Adipokines as potential pharmacological targets for immune inflammatory rheumatic diseases: Focus on rheumatoid arthritis, osteoarthritis, and intervertebral disc degeneration.

Adipokines are a heterogeneous group of signalling molecules secreted prevalently by adipose tissue. Initially considered as regulators of energy metabolism and appetite, adipokines have been recognized for their substantial involvement in musculoskeletal disorders, including osteoarthritis, rheumatoid arthritis, and many others. Understanding the role of adipokines in rheumatic inflammatory and autoimmune diseases, as well as in other musculoskeletal diseases such as intervertebral disc degeneration, is crucial for the development of novel therapeutic strategies. Targeting adipokines, or their signalling pathways, may offer new opportunities for the treatment and management of these conditions. By modulating adipokines levels or activity, it may be possible to regulate inflammation, to maintain bone health, and preserve muscle mass, thereby improving the outcomes and quality of life for individuals affected by musculoskeletal diseases. The aim of this review article is to update the reader on the multifaceted role of adipokines in the main rheumatic diseases such as osteoarthritis and rheumatoid arthritis and to unravel the complex interplay among adipokines, cartilage metabolism, bone remodelling and muscles, which will pave the way for innovative therapeutic intervention in the future. For completeness, the role of adipokines in intervertebral disc degeneration will be also addressed.

Quantification of temporomandibular joint space in patients with juvenile idiopathic arthritis assessed by cone beam computerized tomography.

OBJECTIVE: To describe a method to calculate the total intra-articular volume (inter-osseous space) of the temporomandibular joint (TMJ) determined by cone-beam computed tomography (CBCT). This could be used as a marker of tissue proliferation and different degrees of soft tissue hyperplasia in juvenile idiopathic arthritis (JIA) patients. MATERIALS AND METHODS: Axial single-slice CBCT images of cross-sections of the TMJs of 11 JIA patients and 11 controls were employed. From the top of the glenoid fossa, in the caudal direction, an average of 26 slices were defined in each joint (N = 44). The interosseous space was manually delimited from each slice by using dedicated software that includes a graphic interface. TMJ volumes were calculated by adding the areas measured in each slice. Two volumes were defined: Ve-i and Vi , where Ve-i is the inter-osseous space, volume defined by the borders of the fossa and Vi is the internal volume defined by the condyle. An intra-articular volume filling index (IF) was defined as Ve-i /Vi , which represents the filling of the space. RESULTS: The measured space of the intra-articular volume, corresponding to the intra-articular soft tissue and synovial fluid, was more than twice as large in the JIA group as in the control group. CONCLUSION: The presented method, based on CBCT, is feasible for assessing inter-osseus joint volume of the TMJ and delimits a threshold of intra-articular changes related to intra-articular soft tissue proliferation, based on differences in volumes. Intra-articular soft tissue is found to be enlarged in JIA patients.

Biogeographical Relationships and Diversity in the Peruvian Flora Reported by Hipólito Ruiz and José Pavón: Vegetation, Uses and Anthropology.

The Royal Spanish Botanical Expedition to the Viceroyalty of Peru in the 18th century was one of the most important European expeditions to American territories. Using the herbarium sheets of Ruiz and Pavón (Royal Botanical Garden of Madrid) and their edited works, manuscripts and expedition diaries, we have constructed a database of the collected and observed flora, which has served as the basis for a map containing all of the Peruvian localities of the expedition. Based on the method of bioclimatic belts and our own observations, we have deduced to which type of vegetation the flora studied in the expedition belongs. The uses of the flora per locality were studied, as well as the ethnic groups involved in the different localities. By using a Principal Component Analysis, we have obtained the distribution of the bioclimatic belts whose vegetation was the most explored. In order to observe the bioclimatic tendency of plant uses, a Detrended Correspondence Analysis (DCA) was conducted to identify the distribution of localities with the highest frequencies of plant uses. The expedition's explorations focused on the most humid areas of the thermo- and mesotropical belts, from where a large number of plants with practical uses were obtained.

Global patterns of vascular plant alpha diversity.

Global patterns of regional (gamma) plant diversity are relatively well known, but whether these patterns hold for local communities, and the dependence on spatial grain, remain controversial. Using data on 170,272 georeferenced local plant assemblages, we created global maps of alpha diversity (local species richness) for vascular plants at three different spatial grains, for forests and non-forests. We show that alpha diversity is consistently high across grains in some regions (for example, Andean-Amazonian foothills), but regional 'scaling anomalies' (deviations from the positive correlation) exist elsewhere, particularly in Eurasian temperate forests with disproportionally higher fine-grained richness and many African tropical forests with disproportionally higher coarse-grained richness. The influence of different climatic, topographic and biogeographical variables on alpha diversity also varies across grains. Our multi-grain maps return a nuanced understanding of vascular plant biodiversity patterns that complements classic maps of biodiversity hotspots and will improve predictions of global change effects on biodiversity.

WISP-2 modulates the induction of inflammatory mediators and cartilage catabolism in chondrocytes.

Wnt-1 inducible signaling pathway protein 2 (WISP-2/CCN5) is a recently identified adipokine that has been described as an important mediator of canonical Wnt activation in adipogenic precursor cells. In osteoarthritis (OA), the most common form of arthritis, chondrocytes exhibit aberrant and increased production of pro-inflammatory mediators and matrix degrading enzymes such as IL-1ß and MMP-13. Although recent evidence suggests a role for Wnt signaling in OA physiopathology, little is known about the involvement of WISP-2 in cartilage degradation. In the present study, we determined the expression of WISP-2 in healthy and OA human chondrocytes. WISP-2 expression is modulated along chondrocyte differentiation and downregulated at the onset of hypertrophy by inflammatory mediators. We also investigated the effect of WISP-2 on cartilage catabolism and performed WISP-2 loss-of-function experiments using RNA interference technology in human T/C-28a2 immortalized chondrocytes. We demonstrated that recombinant human WISP-2 protein reduced IL-1ß-mediated chondrocyte catabolism, that IL-1ß and WNT/b-catenin signaling pathways are involved in rhWISP-2 protein and IL-1ß effects in human chondrocytes, and that WISP-2 has a regulatory role in attenuating the catabolic effects of IL-1ß in chondrocytes. Gene silencing of WISP-2 increased the induction of the catabolic markers MMP-13 and ADAMTS-5 and the inflammatory mediators IL-6 and IL-8 triggered by IL-1ß in human primary OA chondrocytes in a Wnt/ß-catenin dependent manner. In conclusion, here we have shown for the first time that WISP-2 may have relevant roles in modulating the turnover of extracellular matrix in the cartilage and that its downregulation may detrimentally alter the inflammatory environment in OA cartilage. We also proved the participation of Wnt/ß-catenin signaling pathway in these processes. Thus, targeting WISP-2 might represent a potential therapeutical approach for degenerative and/or inflammatory diseases of musculoskeletal system, such as osteoarthritis.

TMJ contrast enhancement in CBCT images using a new algorithm.

Magnetic resonance imaging (MRI) is considered the gold standard to reliably diagnose inflammation in the temporomandibular joint (TMJ) of patients with juvenile idiopathic arthritis (JIA). However, even MRI imaging is dependent on the familiarity of the radiologist with the normal appearance of the TMJ; therefore, new approaches are needed. Our purpose here is to improve imaging quality of cone beam computed tomography (CBCT) as a tool to help in the diagnosis of JIA in the TMJ. We have designed and applied a filter (the Stacking Enhancement Filter) over a stock of CBCT images from the TMJs of two patients with JIA. We then made a visual comparison of the results with archival images from MRI of the same patients, to show that the filter substantially improves the visual quality of the image. The work on the image contrast and the increase of the difference of appearance between tissues of different densities (all the anatomical structures that are present within the joint) leads to an improvement of the resulting images of the TMJ without the use of a chemical contrast agent. We conclude that CBCT could be used as a filter tool for the analysis of the TMJs affected by arthritis. Our image processing technique yields images that possible improve the range of use of CBCT.

Patrones de distribución de las especies de Senecio L. (Asteraceae) en el Perú / Distribution patterns of the Peruvian species of Senecio L. (Asteraceae)

Resumen En el presente trabajo se analiza la distribución de las especies peruanas del género Senecio, a partir de 4342 pliegos de herbario con localidades y coordenadas geográficas disponibles. Para conocer cómo están relacionadas con el clima se usó el método de los pisos bioclimáticos de Rivas-Martínez, y el modelo de Koppen-Geiger para observar su comportamiento frente a cambios climáticos a 50 y 100 años. Para observar cómo es la distribución departamental de las especies y la relación entre departamentos en cuanto a su presencia-ausencia, se recurrió a un clúster (UPGMA, coeficiente de Sorensen). Un Análisis de Componentes Principales (ACP) reveló la correlación de cada especie con la altitud media, variables climáticas medias e Índice de Termicidad medio de las localidades de una especie, estableciendo 10 grupos ordenados por pisos bioclimáticos. Diferentes modelos de distribución fueron cartografiados correspondiéndose con pisos bioclimáticos y provincias biogeográficas del Perú. La Cordillera Blanca se configura como una auténtica barrera biogeográfica separando numerosas localidades del N del Perú del resto de las posiciones de Senecio.

Abstract This paper analyses the distribution of Peruvian species of the genus Senecio, based on 4342 herbarium sheets with available localities and geographical coordinates. The Rivas-Martínez method of bioclimatic belts and the Koppen-Geiger model were used to determine how they are related to climate, and to observe their response in the face of climatic changes over 50 and 100 years. To observe the departmental distribution of the species and the relationship between departments in terms of presence-absence (UPGMA, Sorensen's coefficient) was used. A Principal Component Analysis (PCA) revealed the correlation of each species with mean altitude, mean climatic variables and mean Thermicity Index of the localities of a species, establishing 10 groups ordered by bioclimatic belts. Different distribution patterns were mapped, corresponding to bioclimatic belts and biogeographical provinces of Peru. The Cordillera Blanca forms an authentic biogeographical barrier separating numerous localities in northern Peru from the rest of the Senecio positions.

Asprosin in health and disease, a new glucose sensor with central and peripheral metabolic effects.

Adipose tissue malfunction leads to altered adipokine secretion which might consequently contribute to an array of metabolic diseases spectrum including obesity, diabetes mellitus, and cardiovascular disorders. Asprosin is a novel diabetogenic adipokine classified as a caudamin hormone protein. This adipokine is released from white adipose tissue during fasting and elicits glucogenic and orexigenic effects. Although white adipose tissue is the dominant source for this multitask adipokine, other tissues also may produce asprosin such as salivary glands, pancreatic B-cells, and cartilage. Significantly, plasma asprosin levels link to glucose metabolism, lipid profile, insulin resistance (IR), and ß-cell function. Indeed, asprosin exhibits a potent role in the metabolic process, induces hepatic glucose production, and influences appetite behavior. Clinical and preclinical research showed dysregulated levels of circulating asprosin in several metabolic diseases including obesity, type 2 diabetes mellitus (T2DM), polycystic ovarian syndrome (PCOS), non-alcoholic fatty liver (NAFLD), and several types of cancer. This review provides a comprehensive overview of the asprosin role in the etiology and pathophysiological manifestations of these conditions. Asprosin could be a promising candidate for both novel pharmacological treatment strategies and diagnostic tools, although developing a better understanding of its function and signaling pathways is still needed.

Monomeric C reactive protein (mCRP) regulates inflammatory responses in human and mouse chondrocytes.

C-reactive protein (CRP) is an acute-phase protein that is used as an established biomarker to follow disease severity and progression in a plethora of inflammatory diseases. However, its pathophysiologic mechanisms of action are still poorly defined and remain elusive. CRP, in its pentameric form, exhibits weak anti-inflammatory activity. On the contrary, the monomeric isoform (mCRP) exhibits potent pro-inflammatory properties in endothelial cells, leukocytes, and platelets. So far, no data exists regarding mCRP effects in human or mouse chondrocytes. This work aimed to verify the pathophysiological relevance of mCRP in the etiology and/or progression of osteoarthritis (OA). We investigated the effects of mCRP in cultured human primary chondrocytes and in the chondrogenic ATDC5 mouse cell line. We determined mRNA and protein levels of relevant factors involved in inflammatory responses and the modulation of nitric oxide synthase type II (NOS2), an early inflammatory molecular target. We demonstrate, for the first time, that monomeric C reactive protein increases NOS2, COX2, MMP13, VCAM1, IL-6, IL-8, and LCN2 expression in human and murine chondrocytes. We also demonstrated that NF-kB is a key factor in the intracellular signaling of mCRP-driven induction of pro-inflammatory and catabolic mediators in chondrocytes. We concluded that mCRP exerts a sustained catabolic effect on human and murine chondrocytes, increasing the expression of inflammatory mediators and proteolytic enzymes, which can promote extracellular matrix (ECM) breakdown in healthy and OA cartilage. In addition, our results implicate the NF-kB signaling pathway in catabolic effects mediated by mCRP.

HLA-B*08 Identified as the Most Prominently Associated Major Histocompatibility Complex Locus for Anti-Carbamylated Protein Antibody-Positive/Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis.

OBJECTIVE: Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti-carbamylated protein antibody-positive (anti-CarP+) RA. METHODS: Analyses were restricted to RA patients who were anti-cyclic citrullinated peptide antibody negative (anti-CCP-), because the anti-CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti-CCP- RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for ~8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti-CarP status in RA patients was tested with logistic regression and combined with inverse-variance meta-analysis. Significance of the associations was assessed according to a study-specific threshold of P < 2.0 × 10-5 . RESULTS: The HLA-B*08 allele and its correlated amino acid variant Asp-9 showed a significant association with anti-CarP+/anti-CCP- RA (P < 3.78 × 10-7 ; I2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti-CarP-/anti-CCP- RA patients, and anti-CCP- RA patients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RA patients could be separated from other antibody-defined subsets of RA patients in whom an association with the HLA-B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti-CarP+/anti-CCP- RA after accounting for the presence of the HLA-B*08 allele. Specifically, the reported association of HLA-DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium. CONCLUSION: These results identify HLA-B*08 carrying Asp-9 as the MHC locus showing the strongest association with anti-CarP+/anti-CCP- RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies.

HLA association with the susceptibility to anti-synthetase syndrome.

OBJECTIVE: To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). METHODS: We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. RESULTS: A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P=1.56E-09, odds ratio-OR [95% confidence interval-CI]=2.54 [1.84-3.50] and 21.4% versus 5.5%, P=18.95E-18, OR [95% CI]=4.73 [3.18-7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P=0.0003, OR [95% CI]=0.48 [0.31-0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P=0.001, OR [95% CI]=2.54 [1.39-4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. CONCLUSIONS: Our results support the association of the HLA complex with the susceptibility to ASSD.

A Phytosociological Study on Andean Rainforests of Peru, and a Comparison with the Surrounding Countries.

This work is a phytosociological approach to the montane rainforests of Peru with the aim of advancing on the diversity of plant communities, which we had already begun in previous research. From 364 phytosociological plots and 3389 species of the South American tropics, we have developed a cluster, using the Sørensen index, to know the similarities between the forests and their parallelism with bioclimatic conditions. After studying the existence of characteristic groups of the Peruvian forests, we have established different communities and phytosociological units for Peru. As a result, we have described seven associations, within three new alliances, which are gathered in the new order Saurauio peruvianae-Condaminetalia corymbosae of the new class Morello pubescentis-Myrsinetea coriaceae. In addition, two associations have been described within the class Pruno rigidae-Oreopanacetea floribundae (mesotropical laurel-like forests), and three for the class Alnetea acuminatae (alder forests and palm groves). The humid forests of Peru are closer to those of Ecuador and to those of the set formed by the three Colombian mountain ranges than to those of Bolivia and Argentina, due to the common flora these share with areas of Paraguay and even of the Parana River region.

Levels of the Novel Endogenous Antagonist of Ghrelin Receptor, Liver-Enriched Antimicrobial Peptide-2, in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a debilitating, chronic, inflammatory, autoimmune disease associated with cachexia. The substitutive therapy of gut hormone ghrelin has been pointed at as a potential countermeasure for the management of metabolic and inflammatory complications in RA. The recent discovery of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous inverse agonist/antagonist of the ghrelin receptor makes feasible the development of a more rational pharmacological approach. This work aimed to assess the serum LEAP2 levels, in a cohort of RA patients, in comparison with healthy individuals and determine its correlation with inflammatory parameters. LEAP2 levels were determined by a commercial ELISA kit, plasma C-reactive protein (CRP) levels were evaluated using immunoturbidimetry, and serum levels of inflammatory mediators, namely IL-6, IL-8, IL-1ß, MIP1α, MCP1, and LCN2, were measured by XMap multiplex assay. LEAP2 serum levels were significantly increased in RA patients (n = 101) compared with control subjects (n = 26). Furthermore, the LEAP2 levels significantly correlated with CRP and inflammatory cytokines, but not with BMI. These data reveal LEAP2 as a new potential RA biomarker and indicated the pharmacological control of LEAP2 levels as a novel approach for the treatment of diseases with alterations on the ghrelin levels, such as rheumatoid cachexia.

Molecular Relationships among Obesity, Inflammation and Intervertebral Disc Degeneration: Are Adipokines the Common Link?

Intervertebral disc degeneration (IVDD) is a chronic, expensive, and high-incidence musculoskeletal disorder largely responsible for back/neck and radicular-related pain. It is characterized by progressive degenerative damage of intervertebral tissues along with metabolic alterations of all other vertebral tissues. Despite the high socio-economic impact of IVDD, little is known about its etiology and pathogenesis, and currently, no cure or specific treatments are available. Recent evidence indicates that besides abnormal and excessive mechanical loading, inflammation may be a crucial player in IVDD. Furthermore, obese adipose tissue is characterized by a persistent and low-grade production of systemic pro-inflammatory factors. In this context, chronic low-grade inflammation associated with obesity has been hypothesized as an important contributor to IVDD through different, but still unknown, mechanisms. Adipokines, such as leptin, produced prevalently by white adipose tissues, but also by other cells of mesenchymal origin, particularly cartilage and bone, are cytokine-like hormones involved in important physiologic and pathophysiological processes. Although initially restricted to metabolic functions, adipokines are now viewed as key players of the innate and adaptative immune system and active modulators of the acute and chronic inflammatory response. The goal of this review is to summarize the most recent findings regarding the interrelationships among inflammation, obesity and the pathogenic mechanisms involved in the IVDD, with particular emphasis on the contribution of adipokines and their potential as future therapeutic targets.

Adipokines: Linking metabolic syndrome, the immune system, and arthritic diseases.

Metabolic syndrome (MetS) represents a cluster of metabolic and cardiovascular complications, including obesity and visceral adiposity, insulin resistance, dyslipidemia, hyperglycemia and hypertension, which directly increase the risk of cardiovascular diseases (CVD) and diabetes mellitus type 2 (DM2). Patients with arthritic diseases, such as rheumatoid arthritis and osteoarthritis, have a higher incidence of CVD. Although recent advances in the treatment of arthritic diseases, the incidence of CVD remains elevated, and MetS has been identified as a possible link between CVD and arthritic diseases. Chronic low-grade inflammation associated with obesity has been established as a significant contributing factor to the increased prevalence of MetS. Adipokines, which play important physiological roles in metabolic activities contributing to the pathogenesis of MetS, are also involved in the regulation of autoimmune and/or inflammatory processes associated with arthritic diseases. Therefore, MetS and dysregulated secretion of pro-inflammatory adipokines have been recognized as a molecular link between CVD and arthritis diseases. In the present paper, we review recent evidence supporting the role played by adipokines, in particular leptin, adiponectin, and lipocalin-2, in the modulation of the immune system, MetS and arthritic diseases. The underlying cellular and molecular mechanisms are discussed, as well as potential new therapeutic strategies.

Distribución bioclimática de plantas medicinales y sus principios activos en el Departamento de Cajamarca (Perú) / Bioclimatic distribution of medicinal plants and its active substances in the Department of Cajamarca (Peru)

This work presents a distribution of medicinal plants and active substances from Cajamarca Department (Peru) under a bioclimatic criterion. The results show that 108 medicinal plants are spread among five bioclimatic belts: infratropical, thermotropical, mesotropical, supratropical and orotropical. As a statistical analysis shows (non-metric multidimensional scaling, MDS), most of them are concentrated in the mesotropical belt and a subhumid precipitation range. In addition a canonical correspondence analysis (CCA), using the altitude (m), the thermicity index (It) and annual precipitation (P) as environmental variables, indicates how active substances are also distributed with tendencies of them, showing phenolic substances and essential oils as mesotropical products, and complex alkaloids to the highest It values, while simple alkaloids to the lowest It values. Most of these molecular compounds are generated under the highest values of the subhumid and humid precipitation intervals. This bioclimatic method can led us to find new medicinal plants and active molecules.

Este trabajo presenta una distribución de plantas medicinales y principios activos en el departamento de Cajamarca (Perú) bajo un criterio bioclimático. Los resultados muestran que 108 plantas medicinales están repartidas entre cinco pisos bioclimáticos: infratropical, termotropical, mesotropical, supratropical y orotropical. Como muestra el análisis estadístico realizado MDS (non-metric multidimensional scaling), la mayoría de plantas se concentra en el piso mesotropical y en el intervalo subhúmedo de precipitaciones. Además, un análisis canónico de correspondencias (CCA), donde intervienen la altitud (h), el índice de termicidad (It) y las precipitaciones anuales (P) como variables ambientales, indica cómo los principios activos también se distribuyen según tendencias de estas, mostrando a los compuestos fenólicos y aceites esenciales como productos mesotropicales, los alcaloides complejos hacia los valores más elevados de It, mientras que los alcaloides simples hacia los más bajos. Asimismo, la mayoría de estos compuestos tienen su óptimo en los valores más elevados del intervalo subhúmedo y el intervalo húmedo de precipitaciones. Este método bioclimático nos puede llevar a encontrar nuevas plantas medicinales y principios activos.

Obesity, Fat Mass and Immune System: Role for Leptin.

Obesity is an epidemic disease characterized by chronic low-grade inflammation associated with a dysfunctional fat mass. Adipose tissue is now considered an extremely active endocrine organ that secretes cytokine-like hormones, called adipokines, either pro- or anti-inflammatory factors bridging metabolism to the immune system. Leptin is historically one of most relevant adipokines, with important physiological roles in the central control of energy metabolism and in the regulation of metabolism-immune system interplay, being a cornerstone of the emerging field of immunometabolism. Indeed, leptin receptor is expressed throughout the immune system and leptin has been shown to regulate both innate and adaptive immune responses. This review discusses the latest data regarding the role of leptin as a mediator of immune system and metabolism, with particular emphasis on its effects on obesity-associated metabolic disorders and autoimmune and/or inflammatory rheumatic diseases.

Inflammatory myopathy in the context of an unusual overlapping laminopathy.

Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.

Inflammatory myopathy in the context of an unusual overlapping laminopathy

Summary Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.

E74-Like Factor (ELF3) and Leptin, a Novel Loop Between Obesity and Inflammation Perpetuating a Pro-Catabolic State in Cartilage.

BACKGROUND/AIMS: The E74-like factor 3 (ELF3) is an inflammatory mediator that participates in cartilage destruction in osteoarthritis. Leptin and other adipokines negatively impact articular cartilage, triggering catabolic and inflammatory responses in chondrocytes. Here, we investigated whether leptin induces ELF3 expression in chondrocytes and the signaling pathway involved in this process. METHODS: We determined mRNA and protein levels of ELF3 by RT-qPCR and Western blotting using cultured human primary chondrocytes and the human T/C-28a2 chondrocyte cell line. Further, we measured luciferase activities of different reporter constructs, and we assessed the contribution of leptin to the induction of ELF3 mRNA by knocking down hLEPR gene expression using siRNA technology. RESULTS: Leptin synergizes with IL-1ß in inducing ELF3 expression in chondrocytes. We also found that PI3K, p38, and JAK2 signaling pathways are at play in the leptin-driven induction of ELF3. Moreover, we confirm the participation of NFΚB in the leptin/IL-1ß synergistic induction of ELF3. CONCLUSION: Here we show, for the first time, the regulation of ELF3 expression by leptin, suggesting that this transcription factor likely mediates the inflammatory responses triggered by leptin in articular chondrocytes.