bone remodeling. However, macrophages are also involved in tissue repair and remodeling, including cartilage. Therefore, reduction of macrophage content in the joints correlates with deleterious effects in OA models. Macrophage population is heterogeneous and dynamic, with phenotype transitions being induced by a variety of stimuli. In order to effectively use the macrophage inflammatory circuit for treatment of OA, it is important to understand macrophage heterogeneity and interactions with surrounding cells and tissues in the joint. In this review, we discuss functional phenotypes of macrophages and specific targeting approaches relevant for OA treatment development.


Assuntos
Osteoartrite , Humanos , Inflamação/patologia , Macrófagos/patologia , Osteoartrite/patologia , Fenótipo , Membrana Sinovial/patologia
17.
Cell Death Dis ; 13(8): 681, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931686

RESUMO

The accumulation of senescent cells is a key characteristic of aging, leading to the progression of age-related diseases such as osteoarthritis (OA). Previous data from our laboratory has demonstrated that high levels of the transmembrane protein connexin 43 (Cx43) are associated with a senescent phenotype in chondrocytes from osteoarthritic cartilage. OA has been reclassified as a musculoskeletal disease characterized by the breakdown of the articular cartilage affecting the whole joint, subchondral bone, synovium, ligaments, tendons and muscles. However, the mechanisms that contribute to the spread of pathogenic factors throughout the joint tissues are still unknown. Here, we show for the first time that small extracellular vesicles (sEVs) released by human OA-derived chondrocytes contain high levels of Cx43 and induce a senescent phenotype in targeted chondrocytes, synovial and bone cells contributing to the formation of an inflammatory and degenerative joint environment by the secretion of senescence-associated secretory associated phenotype (SASP) molecules, including IL-1ß and IL-6 and MMPs. The enrichment of Cx43 changes the protein profile and activity of the secreted sEVs. Our results indicate a dual role for sEVs containing Cx43 inducing senescence and activating cellular plasticity in target cells mediated by NF-kß and the extracellular signal-regulated kinase 1/2 (ERK1/2), inducing epithelial-to-mesenchymal transition (EMT) signalling programme and contributing to the loss of the fully differentiated phenotype. Our results demonstrated that Cx43-sEVs released by OA-derived chondrocytes spread senescence, inflammation and reprogramming factors involved in wound healing failure to neighbouring tissues, contributing to the progression of the disease among cartilage, synovium, and bone and probably from one joint to another. These results highlight the importance for future studies to consider sEVs positive for Cx43 as a new biomarker of disease progression and new target to treat OA.


Assuntos
Vesículas Extracelulares , Osteoartrite , Condrócitos/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Osteoartrite/patologia , Fenótipo
18.
J Endocrinol ; 255(2): 39-51, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35993439

RESUMO

Among patients with knee osteoarthritis (OA), postmenopausal women are over-represented. The purpose of this study was to determine whether deficiency of female sex steroids affects OA progression and to evaluate the protective effect of treatment with a physiological dose of 17ß-estradiol (E2) on OA progression using a murine model. Ovariectomy (OVX) of female mice was used to mimic a postmenopausal state. OVX or sham-operated mice underwent surgery for destabilization of the medial meniscus (DMM) to induce OA. E2 was administered in a pulsed manner for 2 and 8 weeks. OVX of OA mice did not influence the cartilage phenotype or synovial thickness, while both cortical and trabecular subchondral bone mineral density (BMD) decreased after OVX compared with sham-operated mice at 8 weeks post-DMM surgery. Additionally, OVX mice displayed decreased motor activity, reduced threshold of pain sensitivity, and increased number of T cells in the inguinal lymph nodes compared to sham-operated mice 2 weeks after OA induction. Eight weeks of treatment with E2 prevented cartilage damage and thickening of the synovium in OVX OA mice. The motor activity was improved after E2 replacement at the 2 weeks time point, which was also associated with lower pain sensitivity in the OA paw. E2 treatment protected against OVX-induced loss of subchondral trabecular bone. The number of T cells in the inguinal lymph nodes was reduced by E2 treatment after 8 weeks. This study demonstrates that treatment with a physiological dose of E2 exerts a protective role by reducing OA symptoms.


Assuntos
Estradiol , Osteoartrite , Animais , Cartilagem , Modelos Animais de Doenças , Estradiol/farmacologia , Estradiol/uso terapêutico , Feminino , Humanos , Camundongos , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Ovariectomia , Dor
19.
In Vitro Cell Dev Biol Anim ; 58(7): 521-528, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35925448

RESUMO

The articular cartilage is an avascular tissue, and oxygen tensions in its superficial and deeper zones are estimated to be 6% and 1%. Degeneration of the articular cartilage begins from the surface zone in osteoarthritis. We previously reported that monocarboxylate transporter-1, a transmembrane transporter for monocarboxylates, played an essential role in the interleukin-1ß-induced expression of NADPH oxidase-2, a reactive oxygen species-producing enzyme, and reactive oxygen species-dependent death of mouse chondrogenic ATDC5 cells cultured in a normal condition (20% oxygen). Here, we investigated the effect of oxygen tension on interleukin-1ß-induced events described above in ATDC5 cells. Interleukin-1ß induced the death of ATDC5 cells under 20% and 6% oxygen but did not under 2% and 1% oxygen. Interleukin-1ß induced Mct1 (monocarboxylate transporter-1 gene) and Nox2 (NADPH oxidase-2 gene) mRNAs' expression under 20% oxygen in 24 h, respectively, but not under 2% oxygen. On the other hand, a 24-h incubation with interleukin-1ß upregulated the expression of Nos2 (inducible nitric oxide synthase gene) mRNA irrespective of oxygen tension. Furthermore, inhibition of I-κB kinase suppressed the interleukin-1ß-induced expression of Mct1 mRNA in the cells cultured under 20% and 2% oxygen, indicating NF-κB plays an essential role in the induction of the Mct1 gene expression. The results suggest that interleukin-1ß induces monocarboxylate transporter-1 in an oxygen tension-dependent manner required for cell death in ATDC5 cells. These results might explain some part of the degenerative process of the articular cartilage, which begins from its superficial zone in the pathogenesis of osteoarthritis.


Assuntos
Cartilagem Articular , Osteoartrite , Doenças dos Roedores , Animais , Células Cultivadas , Condrócitos , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Camundongos , NADPH Oxidases/metabolismo , NADPH Oxidases/farmacologia , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite/patologia , Oxigênio/metabolismo , Oxigênio/farmacologia , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Doenças dos Roedores/metabolismo , Doenças dos Roedores/patologia
20.
J Anat ; 241(4): 875-895, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35866709

RESUMO

Articular calcified cartilage (ACC) has been dismissed, by some, as a remnant of endochondral ossification without functional relevance to joint articulation or weight-bearing. Recent research indicates that morphologic and metabolic ACC features may be important, reflecting knee joint osteoarthritis (OA) predisposition. ACC is less investigated than neighbouring joint tissues, with its component chondrocytes and mineralised matrix often being either ignored or integrated into analyses of hyaline articular cartilage and subchondral bone tissue respectively. Anatomical variation in ACC is recognised between species, individuals and age groups, but the selective pressures underlying this variation are unknown. Consequently, optimal ACC biomechanical features are also unknown as are any potential locomotory roles. This review collates descriptions of ACC anatomy and biology in health and disease, with a view to revealing its structure/function relationship and highlighting potential future research avenues. Mouse models of healthy and OA joint ageing have shown disparities in ACC load-induced deformations at the knee joint. This raises the hypothesis that ACC response to locomotor forces over time may influence, or even underlie, the bony and hyaline cartilage symptoms characteristic of OA. To effectively investigate the ACC, greater resolution of joint imaging and merging of hierarchical scale data will be required. An appreciation of OA as a 'whole joint disease' is expanding, as is the possibility that the ACC may be a key player in healthy ageing and in the transition to OA joint pathology.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Cartilagem Articular/patologia , Condrócitos/patologia , Cartilagem Hialina/patologia , Articulação do Joelho/patologia , Camundongos , Osteoartrite/patologia
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