Glycoprotein Acetyls Is a Novel Biomarker Predicting Cardiovascular Complications in Rheumatoid Arthritis.

The relationship between rheumatoid arthritis (RA) and early onset atherosclerosis is well depicted, each with an important inflammatory component. Glycoprotein acetyls (GlycA), a novel biomarker of inflammation, may play a role in the manifestation of these two inflammatory conditions. The present study examined a potential mediating role of GlycA within the RA-atherosclerosis relationship to determine whether it accounts for the excess risk of cardiovascular disease over that posed by lipid risk factors. The UK Biobank dataset was acquired to establish associations among RA, atherosclerosis, GlycA, and major lipid factors: total cholesterol (TC), high- and low-density lipoprotein (HDL, LDL) cholesterol, and triglycerides (TGs). Genome-wide association study summary statistics were collected from various resources to perform genetic analyses. Causality among variables was tested using Mendelian Randomization (MR) analysis. Genes of interest were identified using colocalization analysis and gene enrichment analysis. MR results appeared to indicate that the genetic relationship between GlycA and RA and also between RA and atherosclerosis was explained by horizontal pleiotropy (p-value = 0.001 and <0.001, respectively), while GlycA may causally predict atherosclerosis (p-value = 0.017). Colocalization analysis revealed several functionally relevant genes shared between GlycA and all the variables assessed. Two loci were apparent in all relationships tested and included the HLA region as well as SLC22A1. GlycA appears to mediate the RA-atherosclerosis relationship through several possible pathways. GlycA, although pleiotropically related to RA, appears to causally predict atherosclerosis. Thus, GlycA is suggested as a significant factor in the etiology of atherosclerosis development in RA.

Analysis of the Associations of Measurements of Body Composition and Inflammatory Factors with Cardiovascular Disease and Its Comorbidities in a Community-Based Study.

The associations of cardiovascular disease (CVD) with comorbidities and biochemical and body composition measurements are repeatedly described but have not been studied simultaneously. In the present cross-sectional study, information on CVD and comorbidities [type 2 diabetes mellitus (T2DM), hypertension (HTN), and hyperlipidemia (HDL)], body composition, levels of soluble markers, and other measures were collected from 1079 individuals. When we examined the association of each comorbidity and CVD, controlling for other comorbidities, we observed a clear pattern of the comorbidity-related specific associations with tested covariates. For example, T2DM was significantly associated with GDF-15 levels and the leptin/adiponectin (L/A) ratio independently of two other comorbidities; HTN, similarly, was independently associated with extracellular water (ECW) levels, L/A ratio, and age; and HDL was independently related to age only. CVD showed very strong independent associations with each of the comorbidities, being associated most strongly with HTN (OR = 10.89, 6.46-18.38) but also with HDL (2.49, 1.43-4.33) and T2DM (1.93, 1.12-3.33). An additive Bayesian network analysis suggests that all three comorbidities, particularly HTN, GDF-15 levels, and ECW content, likely have a main role in the risk of CVD development. Other factors, L/A ratio, lymphocyte count, and the systemic inflammation response index, are likely indirectly related to CVD, acting through the comorbidities and ECW.

GlycA and CRP Are Genetically Correlated: Insight into the Genetic Architecture of Inflammageing.

Inflammageing is a condition of perpetual low-grade inflammation induced by ageing. Inflammageing may be predicted by the C-reactive protein (CRP) or by a recently described biomarker which measures N-glycosylated side chains of the carbohydrate component of several acute-phase proteins known as GlycA. The objective of this study was to examine in depth the genetic relationships between CRP and GlycA as well as between each of them and other selected cytokines, which may shed light on the mechanisms of inflammageing. Using the Olink 96 Inflammation panel, data on inflammatory mediators for 1518 twins from the TwinsUK dataset were acquired. Summary statistics for genome-wide association studies for several cytokines as well as CRP and GlycA were collected from public sources. Extensive genetic correlation analyses, colocalization and genetic enrichment analyses were carried out to detect the shared genetic architecture between GlycA and CRP. Mendelian randomization was carried out to assess potential causal relationships. GlycA predicted examined cytokines with a magnitude twice as great as that of CRP. GlycA and CRP were significantly genetically correlated (Rg = 0.4397 ± 0.0854, p-value = 2.60 × 10-7). No evidence of a causal relationship between GlycA and CRP, or between these two biomarkers and the cytokines assessed was obtained. However, the aforementioned relationships were explained well by horizontal pleiotropy. Five exonic genetic variants annotated to five genes explain the shared genetic architecture observed between GlycA and CRP: IL6R, GCKR, MLXIPL, SERPINA1, and MAP1A. GlycA and CRP possess a shared genetic architecture, but the relationship between them appears to be modest, which may imply the promotion of differing inflammatory pathways. GlycA appears to be a more robust predictor of cytokines compared to CRP.

Restoration of epigenetic impairment in the skeletal muscle and chronic inflammation resolution as a therapeutic approach in sarcopenia.

Sarcopenia is an age-associated loss of skeletal muscle mass, strength, and function, accompanied by severe adverse health outcomes, such as falls and fractures, functional decline, high health costs, and mortality. Hence, its prevention and treatment have become increasingly urgent. However, despite the wide prevalence and extensive research on sarcopenia, no FDA-approved disease-modifying drugs exist. This is probably due to a poor understanding of the mechanisms underlying its pathophysiology. Recent evidence demonstrate that sarcopenia development is characterized by two key elements: (i) epigenetic dysregulation of multiple molecular pathways associated with sarcopenia pathogenesis, such as protein remodeling, insulin resistance, mitochondria impairments, and (ii) the creation of a systemic, chronic, low-grade inflammation (SCLGI). In this review, we focus on the epigenetic regulators that have been implicated in skeletal muscle deterioration, their individual roles, and possible crosstalk. We also discuss epidrugs, which are the pharmaceuticals with the potential to restore the epigenetic mechanisms deregulated in sarcopenia. In addition, we discuss the mechanisms underlying failed SCLGI resolution in sarcopenia and the potential application of pro-resolving molecules, comprising specialized pro-resolving mediators (SPMs) and their stable mimetics and receptor agonists. These compounds, as well as epidrugs, reveal beneficial effects in preclinical studies related to sarcopenia. Based on these encouraging observations, we propose the combination of epidrugs with SCLI-resolving agents as a new therapeutic approach for sarcopenia that can effectively attenuate of its manifestations.

Relationships between Circulating Biomarkers and Body Composition Parameters in Patients with Metabolic Syndrome: A Community-Based Study.

Metabolic syndrome (MetS) is a complex disease involving multiple physiological, biochemical, and metabolic abnormalities. The search for reliable biomarkers may help to better elucidate its pathogenesis and develop new preventive and therapeutic strategies. In the present population-based study, we looked for biomarkers of MetS among obesity- and inflammation-related circulating factors and body composition parameters in 1079 individuals (with age range between 18 and 80) belonging to an ethnically homogeneous population. Plasma levels of soluble markers were measured by using ELISA. Body composition parameters were assessed using bioimpedance analysis (BIA). Statistical analysis, including mixed-effects regression, with MetS as a dependent variable, revealed that the most significant independent variables were mainly adipose tissue-related phenotypes, including fat mass/weight (FM/WT) [OR (95% CI)], 2.77 (2.01-3.81); leptin/adiponectin ratio (L/A ratio), 1.50 (1.23-1.83); growth and differentiation factor 15 (GDF-15) levels, 1.32 (1.08-1.62); inflammatory markers, specifically monocyte to high-density lipoprotein cholesterol ratio (MHR), 2.53 (2.00-3.15), and a few others. Additive Bayesian network modeling suggests that age, sex, MHR, and FM/WT are directly associated with MetS and probably affect its manifestation. Additionally, MetS may be causing the GDF-15 and L/A ratio. Our novel findings suggest the existence of complex, age-related, and possibly hierarchical relationships between MetS and factors associated with obesity.

Elevated circulating levels of IL-34 are strongly associated with osteoporosis.

In this cross-sectional study, we observed a strong, age-independent association of circulating interleukin-34 (IL-34) levels with osteoporosis. PURPOSE: The reported capacity of IL-34 to induce and enhance osteoclastogenesis suggests its potential involvement in the pathogenesis of osteoporosis. Our study aimed to evaluate whether there is an association between IL-34 expression and osteoporosis. METHODS: We enrolled 30 women with osteoporosis and 230 age-matched non-osteoporotic women as a control group. Osteoporosis diagnosis was based on dual-energy X-ray absorptiometry (DXA) of the lumbar spine and femoral neck. Body composition parameters were assessed by the bioimpedance method. Plasma IL-34 levels were measured by ELISA. RESULTS: In comparison with the control group, the mean plasma IL-34 levels were significantly higher in osteoporotic women (164.61 ± 36.40 pg/ml vs. 665.43 ± 253.67 pg/ml, p = 0.0002), whereas basal metabolic rate (BMR) was significantly lower (1422.03 ± 6.80 kcal vs. 1339.39 ± 17.52 kcal, p = 0.00007). Both variables remained statistically significant after adjustment for age (p < 0.001). We did not observe correlations between plasma IL-34 levels and body composition parameters in osteoporotic and control groups. Multiple logistic regression analysis with osteoporosis status as a dependent variable clearly showed that age, BMR and IL-34 levels were independently and significantly associated with osteoporosis. The calculated odds ratios (OR) were 1.66 (95% CI = 1.16-2.38) for IL-34 levels and 0.22 (95% CI = 0.07-0.65) for BMR. CONCLUSION: The significant (fourfold) elevation of IL-34 plasma levels in osteoporosis patients suggests that circulating IL-34 could be used as a biomarker for osteoporosis.

Pro-Inflammatory Biomarkers Combined with Body Composition Display a Strong Association with Knee Osteoarthritis in a Community-Based Study.

Knee osteoarthritis (KOA) is one of the most common progressive, age-dependent chronic degenerative joint diseases. KOA often develops as a result of a gradual articular cartilage loss caused by its wear and tear. Numerous studies suggest that the degradation of the knee joint involves inflammatory components. This process is also associated with body composition, particularly being overweight and muscle mass loss. The present study aimed to search for novel circulating KOA inflammatory biomarkers, taking into account body composition characteristics. To this aim, we recruited 98 patients diagnosed and radiologically confirmed with KOA and 519 healthy controls from the Arab community in Israel. A panel of soluble molecules, related to inflammatory, metabolic, and musculoskeletal disorders, was measured by ELISA in plasma samples, while several body composition parameters were assessed with bioimpedance analysis. Statistical analysis, including multivariable logistic regression, revealed a number of the factors significantly associated with KOA, independently of age and sex. The most significant independent associations [OR (95% CI)] were fat body mass/body weight index-1.56 (1.20-2.02), systemic immune-inflammation index-4.03 (2.23-7.27), circulating vaspin levels-1.39 (1.15-1.68), follistatin/FSTL1 ratio-1.32 (1.02-1.70), and activin A/FSTL1 ratio-1.33 (1.01-1.75). Further clinical studies are warranted to confirm the relevance of these KOA-associated biological factors. Hereafter, they could serve as reliable biomarkers for KOA in the general human population.

The Anti-Tumorigenic Role of Cannabinoid Receptor 2 in Colon Cancer: A Study in Mice and Humans.

The endocannabinoid system, particularly cannabinoid receptor 2 (CB2 in mice and CNR2 in humans), has controversial pathophysiological implications in colon cancer. Here, we investigate the role of CB2 in potentiating the immune response in colon cancer in mice and determine the influence of CNR2 variants in humans. Comparing wild-type (WT) mice to CB2 knockout (CB2-/-) mice, we performed a spontaneous cancer study in aging mice and subsequently used the AOM/DSS model of colitis-associated colorectal cancer and a model for hereditary colon cancer (ApcMin/+). Additionally, we analyzed genomic data in a large human population to determine the relationship between CNR2 variants and colon cancer incidence. Aging CB2-/- mice exhibited a higher incidence of spontaneous precancerous lesions in the colon compared to WT controls. The AOM/DSS-treated CB2-/- and ApcMin/+CB2-/- mice experienced aggravated tumorigenesis and enhanced splenic populations of immunosuppressive myeloid-derived suppressor cells along with abated anti-tumor CD8+ T cells. Importantly, corroborative genomic data reveal a significant association between non-synonymous variants of CNR2 and the incidence of colon cancer in humans. Taken together, the results suggest that endogenous CB2 activation suppresses colon tumorigenesis by shifting the balance towards anti-tumor immune cells in mice and thus portray the prognostic value of CNR2 variants for colon cancer patients.

A cross-talk between sestrins, chronic inflammation and cellular senescence governs the development of age-associated sarcopenia and obesity.

The rapid increase in both the lifespan and proportion of older adults is accompanied by the unprecedented rise in age-associated chronic diseases, including sarcopenia and obesity. Aging is also manifested by increased susceptibility to multiple endogenous and exogenous stresses enabling such chronic conditions to develop. Among the main physiological regulators of cellular adaption to various stress stimuli, such as DNA damage, hypoxia, and oxidative stress, are sestrins (Sesns), a family of three evolutionarily conserved proteins, Sesn1, 2, and 3. Age-associated sarcopenia and obesity are characterized by two key processes: (i) accumulation of senescent cells in the skeletal muscle and adipose tissue and (ii) creation of a systemic, chronic, low-grade inflammation (SCLGI). Presumably, failed SCLGI resolution governs the development of these chronic conditions. Noteworthy, Sesns activate senolytics, which are agents that selectively eliminate senescent cells, as well as specialized pro-resolving mediators, which are factors that physiologically provide inflammation resolution. Sesns reveal clear beneficial effects in pre-clinical models of sarcopenia and obesity. Based on these observations, we propose a novel treatment strategy for age-associated sarcopenia and obesity, complementary to the conventional therapeutic modalities: Sesn activation, SCLGI resolution, and senescent cell elimination.

Insights into the pleiotropic relationships between chronic back pain and inflammation-related musculoskeletal conditions: rheumatoid arthritis and osteoporotic abnormalities.

ABSTRACT: The ageing process includes the development of debilitating musculoskeletal (MSK) conditions, including chronic back pain (CBP), rheumatoid arthritis (RA), and osteoporosis (OP). The mechanisms involved in the genetic-epidemiological relationships between these MSK phenotypes are controversial and limited and thus require clarification, in particular, between CBP and the other MSK phenotypes. A cross-sectional statistical analysis was conducted using Europeans from the UK Biobank data collection, including 73,794 CBP, 4883 RA, and 7153 OP cases as well as 242,216 calcaneus bone mineral density scores. C-reactive protein (CRP) was measured for 402,165 subjects in this sample. Genetic correlations were assessed to evaluate shared genetic background between traits. Mendelian randomization was performed to assess a causal relationship between CBP and RA and OP along with other risk factors, such as CRP. Colocalization analysis was conducted to identify shared pleiotropic regions between the examined traits. Bayesian modelling was performed to determine a potential pathway that may explain the interrelationships among these traits. Mendelian randomization analyses revealed that CRP causally predicts CBP only (ß = 0.183, 95% CI = 0.077-0.290, P -value = 0.001). Horizontally pleiotropy appeared to explain the relationship between CBP and RA and OP. Through colocalization analysis, several genomic regions emerged describing common genetic influences between CBP and its proposed risk factors, including HLA-DQA1/HLA-DQB1, APOE , SOX5, and MYH7B as well as Histone 1 genes. We speculate that among other factors, CBP and its MSK comorbidities may arise from common inflammatory mechanisms. Colocalized identified genes may aid in advancing or improving the mode of treatment in patients with CBP.

Exploring potential shared genetic influences between rheumatoid arthritis and blood lipid levels.

BACKGROUND AND AIMS: The association between rheumatoid arthritis (RA) and blood lipid levels has often been described as paradoxical, despite the strong association between RA and cardiovascular disease (CVD) risk. We aimed to clarify the genetic architecture that would explain the relationship between RA and blood-lipid levels, while considering inflammation as measured by C-reactive protein (CRP). METHODS: Genome-wide association study (GWAS) summary statistics were collected from the CHARGE Consortium and Global Lipids Genetics Consortium. Blood-lipid levels includes HDL-C, LDL-C, triglycerides (TG), and total cholesterol (TC). Causality was examined by assessing Mendelian Randomization (MR) analysis. Pleiotropy, the identification of shared causal variants between traits, was assessed by conducting colocalization analyses. RESULTS: Using the MR Egger method, RA did not appear to causally predict alterations in lipid factors, rather the MR Egger intercept revealed that the genetic relationship between RA and HDL-C, LDL-C and TC may be explained by horizontal pleiotropy (p=0.003, 0.006, and 0.018, respectively). MR was suggestive of a horizontally pleiotropic relationship between CRP and lipid factors, while a causal relationship could not be ruled out. Recurring genes arising from shared causal genetic variants between RA and varying lipid factors included NAT2/PSD3, FADS2/FADS1, SH2B3, and YDJC. CONCLUSIONS: Horizontal pleiotropy appears to explain the genetic relationship between RA and blood-lipid levels. In addition, blood-lipid levels appear to suggest a horizontally pleiotropic relationship to CRP, if not mediated through RA as well. Consideration of the pleiotropic genes between RA and blood lipid levels may aid in enhancing diagnostic means to predict CVD.

New Horizons in the Treatment of Age-Associated Obesity, Sarcopenia and Osteoporosis.

The rapid increase in both the lifespan and proportion of older adults in developed countries is accompanied by the dramatic growth of age-associated chronic diseases, including obesity, sarcopenia, and osteoporosis. Hence, prevention and treatment of age-associated chronic diseases has become increasingly urgent. The key to achieving this goal is a better understanding of the mechanisms underlying their pathophysiology, some aspects of which, despite extensive investigation, are still not fully understood. Aging, obesity, sarcopenia, and osteoporosis are characterized by the creation of a systemic, chronic, low-grade inflammation (SCLGI). The common mechanisms that govern the development of these chronic conditions include a failed resolution of inflammation. Physiologically, the process of inflammation resolution is provided mainly by specialized pro-resolving mediators (SPMs) acting via cognate G protein-coupled receptors (GPCRs). Noteworthy, SPM levels and the expression of their receptors are significantly reduced in aging and the associated chronic disorders. In preclinical studies, supplementation of SPMs or their stable, small-molecule SPM mimetics and receptor agonists reveals clear beneficial effects in inflammation-related obesity and sarcopenic and osteoporotic conditions, suggesting a translational potential. Age-associated chronic disorders are also characterized by gut dysbiosis and the accumulation of senescent cells in the adipose tissue, skeletal muscle, and bones. Based on these findings, we propose SCLGI resolution as a novel strategy for the prevention/treatment of age-associated obesity, sarcopenia, and osteoporosis. Our approach entails the enhancement of inflammation resolution by SPM mimetics and receptor agonists in concert with probiotics/prebiotics and compounds that eliminate senescent cells and their pro-inflammatory activity.

Targeting chronic inflammation as a potential adjuvant therapy for osteoporosis.

Systemic, chronic, low-grade inflammation (SCLGI) underlies the pathogenesis of various widespread diseases. It is often associated with bone loss, thus connecting chronic inflammation to the pathogenesis of osteoporosis. In postmenopausal women, osteoporosis is accompanied by SCLGI development, likely owing to estrogen deficiency. We propose that SCGLI persistence in osteoporosis results from failed inflammation resolution, which is mainly mediated by specialized, pro-resolving mediators (SPMs). In corroboration, SPMs demonstrate encouraging therapeutic effects in various preclinical models of inflammatory disorders, including bone pathology. Since numerous data implicate gut dysbiosis in osteoporosis-associated chronic inflammation, restoring balanced microbiota by supplementing probiotics and prebiotics could contribute to the efficient resolution of SCGLI. In the present review, we provide evidence for this hypothesis and argue that efficient SCGLI resolution may serve as a novel approach for treating osteoporosis, complementary to traditional anti-osteoporotic medications.

Scoliosis and skeletal muscle mass are strongly associated with low back pain-related disability in humans: An evolutionary anthropology point of view.

OBJECTIVES: To clarify the potential risk factors and etiology of low back pain (LBP)-related disability, including structural changes of the spine (spinal scoliosis) and body composition components in a population with a high prevalence of LBP. METHODS: In this cross-sectional study, two self-reported validated questionnaires were used to collect back pain and disability data in an ethnically homogeneous family-based population sample (N = 1078). The scoliosis angle of trunk rotation was measured by a scoliometer on three spinal levels while the patient was bent forward. Body composition parameters, including relative to weight (WT), fat, relative skeletal muscle mass (SMM/WT), and total body water were determined by bioelectrical impedance analysis. Statistical analysis was conducted, accounting for the familial composition of the sample. RESULTS: The mixed multiple regression analyses with several LBP-related phenotypes as dependent variables consistently showed significant independent associations with scoliosis and SMM/WT, irrespective of other covariates. The odds ratios (OR)/95% CI for scoliosis ranged between 1.40 (1.19-1.64) and 1.51 (1.27-1.80), and from 0.61(0.51-0.72), to 0.71(0.58-0.87) for SMM/WT, depending on the LBP phenotype. The genetic components of the respective correlations between the LBP-phenotypes and scoliosis or SMM/WT were negligible. CONCLUSIONS: The associations between LBP-related conditions and postured scoliosis and SMM/WT were consistent and significant and therefore may serve as markers in predicting the development of LBP-related disability. We interpret the origin of these correlations as the evolutionary event due to the imperfect spine anatomy adaptation to a vertical posture resulting from a quick transition to bipedalism from a quadrupedal ancestor.

Genetic and environmental correlational structure among metabolic syndrome endophenotypes.

Metabolic syndrome (MetS) is diagnosed by the presence of high scores on three or more metabolic traits, including systolic and diastolic blood pressure (SBP, DBP), glucose and insulin levels, cholesterol and triglyceride (TG) levels, and central obesity. A diagnosis of MetS is associated with increased risk of cardiovascular disease and type 2 diabetes. The components of MetS have long been demonstrated to have substantial genetic components, but their genetic overlap is less well understood. The present paper takes a multi-prong approach to examining the extent of this genetic overlap. This includes the quantitative genetic and additive Bayesian network modeling of the large TwinsUK project and examination of the results of genome-wide association study (GWAS) of UK Biobank data through use of LD score regression and examination of the number of genes and pathways identified in the GWASes which overlap across MetS traits. Results demonstrate a modest genetic overlap, and the genetic correlations obtained from TwinsUK and UK Biobank are nearly identical. However, these correlations imply more genetic dissimilarity than similarity. Furthermore, examination of the extent of overlap in significant GWAS hits, both at the gene and pathway level, again demonstrates only modest but significant genetic overlap. This lends support to the idea that in clinical treatment of MetS, treating each of the components individually may be an important way to address MetS.

Understanding the complex genetic architecture connecting rheumatoid arthritis, osteoporosis and inflammation: discovering causal pathways.

Rheumatoid arthritis (RA) and osteoporosis (OP) are two comorbid complex inflammatory conditions with evidence of shared genetic background and causal relationships. We aimed to clarify the genetic architecture underlying RA and various OP phenotypes while additionally considering an inflammatory component, C-reactive protein (CRP). Genome-wide association study summary statistics were acquired from the GEnetic Factors for OSteoporosis Consortium, Cohorts for Heart and Aging Research Consortium and UK Biobank. Mendelian randomization (MR) was used to detect the presence of causal relationships. Colocalization analysis was performed to determine shared genetic variants between CRP and OP phenotypes. Analysis of pleiotropy between traits owing to shared causal single nucleotide polymorphisms (SNPs) was performed using PL eiotropic A nalysis under CO mposite null hypothesis (PLACO). MR analysis was suggestive of horizontal pleiotropy between RA and OP traits. RA was a significant causal risk factor for CRP (ß = 0.027, 95% confidence interval = 0.016-0.038). There was no evidence of CRP→OP causal relationship, but horizontal pleiotropy was apparent. Colocalization established shared genomic regions between CRP and OP, including GCKR and SERPINA1 genes. Pleiotropy arising from shared causal SNPs revealed through the colocalization analysis was all confirmed by PLACO. These genes were found to be involved in the same molecular function 'protein binding' (GO:0005515) associated with RA, OP and CRP. We identified three major components explaining the epidemiological relationship among RA, OP and inflammation: (1) Pleiotropy explains a portion of the shared genetic relationship between RA and OP, albeit polygenically; (2) RA contributes to CRP elevation and (3) CRP, which is influenced by RA, demonstrated pleiotropy with OP.

Deciphering the Causal Relationships Between Low Back Pain Complications, Metabolic Factors, and Comorbidities.

PURPOSE: Low back pain (LBP) is one of the major disabling health conditions in aging societies presenting significant cost burdens to health and social care systems. Its complications and associated disability are often accompanied by mental disorders, metabolic comorbidities, changed body composition, and inflammation. However, their mutual relationships in LBP-associated disability remain unclear. METHODS: In the present case-control study, a self-report validated questionnaire was used to collect LBP disability data in an ethnically homogeneous Israeli Arab sample (489 males and 589 females). Body composition parameters were assessed through bioelectrical impedance analysis and plasma levels of soluble markers by EISA. Comorbidity status was assessed in personal interview and from the individual medical files. RESULTS: Our mixed multiple regression analysis identified that GDF-15 (ß = 0.160, p = 2.95×10-8), vaspin (ß = 0.085, p = 0.003), follistatin (ß = 0.076, p = 0.001), extracellular water (ß = 0.096, p = 0.001), waist hip ratio (ß = 0.072, p = 0.009), mental disorders (ß = 0.077, p = 0.001), and metabolic comorbidities (ß = 0.059, p = 0.02) were significantly associated with LBP disability scores, when controlling for age and sex effects. Additive Bayesian network modelling further suggests that LBP disability appears to be directly influenced by age, sex, GDF-15, and extracellular water, and indirectly by mental and metabolic disorders, waist-hip ratio, and follistatin. LBP, in turn, seems to affect the vaspin levels directly. CONCLUSION: Our data suggest the existence of a complex, age-associated, and probably hierarchical, relationship between LBP disability and mental and metabolic disorders, inflammation-related soluble markers, and body composition parameters.

Specialized, Pro-Resolving Mediators as Potential Therapeutic Agents for Alleviating Fibromyalgia Symptomatology.

OBJECTIVE: To present a hypothesis on a novel strategy in the treatment of fibromyalgia (FM). DESIGN: A narrative review. SETTING: FM as a disease remains a challenging concept for numerous reasons, including undefined etiopathogenesis, unclear triggers, and unsuccessful treatment modalities. We hypothesize that the inflammatome, the entire set of molecules involved in inflammation, acting as a common pathophysiological instrument of gut dysbiosis, sarcopenia, and neuroinflammation, is one of the major mechanisms underlying FM pathogenesis. In this setup, dysbiosis is proposed as the primary trigger of the inflammatome, sarcopenia as the peripheral nociceptive source, and neuroinflammation as the central mechanism of pain sensitization, transmission, and symptomatology of FM. Whereas neuroinflammation is highly considered as a critical deleterious element in FM pathogenesis, the presumed pathogenic roles of sarcopenia and systemic inflammation remain controversial. Nevertheless, sarcopenia-associated processes and dysbiosis have been recently detected in individuals with FM. The prevalence of pro-inflammatory factors in the cerebrospinal fluid and blood has been repeatedly observed in individuals with FM, which supports the idea of a role of the inflammatome in FM pathogenesis. As such, failed inflammation resolution might be one of the underlying pathogenic mechanisms. Accordingly, the application of specialized, inflammation pro-resolving mediators (SPMs) seems most suitable for this goal. CONCLUSIONS: The capability of various SPMs to prevent and attenuate pain has been repeatedly demonstrated in laboratory animal experiments. As SPMs suppress inflammation in a manner that does not compromise host defense, they could be attractive and safe candidates for the alleviation of FM symptomatology, probably in combination with anti-dysbiotic medicine.

Shared Genetic Architecture Between Rheumatoid Arthritis and Varying Osteoporotic Phenotypes.

Rheumatoid arthritis (RA) and low bone mineral density (BMD), an indicator of osteoporosis (OP), appear epidemiologically associated. Shared genetic factors may explain this association. This study aimed to investigate the presence of pleiotropy to clarify the potential genetic association between RA and OP. We examined BMDs at varying skeletal sites reported in UK Biobank as well as OP fracture acquired from the Genetic Factors for Osteoporosis (GEFOS) Consortium and the TwinsUK study. PRSice-2 was used to assess the potential shared genetic overlap between RA and OP. The presence of pleiotropy was examined using colocalization analysis. PRSice-2 revealed that RA was significantly associated with OP fracture (ß = 351.6 ± 83.9, p value = 2.76E-05), total BMD (ß = -1763.5 ± 612.8, p = 4.00E-03), spine BMD (ß = -919.8 ± 264.6, p value = 5.09E-04), and forearm BMD (ß = -66.09 ± 31.40, p value = 3.53E-02). Through colocalization analysis, the same causal genetic variants, associated with both RA and OP, were apparent in 12 genes: PLCL1, BOLL, AC011997.1, TNFAIP3, RP11-158I9.1, CDK6, CHCHD4P2, RP11-505C13.1, PHF19, TRAF1, C5, and C11orf49 with moderate posterior probabilities (>50%). Pleiotropy is involved in the association between RA and OP phenotypes. These findings contribute to the understanding of disease mechanisms and provide insight into possible therapeutic advancements and enhanced screening measures. © 2021 American Society for Bone and Mineral Research (ASBMR).