The role of YAP/TAZ on joint and arthritis.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common forms of arthritis with undefined etiology and pathogenesis. Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ), which act as sensors for cellular mechanical and inflammatory cues, have been identified as crucial players in the regulation of joint homeostasis. Current studies also reveal a significant association between YAP/TAZ and the pathogenesis of OA and RA. The objective of this review is to elucidate the impact of YAP/TAZ on different joint tissues and to provide inspiration for further studying the potential therapeutic implications of YAP/TAZ on arthritis. Databases, such as PubMed, Cochran Library, and Embase, were searched for all available studies during the past two decades, with keywords "YAP," "TAZ," "OA," and "RA."

Increased expression of omentin-1 is associated with synovitis and bone destruction in rheumatoid arthritis.

OBJECTIVES: The aberrant expression of omentin-1 had been reported in type 2 diabetes and cardiovascular disease. Here, we investigated the expression and role of omentin-1 in rheumatoid arthritis (RA). METHODS: The expression of omentin-1 in RA and in the normal population was detected by ELISA and immunohistochemistry, and collagen-induced arthritis (CIA) mice were used to detect the role of omentin-1 in RA. RESULTS: We found that the expression of omentin-1 was elevated in serum of RA patients compared with healthy controls (p=0.004), and in the RA disease activity group compared with the disease remission group (p<0.001). In addition, the level of omentin-1 in RA patients was positively correlated with CRP (r=0.427, p=0.002), ESR (r=0.454, p<0.001) and DAS28 (r=0.496, p<0.001; r=0.661, p<0.001, respectively). Multivariable analysis showed that omentin-1 alone was associated with disease activity state (OR=1.018, p=0.004). Immunohistochemical results showed that omentin-1 was increased in the synovium of RA and CIA mice. Omentin-1 injection resulted in an earlier onset of arthritis, an aggravated arthritic progression, more severe synovial hyperplasia and bone erosion in CIA mice. Moreover, omentin-1 treatment markedly enhanced IL-6, TNF-α, MMP-3, MMP-13 and RANKL in the joint tissue of CIA mice. CONCLUSIONS: Our results suggested that omentin-1 was up-regulated in RA and can exacerbate synovitis and joint destruction which may provide new insight into the pathogenesis of RA.

Glucocorticoids promote joint microenvironment alteration of GABBR1 expression associated with mitigating rheumatoid arthritis.

GABBR1 receptors have been implicated in the progression of rheumatoid arthritis (RA), and p38 MAP kinase (MAPK) was shown to be downregulated by GABA and result in unchecked production of pro-inflammatory cytokine. GABBR1 is a member of GABA receptors, and it is known to be upregulated and plays a vital role in RA. Glucocorticoids are efficient therapeutics in rheumatoid arthritis (RA) and are known to regulate GABA actions; therefore, we intended to investigate the potential of glucocorticoids in RA concerning the potential pathway GABBR1/MAPK. Joint specimens were obtained from collagen-induced arthritis mouse model. A double-blind semi-quantitative analysis of vascularity, cell infiltration, as well as lining thickness by help of a 4-point scale setting was used to assess joint inflammation. Expression of GABBR1 and p38 was evaluated immunohistochemically. In vitro peripheral blood (PB), synovial fluid (SF), and mononuclear cells (MCs) were acquired from RA mice. Western blotting was used for detecting expression of GABBR1 and p38 proteins. The presence of high levels of GABBR1 and p38 was prevalent in RA joints relative to healthy joints and related to the inflammation level. Glucocorticoid treatment alters GABBR1 along with p38 protein expression in joints while reducing joint inflammation. Ex vivo and in vitro assays revealed glucocorticoids have a direct impact on p38, such as the decreased GABBR1 expression level after dexamethasone incubation with SFMC. GABBR1 together with p38 expression in RA joints depends on local inflammation and can be targeted by glucocorticoids.

Suppression of apoptosis impairs phalangeal joint formation in the pathogenesis of brachydactyly type A1.

Apoptosis occurs during development when a separation of tissues is needed. Synovial joint formation is initiated at the presumptive site (interzone) within a cartilage anlagen, with changes in cellular differentiation leading to cavitation and tissue separation. Apoptosis has been detected in phalangeal joints during development, but its role and regulation have not been defined. Here, we use a mouse model of brachydactyly type A1 (BDA1) with an IhhE95K mutation, to show that a missing middle phalangeal bone is due to the failure of the developing joint to cavitate, associated with reduced apoptosis, and a joint is not formed. We showed an intricate relationship between IHH and interacting partners, CDON and GAS1, in the interzone that regulates apoptosis. We propose a model in which CDON/GAS1 may act as dependence receptors in this context. Normally, the IHH level is low at the center of the interzone, enabling the "ligand-free" CDON/GAS1 to activate cell death for cavitation. In BDA1, a high concentration of IHH suppresses apoptosis. Our findings provided new insights into the role of IHH and CDON in joint formation, with relevance to hedgehog signaling in developmental biology and diseases.

Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints.

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.

Integrin signalling in joint development, homeostasis and osteoarthritis.

Integrins are key regulators of cell-matrix interactions during joint development and joint tissue homeostasis, as well as in the development of osteoarthritis (OA). The signalling cascades initiated by the interactions of integrins with a complex network of extracellular matrix (ECM) components and intracellular adaptor proteins orchestrate cellular responses necessary for maintaining joint tissue integrity. Dysregulated integrin signalling, triggered by matrix degradation products such as matrikines, disrupts this delicate balance, tipping the scales towards an environment conducive to OA pathogenesis. The interplay between integrin signalling and growth factor pathways further underscores the multifaceted nature of OA. Moreover, emerging insights into the role of endocytic trafficking in regulating integrin signalling add a new layer of complexity to the understanding of OA development. To harness the therapeutic potential of targeting integrins for mitigation of OA, comprehensive understanding of their molecular mechanisms across joint tissues is imperative. Ultimately, deciphering the complexities of integrin signalling will advance the ability to treat OA and alleviate its global burden.

Increased interleukin-26 in the peripheral joints of patients with axial spondyloarthritis and psoriatic arthritis, co-localizing with CD68-positive synoviocytes.

Objectives: IL26 levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. IL26 can be produced by Th17 cells and locally within joints by tissue-resident cells. IL26 induces osteoblast mineralization in vitro. As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of IL26 in spondyloarthritis. Methods: Serum, peripheral blood mononuclear cells (n = 15-35) and synovial tissue (n = 3-9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, n = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR. Results: Synovial tissue of axSpA patients shows significantly more IL26-positive cells than that of HCs (p < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of IL26 with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. IL26 is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs (p < 0.001 and p < 0.01). However, peripheral blood CD4+ T cells from axSpA and PsA patients show higher positivity for IL26 in the PrimeFlow assay compared with HCs. CD4+ memory T cells from axSpA patients produce more IL26 under Th17-favoring conditions (IL-1ß and IL-23) than cells from PsA and RA patients or HCs. Conclusion: IL26 production is increased in the synovial tissue of SpA and can be localized to CD68+ macrophage-like synoviocytes, whereas circulating IL26+ Th17 cells are only modestly enriched. Considering the osteoproliferative properties of IL26, this offers new therapeutic options independent of Th17 pathways.

Prevalência de saúde cardiovascular ideal na população brasileira - Pesquisa Nacional de Saúde (2013) / Ideal cardiovascular health prevalence in the Brazilian population - National Health Survey (2013)

RESUMO: A prevenção primordial é definida como a prevenção inicial de fatores de risco, por meio da adoção de comportamentos mais saudáveis. Dentro desse conceito, a American Heart Association (AHA) definiu sete métricas, baseadas em evidências, para se alcançar uma saúde cardiovascular (SCV) ideal. O objetivo deste trabalho foi avaliar a prevalência de SCV na população brasileira, segundo sexo, faixa etária e região de moradia, utilizando os dados da última Pesquisa Nacional de Saúde (PNS), de 2013. Foram avaliados, como preconizado pela AHA, de forma conjunta (número de fatores) e isolada, quatro fatores comportamentais (tabagismo, atividade física, índice de massa corporal e dieta) e três biológicos (pressão arterial, glicemia e níveis de colesterol). A população brasileira atingiu prevalências menores de 1%, de sete fatores em nível ideal. Isoladamente, 3,2% da população apresentaram a dieta em nível ideal, seguido da atividade física (23,6%) e índice de massa corporal (43,7%). A população entre 18 e 35 anos apresentou a maior prevalência de número de métricas conjuntas em nível ideal (0,5%), valor também atingido pela população geral da Região Norte. Os resultados indicam que devem ser realizados ainda maiores esforços por meio de políticas públicas de prevenção primordial para atingir metas adequadas de SCV na população brasileira.

ABSTRACT: Primordial prevention is defined as the initial prevention of risk factors, through the adoption of healthier behaviors. Within this concept, the American Heart Association (AHA) has defined seven metrics, based on evidence, to achieve ideal cardiovascular health. The aim of this study was to evaluate the prevalence of cardiovascular health in the Brazilian population, according to sex, age, and region of residence, using data from the latest National Health Survey (2013). We assessed the risk factors, as recommended by the AHA, combined (number of factors) and individually: four behavioral (smoking, physical activity, body mass index and diet) and three biological factors (blood pressure, blood glucose and cholesterol levels). The Brazilian population has reached very low prevalence (1%), for the sum of 7 factors in ideal level. Individually, 3.2% of the population consumed ideal diet, followed by physical activity (23.6%) and body mass index (43.7%). The subjects aged between 18 and 35 years showed higher prevalence of metrics combined at the optimal levels (0.5%), which was also reached by the population of the Northern region. These results indicate that greater efforts are urgent by public policies at the level of primordial prevention in order to achieve appropriate targets of cardiovascular health in the Brazilian population.

Curvas ângulo-tempo das articulações dos eqüinos marchadores / Joint angle-time curves of Brazilian gaited horses

Gráficos com demonstração das curvas ângulo-tempo das articulações dos membros dos eqüinos foram avaliados por meio da análise de imagens digitalizadas tomadas de 10 cavalos e 13 éguas da raça Mangalarga Marchador. Foram utilizados marcadores reflexivos adesivos colocados em 19 pontos articulares dos eqüinos, procedendo-se à filmagem com freqüência de 250 quadros por segundo e utilizando-se o aplicativo Simi-motion 3D 6.0 para digitalização e análise das imagens. A utilização dos marcadores reflexivos adesivos constituiu boa metodologia para análise dos movimentos dos segmentos ósseos dos eqüinos. Os resultados observados indicam haver, durante a locomoção dos eqüinos marchadores brasileiros, comportamento similar das articulações quando comparados com eqüinos de sela europeus, apresentando mesmo padrão das curvas de ângulo-tempo e não havendo grandes diferenças entre os pontos máximos de flexão e extensão.

Images of 10 horses and 13 mares of Mangalarga Marchador breed were taken and digitalized to analyze the joint angle-time curves. Reflexives and adhesives markers were glued on 19 articulations points of the hindlimbs and forelimbs of the horses. The images were taken at 250 frames per second and the digitalization and analysis were made using a Simi-motion 3D 6.0 software. The results demonstrated that the methodology using reflexives and adhesives markers was efficient to make analyses of the bone segment movements of the horses. This study concluded that the Brazilian gaited horses have a similar angle-joint curve as the European warmblood horses and there are no great differences of the maximum extension and flexion points.