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1.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204587

RESUMO

Structural disturbances of the subchondral bone are a hallmark of osteoarthritis (OA), including sclerotic changes, cystic lesions, and osteophyte formation. Osteocytes act as mechanosensory units for the micro-cracks in response to mechanical loading. Once stimulated, osteocytes initiate the reparative process by recruiting bone-resorbing cells and bone-forming cells to maintain bone homeostasis. Osteocyte-expressed sclerostin is known as a negative regulator of bone formation through Wnt signaling and the RANKL pathway. In this review, we will summarize current understandings of osteocytes at the crossroad of allometry and mechanobiology to exploit the relationship between osteocyte morphology and function in the context of joint aging and osteoarthritis. We also aimed to summarize the osteocyte dysfunction and its link with structural and functional disturbances of the osteoarthritic subchondral bone at the molecular level. Compared with normal bones, the osteoarthritic subchondral bone is characterized by a higher bone volume fraction, a larger trabecular bone number in the load-bearing region, and an increase in thickness of pre-existing trabeculae. This may relate to the aberrant expressions of sclerostin, periostin, dentin matrix protein 1, matrix extracellular phosphoglycoprotein, insulin-like growth factor 1, and transforming growth factor-beta, among others. The number of osteocyte lacunae embedded in OA bone is also significantly higher, yet the volume of individual lacuna is relatively smaller, which could suggest abnormal metabolism in association with allometry. The remarkably lower percentage of sclerostin-positive osteocytes, together with clustering of Runx-2 positive pre-osteoblasts, may suggest altered regulation of osteoblast differentiation and osteoblast-osteocyte transformation affected by both signaling molecules and the extracellular matrix. Aberrant osteocyte morphology and function, along with anomalies in molecular signaling mechanisms, might explain in part, if not all, the pre-osteoblast clustering and the uncoupled bone remodeling in OA subchondral bone.


Assuntos
Homeostase , Articulações/fisiologia , Osteoartrite/etiologia , Osteoartrite/metabolismo , Osteócitos/metabolismo , Animais , Biomarcadores , Remodelação Óssea , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Suscetibilidade a Doenças , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteoartrite/diagnóstico por imagem , Osteoartrite/patologia , Osteoblastos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
2.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208590

RESUMO

Osteoarthritis (OA) is the most common musculoskeletal disorder causing a great disability and a reduction in the quality of life. In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) degradation. Given the lack of therapies for the treatment of OA, in this study, we explore biomarkers that enable the development of new therapeutical approaches. We analyze the set of secreted proteins in AC and SF co-cultures by stable isotope labeling with amino acids (SILAC). We describe, for the first time, 115 proteins detected in SF-AC co-cultures stimulated by fibronectin fragments (Fn-fs). We also study the role of the vasoactive intestinal peptide (VIP) in this secretome, providing new proteins involved in the main events of OA, confirmed by ELISA and multiplex analyses. VIP decreases proteins involved in the inflammatory process (CHI3L1, PTX3), complement activation (C1r, C3), and cartilage ECM degradation (DCN, CTSB and MMP2), key events in the initiation and progression of OA. Our results support the anti-inflammatory and anti-catabolic properties of VIP in rheumatic diseases and provide potential new targets for OA treatment.


Assuntos
Condrócitos/metabolismo , Fibroblastos/metabolismo , Osteoartrite/metabolismo , Proteoma , Proteômica , Membrana Sinovial/citologia , Peptídeo Intestinal Vasoativo/metabolismo , Biomarcadores , Condrócitos/efeitos dos fármacos , Técnicas de Cocultura , Citocinas/metabolismo , Suscetibilidade a Doenças , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Osteoartrite/etiologia , Osteoartrite/patologia , Proteômica/métodos , Peptídeo Intestinal Vasoativo/farmacologia
3.
Hum Genet ; 140(8): 1201-1216, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33978893

RESUMO

Intermediate-sized insertions are one of the structural variants contributing to genome diversity. However, due to technical difficulties in identifying them, their importance in disease pathogenicity and gene expression regulation remains unclear. We used whole-genome sequencing data of 174 Japanese samples to characterize intermediate-sized insertions using a highly-accurate insertion calling method (IMSindel software and joint-call recovery) and obtained a catalogue of 4254 insertions. We constructed an imputation panel comprising of insertions and SNVs from all samples, and conducted imputation of intermediate-sized insertions for 82 publicly-available Japanese samples. Positive Predictive Value of imputation, evaluated using Nanopore long-read sequencing data, was 97%. Subsequent eQTL analysis predicted 128 (~ 3.0%) insertions as causative for gene expression level changes. Enrichment analysis of causal insertions for genome regulatory elements showed significant associations with CTCF-binding sites, super-enhancers, and promoters. Among 17 causal insertions found in the same causal set with GWAS hits, there were insertions associated with changes in expression of cancer-related genes such as BRCA1, ZNF222, and ABCB10. Analysis of insertions sequences revealed that 461 insertions were short tandem duplications frequently found in early-replicating regions of genome. Furthermore, comparison of functional importance of intermediate-sized insertions with that of intermediate-sized deletions detected in the same sample set in our previous study showed that insertions were more frequent in genic regions, and proportion of functional candidates was smaller in insertions. Here, we characterize a high-confidence set of intermediate-sized insertions and indicate their importance in gene expression regulation. Our results emphasize the importance of considering intermediate-sized insertions in trait association studies.


Assuntos
Regulação da Expressão Gênica , Genoma Humano , Mutagênese Insercional , Proteínas de Neoplasias/genética , Neoplasias/genética , Osteoartrite/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Sequência de Bases , Sítios de Ligação , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Mapeamento Cromossômico , Bases de Dados Genéticas , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Humanos , Japão , Anotação de Sequência Molecular , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Software , Sequenciamento Completo do Genoma
4.
Cell Prolif ; 54(6): e13047, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33960555

RESUMO

OBJECTIVES: Circular RNAs (circRNAs) are noncoding RNAs that compete against other endogenous RNA species, such as microRNAs, and have been implicated in many diseases. In this study, we investigated the role of a new circRNA (circSLC7A2) in osteoarthritis (OA). MATERIALS AND METHODS: The relative expression of circSLC7A2 was significantly lower in OA tissues than it was in matched controls, as shown by real-time quantitative polymerase chain reaction (RT-qPCR). Western blotting, RT-qPCR and immunofluorescence experiments were employed to evaluate the roles of circSLC7A2, miR-4498 and TIMP3. The in vivo role and mechanism of circSLC7A2 were also conformed in a mouse model. RESULTS: circSLC7A2 was decreased in OA model and the circularization of circSLC7A2 was regulated by FUS. Loss of circSLC7A2 reduced the sponge of miR-4498 and further inhibited the expression of TIMP3, subsequently leading to an inflammatory response. We further determined that miR-4498 inhibitor reversed circSLC7A2-knockdown-induced OA phenotypes. Intra-articular injection of circSLC7A2 alleviated in vivo OA progression in a mouse model of anterior cruciate ligament transection (ACLT). CONCLUSIONS: The circSLC7A2/miR-4498/TIMP3 axis of chondrocytes catabolism and anabolism plays a critical role in OA development. Our results suggest that circSLC7A2 may serve as a new therapeutic target for osteoarthritis.


Assuntos
Osteoartrite/genética , RNA Circular/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Animais , Apoptose , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Regulação para Baixo , Regulação da Expressão Gênica , Humanos , Camundongos , MicroRNAs/genética , Osteoartrite/patologia , RNA Circular/análise , Inibidor Tecidual de Metaloproteinase-3/análise
5.
Life Sci ; 278: 119553, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33932445

RESUMO

AIMS: We have evaluated the potential of a three-dimensional (3D) thermoreversible gelation polymer (TGP) matrix in enhancing miRNA 140 expression (a biomarker correlating with homeostasis and cartilage regeneration) during the in vitro expansion of osteoarthritis (OA)-affected human chondrocytes. MATERIALS AND METHODS: OA-chondrocytes were cultured in two-dimensional (2D) monolayer followed by culture in 3D-TGP. miRNA 140 expression levels in cell culture supernatant followed by expression in the cell lysate of both 2D and 3D-TGP cultures were analyzed. KEY FINDINGS: The expression of miRNA 140 in cell culture supernatant from the 3D-TGP group was 0.001 to 0.002% that in 2D culture supernatant while in the cell lysate, miRNA 140 expression in the 3D-TGP was nearly 30-fold higher than that of 2D group. SIGNIFICANCE: The 3D-TGP matrix allows enhanced expression of miRNA 140 in OA-affected human chondrocytes in vitro which after necessary validations can be applied in clinical transplantation to significantly improve the outcome.


Assuntos
Condrócitos/patologia , MicroRNAs/genética , Osteoartrite/genética , Regulação para Cima , Técnicas de Cultura de Células , Células Cultivadas , Condrócitos/metabolismo , Humanos , Osteoartrite/patologia , Polímeros/química , Tecidos Suporte/química
6.
Int J Mol Sci ; 22(5)2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33800062

RESUMO

Autophagy is involved in different degenerative diseases and it may control epigenetic modifications, metabolic processes, stem cells differentiation as well as apoptosis. Autophagy plays a key role in maintaining the homeostasis of cartilage, the tissue produced by chondrocytes; its impairment has been associated to cartilage dysfunctions such as osteoarthritis (OA). Due to their location in a reduced oxygen context, both differentiating and mature chondrocytes are at risk of premature apoptosis, which can be prevented by autophagy. AutophagomiRNAs, which regulate the autophagic process, have been found differentially expressed in OA. AutophagomiRNAs, as well as other regulatory molecules, may also be useful as therapeutic targets. In this review, we describe and discuss the role of autophagy in OA, focusing mainly on the control of autophagomiRNAs in OA pathogenesis and their potential therapeutic applications.


Assuntos
Autofagia/fisiologia , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Animais , Autofagia/efeitos dos fármacos , Diferenciação Celular , Senescência Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/fisiologia , Modelos Animais de Doenças , Humanos , MicroRNAs , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
7.
Int J Mol Sci ; 22(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33916928

RESUMO

Osteoarthritis (OA), a degenerative joint disorder, has been reported as the most common cause of disability worldwide. The production of inflammatory cytokines is the main factor in OA. Previous studies have been reported that obeticholic acid (OCA) and OCA derivatives inhibited the release of proinflammatory cytokines in acute liver failure, but they have not been studied in the progression of OA. In our study, we screened our small synthetic library of OCA derivatives and found T-2054 had anti-inflammatory properties. Meanwhile, the proliferation of RAW 264.7 cells and ATDC5 cells were not affected by T-2054. T-2054 treatment significantly relieved the release of NO, as well as mRNA and protein expression levels of inflammatory cytokines (IL-6, IL-8 and TNF-α) in LPS-induced RAW 264.7 cells. Moreover, T-2054 promoted extracellular matrix (ECM) synthesis in TNF-α-treated ATDC5 chondrocytes. Moreover, T-2054 could relieve the infiltration of inflammatory cells and degeneration of the cartilage matrix and decrease the levels of serum IL-6, IL-8 and TNF-α in DMM-induced C57BL/6 mice models. At the same time, T-2054 showed no obvious toxicity to mice. Mechanistically, T-2054 decreased the extent of p-p65 expression in LPS-induced RAW 264.7 cells and TNF-α-treated ATDC5 chondrocytes. In summary, we showed for the first time that T-2054 effectively reduced the release of inflammatory mediators, as well as promoted extracellular matrix (ECM) synthesis via the NF-κB-signaling pathway. Our findings support the potential use of T-2054 as an effective therapeutic agent for the treatment of OA.


Assuntos
Anti-Inflamatórios/farmacologia , Ácido Quenodesoxicólico/análogos & derivados , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Biomarcadores , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Cartilagem/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Óxido Nítrico/biossíntese , Osteoartrite/tratamento farmacológico , Osteoartrite/etiologia , Osteoartrite/patologia , Células RAW 264.7
8.
Res Vet Sci ; 136: 377-384, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33799167

RESUMO

BACKGROUND: Osteoarthritis is currently one of the most common chronic diseases. As life expectancy increases, its prevalence and incidence are expected to rise. At present, more and more evidences prove the correlation between the complement system and osteoarthritis (OA). This study aims to investigate complement C5's influence on the effect of MK801 on osteoarthritis synovial fibroblasts (OA-SFs). METHODS: We used IL-1b to induce OA-SFs derived from mice to obtain OA-SFs. And we performed RT-PCR and Western Blot assays to evaluate the expression levels of associated mRNA and protein. The alteration of MAC expression on OA-SFs cell membrane was evaluated by immunofluorescence assay. The expression of related inflammatory factors of OA-SFs was evaluated by ELISA experiment. RESULTS: MK801 could significantly inhibit the expression of osteoarthritis (OA) marker factors, such as: membrane attack complex (MAC), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-13 (MMP13). Meanwhile, MK801 can significantly inhibit the expression of complement C5 (C5) in OA-SFs. Immunofluorescence assay showed that MAC expression on OA-SFs cell membrane was significantly inhibited by MK801. The nucleo-plasmic separation experiment demonstrated that MK801 could significantly inhibit the activation of Nuclear factor-κB (NF-κB) signaling pathway in OA-SFs. Futhermore, koncking down the expression of C5 reversed the inhibition MK801 on the expression of OA-SFs inflammatory factors. CONCLUSIONS: These results illustrated two points: first, MK801 inhibited the generation of MAC and the release of inflammation factors in OA-SFs through C5; second: MK801 inhibited the activation of NF-κB signaling pathway in OA-SFs.


Assuntos
Complemento C5/metabolismo , Maleato de Dizocilpina/uso terapêutico , Fibroblastos/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Animais , Western Blotting , Células Cultivadas , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Fibroblastos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , RNA Mensageiro , Transdução de Sinais , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/imunologia , Membrana Sinovial/citologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Int J Mol Sci ; 22(5)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801461

RESUMO

Osteoarthritis (OA) is a significant cause of pain in both humans and horses with a high socio-economic impact. The horse is recognized as a pertinent model for human OA. In both species, regenerative therapy with allogeneic mesenchymal stem cells (MSCs) appears to be a promising treatment but, to date, no in vivo studies have attempted to compare the effects of different cell sources on the same individuals. The objective of this study is to evaluate the ability of a single blinded intra-articular injection of allogeneic bone-marrow (BM) derived MSCs and umbilical cord blood (UCB) derived MSC to limit the development of OA-associated pathological changes compared to placebo in a post-traumatic OA model applied to all four fetlock joints of eight horses. The effect of the tissue source (BM vs. UCB) is also assessed on the same individuals. Observations were carried out using clinical, radiographic, ultrasonographic, and magnetic resonance imaging methods as well as biochemical analysis of synovial fluid and postmortem microscopic and macroscopic evaluations of the joints until Week 12. A significant reduction in the progression of OA-associated changes measured with imaging techniques, especially radiography, was observed after injection of bone-marrow derived mesenchymal stem cells (BM-MSCs) compared to contralateral placebo injections. These results indicate that allogeneic BM-MSCs are a promising treatment for OA in horses and reinforce the importance of continuing research to validate these results and find innovative strategies that will optimize the therapeutic potential of these cells. However, they should be considered with caution given the low number of units per group.


Assuntos
Artrite Experimental/prevenção & controle , Medula Óssea/crescimento & desenvolvimento , Sangue Fetal/citologia , Células-Tronco Mesenquimais/citologia , Osteoartrite/prevenção & controle , Líquido Sinovial/citologia , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Feminino , Cavalos , Injeções Intra-Articulares , Masculino , Transplante de Células-Tronco Mesenquimais , Osteoartrite/etiologia , Osteoartrite/patologia
10.
Molecules ; 26(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924083

RESUMO

Osteoarthritis (OA) is a degenerative joint disease and an important cause of incapacitation. There is a lack of drugs and effective treatments that stop or slow the OA progression. Modern pharmacological treatments, such as analgesics, have analgesic effects but do not affect the course of OA. Long-term use of these drugs can lead to serious side effects. Given the OA nature, it is likely that lifelong treatment will be required to stop or slow its progression. Therefore, there is an urgent need for disease-modifying OA treatments that are also safe for clinical use over long periods. Phytonutraceuticals are herbal products that provide a therapeutic effect, including disease prevention, which not only have favorable safety characteristics but may have an alleviating effect on the OA and its symptoms. An estimated 47% of OA patients use alternative drugs, including phytonutraceuticals. The review studies the efficacy and action mechanism of widely used phytonutraceuticals, analyzes the available experimental and clinical data on the effect of some phytonutraceuticals (phytoflavonoids, polyphenols, and bioflavonoids) on OA, and examines the known molecular effect and the possibility of their use for chondroprotection.


Assuntos
Suplementos Nutricionais , Flavonoides/uso terapêutico , Osteoartrite/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Analgésicos/química , Analgésicos/uso terapêutico , Flavonoides/química , Humanos , Osteoartrite/patologia , Compostos Fitoquímicos/química , Polifenóis/química , Polifenóis/uso terapêutico
11.
Biomed Res Int ; 2021: 6681925, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791375

RESUMO

Total hip arthroplasty (THA) is a cost-effective treatment for osteoarthritis (OA), and osteolysis is a common complication of THA. This study was aimed at exploring the relevant molecular biomarkers for osteolysis after THA. We performed RNA sequence to identify and characterize expressed mRNAs and lncRNAs in OA and osteolysis. Differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) in OA and osteolysis were acquired, as well as shared DEmRNAs/DElncRNAs in OA and osteolysis and osteolysis-specific DEmRNAs/DElncRNAs. Then, shared and osteolysis-specific DElncRNA-DEmRNA coexpression networks were constructed to further investigate the function of DElncRNAs and DEmRNAs in OA and osteolysis. In total, 343 DEmRNAs and 25 DElncRNAs in OA, 908 DEmRNAs and 107 DElncRNAs in osteolysis, and 406 DEmRNAs and 46 DElncRNAs between OA and osteolysis were acquired. A total of 136 shared DEmRNAs and 9 shared DElncRNAs in OA and osteolysis and 736 osteolysis-specific DEmRNAs and 103 osteolysis-specific DElncRNAs were acquired. Then, 128 shared DElncRNA-DEmRNA coexpression pairs and 522 osteolysis-specific DElncRNA-DEmRNA coexpression pairs were identified. The present study highlighted the roles of four interaction pairs, including two shared lncRNA-mRNA interaction pairs in OA and osteolysis (AC111000.4 and AC016831.6), which may function in the immune process of OA and osteolysis by regulating CD8A and CD8B, respectively, and two osteolysis-specific interaction pairs (AC090607.4-FOXO3 and TAL1-ABALON), which may play an important role in osteoclastogenesis.


Assuntos
Artroplastia de Quadril , Redes Reguladoras de Genes , Osteoartrite , Osteólise , RNA Longo não Codificante/biossíntese , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/cirurgia , Osteólise/genética , Osteólise/metabolismo , Osteólise/patologia , Osteólise/cirurgia , RNA Longo não Codificante/genética , Análise de Sequência de RNA
12.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804203

RESUMO

Osteoarthritis (OA) is a common degenerative disease that results in joint inflammation as well as pain and stiffness. A previous study has reported that Cornus officinalis (CO) extract inhibits oxidant activities and oxidative stress in RAW 264.7 cells. In the present study, we isolated bioactive compound(s) by fractionating the CO extract to elucidate its antiosteoarthritic effects. A single bioactive component, morroniside, was identified as a potential candidate. The CO extract and morroniside exhibited antiosteoarthritic effects by downregulating factors associated with cartilage degradation, including cyclooxygenase-2 (Cox-2), matrix metalloproteinase 3 (Mmp-3), and matrix metalloproteinase 13 (Mmp-13), in interleukin-1 beta (IL-1ß)-induced chondrocytes. Furthermore, morroniside prevented prostaglandin E2 (PGE2) and collagenase secretion in IL-1ß-induced chondrocytes. In the destabilization of the medial meniscus (DMM)-induced mouse osteoarthritic model, morroniside administration attenuated cartilage destruction by decreasing expression of inflammatory mediators, such as Cox-2, Mmp3, and Mmp13, in the articular cartilage. Transverse microcomputed tomography analysis revealed that morroniside reduced DMM-induced sclerosis in the subchondral bone plate. These findings suggest that morroniside may be a potential protective bioactive compound against OA pathogenesis.


Assuntos
Cornus/química , Glicosídeos/farmacologia , Inflamação/tratamento farmacológico , Meniscos Tibiais/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Animais , Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Dinoprostona/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosídeos/química , Humanos , Interleucina-1beta/genética , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Meniscos Tibiais/patologia , Meniscos Tibiais/cirurgia , Camundongos , Osteoartrite/genética , Osteoartrite/patologia , Osteoartrite/cirurgia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Cultura Primária de Células , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
13.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806315

RESUMO

Systemic injection of a nerve growth factor (NGF) antibody has been proven to have a significant relevance in relieving osteoarthritis (OA) pain, while its adverse effects remain a safety concern for patients. A local low-dose injection is thought to minimize adverse effects. In this study, OA was induced in an 8-week-old male Sprague-Dawley (SD) rat joint by monoiodoacetate (MIA) injection for 2 weeks, and the effect of weekly injections of low-dose (1, 10, and 100 µg) NGF antibody or saline (control) was evaluated. Behavioral tests were performed, and at the end of week 6, all rats were sacrificed and their knee joints were collected for macroscopic and histological evaluations. Results showed that 100 µg NGF antibody injection relieved pain in OA rats, as evidenced from improved weight-bearing performance but not allodynia. In contrast, no significant differences were observed in macroscopic and histological scores between rats from different groups, demonstrating that intra-articular treatment does not worsen OA progression. These results suggest that local administration yielded a low effective NGF antibody dose that may serve as an alternative approach to systemic injection for the treatment of patients with OA.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Experimental/terapia , Fator de Crescimento Neural/antagonistas & inibidores , Osteoartrite/terapia , Manejo da Dor/métodos , Animais , Artrite Experimental/patologia , Artrite Experimental/fisiopatologia , Cartilagem Articular/patologia , Relação Dose-Resposta Imunológica , Hiperalgesia/fisiopatologia , Hiperalgesia/terapia , Injeções Intra-Articulares , Ácido Iodoacético/toxicidade , Masculino , Fator de Crescimento Neural/imunologia , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Ratos , Ratos Sprague-Dawley , Suporte de Carga/fisiologia
14.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803113

RESUMO

Obesity is a risk factor for osteoarthritis (OA) development and progression due to an altered biomechanical stress on cartilage and an increased release of inflammatory adipokines from adipose tissue. Evidence suggests an interplay between loading and adipokines in chondrocytes metabolism modulation. We investigated the role of loading, as hydrostatic pressure (HP), in regulating visfatin-induced effects in human OA chondrocytes. Chondrocytes were stimulated with visfatin (24 h) and exposed to high continuous HP (24 MPa, 3 h) in the presence of visfatin inhibitor (FK866, 4 h pre-incubation). Apoptosis and oxidative stress were detected by cytometry, B-cell lymphoma (BCL)2, metalloproteinases (MMPs), type II collagen (Col2a1), antioxidant enzymes, miRNA, cyclin D1 expressions by real-time PCR, and ß-catenin protein by western blot. HP exposure or visfatin stimulus significantly induced apoptosis, superoxide anion production, and MMP-3, -13, antioxidant enzymes, and miRNA gene expression, while reducing Col2a1 and BCL2 mRNA. Both stimuli significantly reduced ß-catenin protein and increased cyclin D1 gene expression. HP exposure exacerbated visfatin-induced effects, which were counteracted by FK866 pre-treatment. Our data underline the complex interplay between loading and visfatin in controlling chondrocytes' metabolism, contributing to explaining the role of obesity in OA etiopathogenesis, and confirming the importance of controlling body weight for disease treatment.


Assuntos
Adipocinas/biossíntese , Apoptose , Condrócitos/metabolismo , Regulação da Expressão Gênica , Osteoartrite/metabolismo , Idoso , Células Cultivadas , Condrócitos/patologia , Feminino , Humanos , Pressão Hidrostática , Masculino , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/farmacologia , Osteoartrite/patologia
15.
Nat Commun ; 12(1): 1706, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731712

RESUMO

Our incomplete understanding of osteoarthritis (OA) pathogenesis has significantly hindered the development of disease-modifying therapy. The functional relationship between subchondral bone (SB) and articular cartilage (AC) is unclear. Here, we found that the changes of SB architecture altered the distribution of mechanical stress on AC. Importantly, the latter is well aligned with the pattern of transforming growth factor beta (TGFß) activity in AC, which is essential in the regulation of AC homeostasis. Specifically, TGFß activity is concentrated in the areas of AC with high mechanical stress. A high level of TGFß disrupts the cartilage homeostasis and impairs the metabolic activity of chondrocytes. Mechanical stress stimulates talin-centered cytoskeletal reorganization and the consequent increase of cell contractile forces and cell stiffness of chondrocytes, which triggers αV integrin-mediated TGFß activation. Knockout of αV integrin in chondrocytes reversed the alteration of TGFß activation and subsequent metabolic abnormalities in AC and attenuated cartilage degeneration in an OA mouse model. Thus, SB structure determines the patterns of mechanical stress and the configuration of TGFß activation in AC, which subsequently regulates chondrocyte metabolism and AC homeostasis.


Assuntos
Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Estresse Mecânico , Fator de Crescimento Transformador beta/metabolismo , Animais , Osso e Ossos/patologia , Linhagem Celular , Condrócitos/metabolismo , Citoesqueleto/metabolismo , Homeostase , Humanos , Integrina alfaV/genética , Integrina alfaV/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoartrite/metabolismo , Osteoartrite/patologia , Transdução de Sinais , Talina/metabolismo
16.
Acta Biochim Biophys Sin (Shanghai) ; 53(4): 400-409, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33677475

RESUMO

Persistent hypotonic and inflammatory conditions in the joint cavity can lead to the loss of cartilage matrix and cell death, which are the important mechanisms of osteoarthritis (OA) onset. Previous studies have confirmed that the existence of a hypotonic environment is a red flag for inflammation, as hypotonic environment induces the opening of the chloride channel of the cell and promotes chloride ion efflux, which prompts the cell volume to increase. Chloride channels play an important role in the regulation of mineralization and chondrocyte death. Here, we reported that OA chondrocytes showed a significant increase of cell death rate and the imbalance of cartilage matrix catabolism. We found that the distribution of skeleton protein F-actin was disordered. In addition, the volume-sensitive chloride current of OA chondrocytes decreased significantly with the increase of the expression levels of inflammation-related proteins caspase-1, caspase-3, and NLRP3. Moreover, interleukin-1ß (IL-1ß) showed a potential to activate the chloride current of normal chondrocytes. These results indicate that IL-1ß-induced chloride channel opening in chondrocytes may be closely related to the occurrence of OA. This chloride channel opening process may therefore be a potential target for the treatment of OA.


Assuntos
Cloretos/metabolismo , Condrócitos/metabolismo , Interleucina-1beta/metabolismo , Osteoartrite/metabolismo , Idoso , Idoso de 80 Anos ou mais , Condrócitos/patologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Transporte de Íons , Masculino , Osteoartrite/patologia
17.
Adv Clin Chem ; 101: 95-120, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33706891

RESUMO

Osteoarthritis (OA) is a multifactorial disease with huge phenotypic heterogeneity. The disease affects all tissues in the joint, and the loss of articular cartilage is its hallmark. The main biochemical components of the articular cartilage are type II collagen, aggrecan, and water. Transforming growth factor-beta (TGF-ß) signaling is one of the signaling pathways that maintains the healthy cartilage. However, the two subpathways of the TGF-ß signaling-TGF-ß and bone morphogenetic proteins (BMP) subpathways, lose their balance in OA, resulting an increased expression of cartilage degradation enzymes including matrix metallopeptidase 13 (MMP13), cathepsin B (CTSB), and cathepsin K (CTSK) and a decreased expression of aggrecan (ACAN). Thus, restoring the balance of two subpathways might provide a new avenue for treating OA patients. Further, metabolic changes are seen in OA and can be used to distinguish different subtypes of OA patients. Metabolomics studies showed that at least three endotypes of OA can be distinguished: 11% of OA patients are characterized by an elevated blood butyryl carnitine, 33% of OA patients have significant reduced arginine concentration, and 56% with metabolic alteration in phospholipid metabolism. While these findings need to be confirmed, they are promising personalized medicine tools for OA management.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Biomarcadores/metabolismo , Proteínas Morfogenéticas Ósseas/genética , Cartilagem/metabolismo , Cartilagem/patologia , Humanos , Sinais de Exportação Nuclear , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
18.
Biomed Res Int ; 2021: 6380141, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33708990

RESUMO

The aim of this study was to investigate the therapeutic efficacy and safety of transplanting human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in the treatment of cartilage injury. First, the articular cartilage defect model in rabbits was constructed. Then, the identified hUCB-MSCs and rabbit bone marrow stem cells (rBM-MSCs) were transplanted into the bone defect, respectively, and the cartilage repair effect was observed by hematoxylin-eosin (HE) staining and immunohistochemistry. Besides, the glycosaminoglycan (GAG) content and biomechanics of the restoration area were also evaluated. In our study, hUCB-MSCs and rBM-MSCs exhibited typical MSC characteristics, with positive expressions of CD73, CD105, and CD90 and negative for CD45, CD34, CD14, and HLA-DR. After the transplantation of hUCB-MSCs and rBM-MSCs, the overall quality of cartilage tissue was significantly improved, and the recipients did not show significant side effects in general. However, the expression of matrix metalloproteinase-13 (MMP-13) in the de novo tissues of the hUCB-MSCs and rBM-MSCs groups was both increased, indicating that the novel tissues may have some potential osteoarthritic changes. In conclusion, our results suggest the therapeutic effect of hUCB-MSCs transplantation in cartilage regeneration, providing a promising future in the clinical treatment of cartilage injury.


Assuntos
Antígenos de Diferenciação/metabolismo , Cartilagem Articular , Sangue Fetal/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Osteoartrite , Animais , Cartilagem Articular/lesões , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Xenoenxertos , Humanos , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/terapia , Coelhos
19.
Ned Tijdschr Geneeskd ; 1652021 02 25.
Artigo em Holandês | MEDLINE | ID: mdl-33651517

RESUMO

A 78-year-old man was evaluated at the outpatient orthopaedic clinic with progressive pain in the right groin. X-ray revealed osteoarthritis of the right hip and fibrous dysplasia of the proximal femur. Total hip arthroplasty was performed using a cemented long-stem femoral component spanning the entire lesion.


Assuntos
Artroplastia de Quadril , Fêmur/patologia , Displasia Fibrosa Óssea/patologia , Virilha/patologia , Prótese de Quadril , Osteoartrite/patologia , Dor/diagnóstico , Idoso , Displasia Fibrosa Óssea/diagnóstico , Displasia Fibrosa Óssea/terapia , Quadril/patologia , Quadril/cirurgia , Articulação do Quadril/patologia , Articulação do Quadril/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/diagnóstico , Osteoartrite/terapia , Dor/etiologia , Dor/cirurgia , Radiografia
20.
Vet Surg ; 50(4): 713-728, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33710628

RESUMO

Navicular syndrome has been traditionally characterized by progressive lameness with chronic degeneration of the navicular bone. Advances in imaging techniques have revealed that its associated soft tissue structures are also affected. This distribution of lesions is explained by conceptualizing the equine navicular apparatus as an enthesis organ that facilitates the dissemination of mechanical stress throughout the tissues of the foot. The navicular apparatus has the same structural adaptations to mechanical stress as the human Achilles tendon complex. These adaptations efficiently dissipate mechanical force away from the tendon's bony attachment site, thereby protecting it from failure. The comparison of these two anatomically distinct structural systems demonstrates their similar adaptations to mechanical forces, and illustrates that important functional insights can be gained from studying anatomic convergences and cross-species comparisons of function. Such a functional conceptualization of the equine navicular apparatus resolves confusion about the diagnosis of navicular syndrome and offers insights for the development of mechanically based therapies. Through comparison with the human Achilles complex, this review (1) re-conceptualizes the equine navicular apparatus as an enthesis organ in which mechanical forces are distributed throughout the structures of the organ; (2) describes the relationship between failure of the navicular enthesis organ and lesions of navicular syndrome; (3) considers the therapeutic implications of navicular enthesis organ degeneration as a form of chronic osteoarthritis; and based upon these implications (4) proposes a focus on whole body posture/motion for the development of prehabilitative and rehabilitative therapies similar to those that have already proven effective in humans.


Assuntos
Doenças do Pé/veterinária , Doenças dos Cavalos/terapia , Osteoartrite/veterinária , Ossos do Tarso/patologia , Animais , Fenômenos Biomecânicos , Doença Crônica/veterinária , Doenças do Pé/etiologia , Doenças do Pé/patologia , Doenças do Pé/terapia , Doenças dos Cavalos/etiologia , Doenças dos Cavalos/patologia , Cavalos , Osteoartrite/etiologia , Osteoartrite/patologia , Osteoartrite/terapia , Tendões/patologia
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