The Role of the Trabecular Bone Score in the Assessment of Osteoarticular Disorders in Patients with HFE-Hemochromatosis: A Single-Center Study from Poland.

Type 1 hereditary hemochromatosis (HH) is an autosomal, recessive genetic entity with systemic iron overload. Iron homeostasis disorders develop as a result of HFE gene mutations, which are associated with hepcidin arthropathy or osteoporosis and may cause permanent disability in HH patients despite a properly conducted treatment with phlebotomies. In this study, selected parameters of calcium and phosphate metabolism were analyzed in combination with the assessment of bone mineral density (BMD) disorders in patients from northern Poland with clinically overt HFE-HH. BMD was determined by a dual-energy X-ray absorptiometry (DXA) test with the use of the trabecular bone score (TBS) function. The study included 29 HH patients (mean age = 53.14 years) who were compared with 20 healthy volunteers. A significantly lower TBS parameter and serum 25-OH-D3 concentration, a higher concentration of intact parathormone and more a frequent occurrence of joint pain were found in HH patients compared with the control group. In HH patients, the diagnosis of liver cirrhosis was associated with lower serum 25-OH-D3 and osteocalcin concentrations. In HH, DXA with the TBS option is a valuable tool in the early assessment of the bone microarchitecture and fracture risk. A supplementation of vitamin D, monitoring its concentration, should be considered especially in HH patients with liver damage and liver cirrhosis.

Fatty acid sensing GPCR (GPR84) signaling safeguards cartilage homeostasis and protects against osteoarthritis.

It is well known that free fatty acids (FFAs) have beneficial effects on the skeletal system, however, which fatty acid sensing GPCR(s) and how the GPCR(s) regulating cartilage development and osteoarthritis (OA) pathogenesis is largely unknown. In this study, we found Gpr84, a receptor for medium-chain FFAs (MCFA), was the only FFA-sensing GPCR in human and mouse chondrocytes that exhibited elevated expression when stimulated by interleukin (IL)-1ß. Gpr84-deficiency upregulated cartilage catabolic regulator expression and downregulated anabolic factor expression in the IL-1ß-induced cell model and the destabilization of the medial meniscus (DMM)-induced OA mouse model. Gpr84-/- mice exhibited an aggravated OA phenotype characterized by severe cartilage degradation, osteophyte formation and subchondral bone sclerosis. Moreover, activating Gpr84 directly enhanced cartilage extracellular matrix (ECM) generation while knockout of Gpr84 suppressed ECM-related gene expression. Especially, the agonists of GPR84 protected human OA cartilage explants against degeneration by inducing cartilage anabolic factor expression. At the molecular level, GPR84 activation inhibited IL-1ß-induced NF-κB signaling pathway. Furthermore, deletion of Gpr84 had little effect on articular and spine cartilaginous tissues during skeletal growth. Together, all of our results demonstrated that fatty acid sensing GPCR (Gpr84) signaling played a critical role in OA pathogenesis, and activation of GPR84 or MCFA supplementation has potential in preventing the pathogenesis and progression of OA without severe cartilaginous side effect.

The neurohypophysial oxytocin and arginine vasopressin system is activated in a knee osteoarthritis rat model.

Osteoarthritis (OA) causes chronic joint pain and significantly impacts daily activities. Hence, developing novel treatment options for OA has become an increasingly important area of research. Recently, studies have reported that exogenous, as well as endogenous, hypothalamic-neurohypophysial hormones, oxytocin (OXT) and arginine-vasopressin (AVP), significantly contribute to nociception modulation. Moreover, the parvocellular OXT neurone (parvOXT) extends its projection to the superficial spinal dorsal horn, where it controls the transmission of nociceptive signals. Meanwhile, AVP produced in the magnocellular AVP neurone (magnAVP) is released into the systemic circulation where it contributes to pain management at peripheral sites. The parvocellular AVP neurone (parvAVP), as well as corticotrophin-releasing hormone (CRH), suppresses inflammation via activation of the hypothalamic-pituitary adrenal (HPA) axis. Previously, we confirmed that the OXT/AVP system is activated in rat models of pain. However, the roles of endogenous hypothalamic-neurohypophysial hormones in OA have not yet been characterised. In the present study, we investigated whether the OXT/AVP system is activated in a knee OA rat model. Our results show that putative parvOXT is activated and the amount of OXT-monomeric red fluorescent protein 1 positive granules in the ipsilateral superficial spinal dorsal horn increases in the knee OA rat. Furthermore, both magnAVP and parvAVP are activated, concurrent with HPA axis activation, predominantly modulated by AVP, and not CRH. The OXT/AVP system in OA rats was similar to that in systemic inflammation models, including adjuvant arthritis; however, magnocellular OXT neurones (magnOXT) were not activated in OA. Hence, localised chronic pain conditions, such as knee OA, activate the OXT/AVP system without impacting magnOXT.

Genetic Predictors of Response to Acupuncture for Aromatase Inhibitor-Associated Arthralgia Among Breast Cancer Survivors.

Objective: To evaluate the associations between polymorphisms in two genes, catechol-O-methyltransferase and T-cell leukemia/lymphoma 1 A, and acupuncture-mediated pain reduction among breast cancer survivors with aromatase inhibitor-associated arthralgia. Design, Setting, and Subjects: Biospecimens were obtained from 38 patients enrolled in a clinical trial of acupuncture for aromatase inhibitor-associated arthralgia in postmenopausal hormone receptor-positive breast cancer survivors. Methods: We used polymerase chain reaction to genotype the rs4680 (Val158Met) and rs4633 (His62His) variants in the catechol-O-methyltransferase gene and rs2369049 (A > G) and rs7158782 (A > G) variants in the T-cell leukemia/lymphoma 1 A gene. Response to acupuncture was defined by 30% reduction in end-of-treatment average pain, measured by the Brief Pain Inventory. We used Fisher exact tests to evaluate associations between genotype and treatment response. Results: Among participants, all six (15.8%) subjects who expressed AA in locus rs4680 responded to acupuncture. In a combined analysis, the 18 (47.4%) subjects with the responder genotype at either rs4680 (AA) or rs2369049 (GG or AG) were significantly more likely to respond to acupuncture than those without (77.8% vs 45.0%, P = 0.039). Conclusions: Specific genetic variations at loci rs4680 and rs2369049 are associated with response to acupuncture-type intervention for management of arthralgia. These results serve as a proof of concept for applying a precision medicine framework to the study of cancer pain management.

Vitamin D Levels, Vitamin D Receptor Polymorphisms, and Inflammatory Cytokines in Aromatase Inhibitor-Induced Arthralgias: An Analysis of CCTG MA.27.

BACKGROUND: Approximately half of women taking aromatase inhibitor (AI) therapy develop AI-induced arthralgia (AIA), and many might discontinue AI therapy because of the pain. Using plasma samples from the MA.27 study, we assessed several factors potentially associated with AIA. PATIENTS AND METHODS: MA.27 is a phase III adjuvant trial comparing 2 AIs, exemestane versus anastrozole. Within an 893-participant nested case-control AIA genome-wide association study, we nested a 72 AIA case-144 control assessment of vitamin D plasma concentrations, corrected for seasonal and geographic variation. We also examined 9 baseline inflammatory cytokines: interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, interferon (IFN)γ, IL-10, IL-12p70, IL-17, IL-23, and chemokine ligand (CCL)-20. Finally, we analyzed the multivariate effects of baseline factors: vitamin D level, previously identified musculoskeletal single nucleotide polymorphisms, age, body mass index, and vitamin D receptor (VDR) Fok-I variant genotype on AIA development. RESULTS: Changes in vitamin D from baseline to 6 months were not significantly different between cases and controls. Elevated inflammatory cytokine levels were not associated with development of AIA. The multivariate model included no clinical factors associated with AIA. However, women with the VDR Fok-I variant genotype were more likely to have a lower IL-1ß level (P = .0091) and less likely to develop AIA after 6 months of AI compared with those with the wild type VDR (P < .0001). CONCLUSION: In this nested case-control correlative study, vitamin D levels were not significantly associated with development of AIA; however, patients with the Fok-I VDR variant genotype were more likely to have a significant reduction in IL-1ß level, and less likely to develop AIA.

Molecular basis of aromatase inhibitor associated arthralgia: known and potential candidate genes and associated biomarkers.

INTRODUCTION: Aromatase inhibitors (AIs) are routinely used for the adjuvant treatment of women with hormone receptor-positive early breast cancer. AIs are widely prescribed in the postmenopausal setting, as they are effective at preventing recurrence. However, their use is complicated by significant adverse effects, particularly arthralgia, noted in up to 50% of treated patients, and thereby affects quality of life and AI compliance. The mechanism by which AIs cause arthralgia is largely unknown, although there is a growing body of literature which suggests that there may be multiple intersecting mechanisms. Areas covered: This review describes the evidence for the mechanistic basis of AI arthralgia as well as potential pathways that could contribute to the development of AI associated arthralgia. Expert opinion: Interplay of multiple factors, such as interpatient variability in AI metabolism, possibly related to pharmacogenetic factors, the sudden decline of estrogen synthesis, vitamin D status, as well as upregulation of cytokines and inflammation pathways may precipitate or exacerbate muscle and joint pain are linked during AI therapy. However, much more research is needed in this area given the frequency and severity of AI-associated arthralgia.

Analgesic effect of different moxibustion durations in rheumatoid arthritis rats.

OBJECTIVE: To observe the influence of different moxibustion durations on hypothalamic pro-opiomelanocortin (POMC) and prodynorphin (PDYN) mRNA expressions and plasma beta-endorphin (beta-EP) content in rheumatoid arthritis (RA) rats, to understand the mechanism of moxibustion analgesia and its dose-effect relationship. METHODS: Twelve male Wistar rats were randomly selected from 48 male Wistar rats as a normal control group. The RA model was created by raising rats in a windy (blowing with electric fan), cold (6 degrees C +/- 2 degrees C), and wet (80%-90% humidity) environment for 20 days, 12 h each day. This was followed by injection of Freund's complete adjuvant (0.15 mL) into the ankle. Then, rats were randomly divided into a model group, moxibustion group I, and moxibustion group II, with 12 rats in each group. In moxibustion groups I and II, moxibustion was given at Shenshu (BL 23) and Zusanli (ST 36) for 20 and 40 min, respectively, once daily for 15 days. Hypothalamic POMC and PDYN mRNA expression levels and plasma beta-EP content were determined. RESULTS: Compared with the normal group, the pressure pain threshold decreased, while the hypothalamic POMC and PDYN mRNA expression levels and plasma beta-EP content increased in the moxibustion groups (P < 0.01). Compared with the model group, the pressure pain threshold, hypothalamic POMC and PDYN mRNA expression levels and plasma beta-EP content in the moxibustion groups increased significantly (P < 0.01). Compared the moxibustion group I, the pain threshold, hypothalamic POMC and PDYN mRNA expression levels and plasma beta-EP content in moxibustion group II significantly increased (P < 0.01). CONCLUSION: Moxibustion has an analgesic effect and increases hypothalamic POMC and PDYN mRNA expression levels and plasma beta-EP content in RA rats.The analgesic effect in moxibustion group II is betterthan that in moxibustion group I.

Association of functional polymorphisms in CYP19A1 with aromatase inhibitor associated arthralgia in breast cancer survivors.

INTRODUCTION: Aromatase inhibitor-associated arthralgia (AIAA) is a common and often debilitating symptom in breast cancer survivors. Since joint symptoms have been related to estrogen deprivation through the menopausal transition, we hypothesized that genetic polymorphisms in CYP19A1, the final enzyme in estrogen synthesis, may be associated with the occurrence of AIAA. METHODS: We performed a cross-sectional study of postmenopausal women with stage 0 to III breast cancer receiving adjuvant aromatase inhibitor (AI) therapy. Patient-reported AIAA was the primary outcome. DNA was genotyped for candidate CYP19A1 polymorphisms. Serum estrogen levels were evaluated by radioimmunoassay. Multivariate analyses were performed to examine associations between AIAA and genetic variants controlling for possible confounders. RESULTS: Among 390 Caucasian participants, 50.8% reported AIAA. Women carrying at least one 8-repeat allele had lower odds of AIAA (adjusted odds ratio (AOR) 0.41, 95% confidence interval (CI) 0.21 to 0.79, P = 0.008) after adjusting for demographic and clinical covariates. Estradiol and estrone were detectable in 47% and 86% of subjects on AIs, respectively. Although these post-AI levels were associated with multiple genotypes, they were not associated with AIAA. In multivariate analyses, women with more recent transition into menopause (less than five years) were significantly more likely to report AIAA than those greater than ten years post-menopause (AOR 3.31, 95% CI 1.72 to 6.39, P < 0.001). CONCLUSIONS: Functional polymorphism in CYP19A1 and time since menopause are associated with patient-reported AIAA, supporting the hypothesis that the host hormonal environment contributes to the pathophysiology of AAIA. Prospective investigation is needed to further delineate relationships between host genetics, changing estrogen levels and AIAA.

[Comparative study of regulation of TLR/TRAF signaling pathway of classic prescriptions that deals with arthralgia syndrome based on relevent theory of prescription and syndrome].

OBJECTIVE: Based on relevent theory of prescription and syndrome, to compare the gene expression differences of TLR2, TRAF6, and Faslg with adjuvant arthritis in rat spleen among Wutou decoction, Guizhi Shaoyao Zhimu decoction and Baihu Guizhi decoction. METHOD: The experiment animal model of adjuvant arthritis in rats was established. Relative expression amount of TLR2, TRAF6, and Faslg in rats spleen was detected by SYBR Green I dye methods and implementation of fluorescence quantitative PCR technology with 18sRNA as an internal gene. 2(delta delta CT) method was used for computing and data analysis. RESULT: TLR2, TRAF6, and Faslg gene in adjuvant arthritis rat spleen was significantly higher than those in the blank group. The various doses of Wutou decoction, Guizhi Shaoyao Zhimu decoction and Baihu Guizhi decoction can significantly inhibit or reduce the abnormally high expression of TLR2, TRAF6, and Faslg genes. The gene expression level caused by three decoctions mentioned above was followed by strong to weak as Wutou decoction Guizhi Shaoyao Zhimu decoction and Baihu Guizhi decoction with the clinical equivalent dose, but the strength of the trend to reduce the role of TRAF6 is just the opposite with the TLR2 and Faslg genes. CONCLUSION: Wutou decoction, Guizhi Shaoyao Zhimu decoction and Baihu Guizhi decoction can reduce the abnormally high expression of TLR2, TRAF6 and Faslg in rat spleen with adjuvant arthritis, but the differences of intensity exist and remain relatively consistent with that of pharmacodynamics and regulation trends of T cell subsets. Results suggest that the suppression of TLR2/TRAF6 signal pathway and apoptosis Faslg receptor gene may be the reasons that the pharmacodynamics of three decoctions on peripheral T cell subsets in regulating intensity was different.

TNF receptor-associated periodic syndrome (TRAPS): description of a novel TNFRSF1A mutation and response to etanercept.

TRAPS is the most common of the autosomal dominant periodic fever syndromes. It is caused by mutations in the TNFRSF1A gene, which encodes for the type 1 TNF-receptor (TNFR1). We describe here a Brazilian patient with TRAPS associated to a novel TNFRSF1A de novo mutation and the response to anti-TNF therapy. The patient is a 9-year-old girl with recurrent fevers since the age of 3 years, usually lasting 3 to 7 days, and recurring every other week. These episodes are associated with mild abdominal pain, nausea, vomiting and generalized myalgia. Recurrent conjunctivitis and erysipela-like skin lesions in the lower limbs also occur. Laboratory studies show persistent normocytic normochromic anemia, thrombocytosis, elevated erythrocyte sedimentation rate and C-reactive protein. IgD levels are normal. Mutational screening of TNFRSF1A revealed the association of a novel C30F mutation with the common R92Q low-penetrance mutation. The R92Q mutation is seen in 5% of the general population and is associated with an atypical inflammatory phenotype. The patient had a very good response to etanercept, with cessation of fever and normalization of inflammatory markers. Our report expands the spectrum of TNFRSF1A mutations associated with TRAPS, adding further evidence for possible additive effects of a low-penetration R92Q and cysteine residue mutations, and confirms etanercept as an efficacious treatment alternative.

New CIAS1 mutation and anakinra efficacy in overlapping of Muckle-Wells and familial cold autoinflammatory syndromes.

OBJECTIVES: Muckle-Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS) are rare periodic fevers associated with CIAS1 mutations. A third entity, the chronic infantile neurological, cutaneous, articular (CINCA) syndrome was also recently associated with mutation in the same gene. A phenotypic and genotypic continuum seems to exist from the most benign (FCAS) to the most severe forms (CINCA). Although a CIAS1 mutation can be associated with two different phenotypes. METHODS: We report a family of three patients exhibiting the MWS and FCAS phenotypes. These phenotypes were associated with a novel missense mutation in CIAS1. RESULTS: Anakinra controlled inflammatory flares in the three patients. CONCLUSIONS: FCAS, MWS and CINCA could be different phenotype expressions of the same disease.

Successful treatment of renal amyloidosis due to familial cold autoinflammatory syndrome using an interleukin 1 receptor antagonist.

Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterized by episodic fever, arthralgias, conjunctivitis, and rash triggered by cold exposure. FCAS is rarely associated with progressive renal insufficiency caused by renal amyloidosis. The genetic defect in patients with this disorder is caused by a mutation in the gene encoding the protein cryopyrin, leading to uninhibited activation of systemic inflammation through specific cellular signaling with increased production of a number of key cytokines, including interleukin 1. We describe the successful treatment of a patient with renal amyloidosis caused by FCAS by using a novel interleukin 1-receptor antagonist. Use of specific anticytokine therapy may be a new paradigm in the treatment of patients with renal amyloidosis caused by systemic inflammatory diseases.

GABA(B2) receptor subunit mRNA decreases in the thalamus of monoarthritic animals.

Many studies have implicated GABA(B) receptors in pain transmission mechanisms, especially in the spinal cord. In the thalamus, mRNA expression of the GABA(B(1b)) isoform was shown to be regulated in relay nuclei in response to chronic noxious input arising from experimental monoarthritis. GABA(B(1a)) and GABA(B2) mRNA expression was here determined by in situ hybridisation in the brain of control, 2, 4, 7 and 14 days monoarthritic rats, to evaluate whether this expression was regulated by chronic noxious input in thalamic nuclei. mRNA labelling was analysed quantitatively in the ventrobasal complex, posterior, central medial/central lateral and reticular thalamic nuclei; the thalamic visual relay and dentate gyrus were examined for control. No mRNA expression was detected for GABA(B(1a)) in control and monoarthritic animals. Similarly, GABA(B2) mRNA was not found in the reticular nucleus. However, GABA(B2) mRNA expression was observed in the ventrobasal complex, posterior and central medial/central lateral nuclei of control animals. A significant decrease of 42% at 2 days and 27% at 4 days of monoarthritis was observed in the ventrobasal complex contralaterally, when compared with controls, returning to basal levels at 7 days of monoarthritis. In the ipsilateral posterior nucleus, there was a significant decrease of 38% at 2 days of monoarthritis. No significant changes were observed in central medial/central lateral nuclei. The data suggest that GABA(B2) mRNA expression in the ventrobasal complex and posterior nucleus is regulated by noxious input and that GABA(B) receptors might play a role in the plasticity of these relay nuclei during chronic inflammatory pain.