Context MicroRNAs (miRNAs) are short, single-stranded, non-coding RNAs which regulate gene expression. They originate from various tissues including bone and regulate different biological mechanisms including bone metabolism. Objective The aim of this project was to investigate circulating miRNAs as promising biomarkers for treatment monitoring in women with postmenopausal osteoporosis on denosumab (DMAB) therapy. Design, Setting and Patients In this prospective, observational, single-centre study twenty-one postmenopausal women treated with DMAB were included for a longitudinal follow-up of two years. Interventions and Main Outcome Measures Next-generation sequencing (NGS) was performed to screen for serological miRNAs at defined time points (baseline, month 6 and month 24). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to confirm NGS findings in the entire cohort. Bone turnover markers (BTM) P1NP and CTX, and bone mineral density (BMD) by Dual X-Ray absorptiometry (DXA) were assessed and correlated to miRNAs. Results BMD at the hip (5,5%, p = 0.0006) and lumbar spine significantly increased (11,4%, p-value = 0.017) and CTX (64,1%, p < 0.0001) and P1NP (69,3%, p < 0.0001) significantly decreased during treatment. NGS analysis revealed significant changes in miRNAs after 2-years of DMAB treatment, but not after 6-months. Seven miRNAs were confirmed by RT-qPCR to be significantly changed during a 2-year course of DMAB treatment compared to baseline. Four of these were found to be mainly transcribed in blood cells including monocytes. Correlation analysis identified a significant correlation between change in miRNA and change in BTMs as well as BMD. Based on effect size and correlation strength, miR-454-3p, miR-26b-5p and miR-584-5p were defined as top biomarker candidates with the strongest association to the sustained effect of denosumab on bone in osteoporotic patients. Conclusions Two years of DMAB-treatment resulted in the upregulation of 7 miRNAs, four of which are mainly transcribed in monocytes indicating a potential impact of DMAB on circulating osteoclast precursor cells. These changes were associated to BMD gain and BTM suppression and could therefore be useful for monitoring DMAB-treatment response.
Objective MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and psoriatic arthritis (PsA) is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients. Methods Expression of miRNAs was analyzed by RT-qPCR in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analyzed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population. Results 141 patients and controls were analyzed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both(adj. p< 0.05). 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls (AUC ≥0.70, all p< 0.05). Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly different regulated between PsO and PsA. A combination of these miRNAs increased AUC to 0.92 in multivariate regression model to discriminate PsO and PsA. Conclusion miRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, 5 of them previously reported to be involved in bone and cartilage metabolism, indicating intimate association of psoriatic inflammation and bone/cartilage changes.
BackgroundMicroRNAs (miRNAs) are small non-coding RNAs that control gene expression. Specific miRNA signatures have been identified in numerous diseases and may serve as potential biomarkers or new drug targets. Whether certain miRNA signatures are associated with psoriatic joint disease is currently unknown.ObjectivesTo search for circulating miRNA signatures in psoriasis patients with subclinical joint disease and in patients with psoriatic arthritis (PsA).MethodsAnalyses of serum miRNA were done in three groups: (1) PsA patients fulfilling CASPAR criteria (PsA), (2) healthy controls without past or present signs of musculoskeletal disease (HC) and (3) psoriasis patients with musculoskeletal pain but no signs of clinical PsA (PsO). PsO and PsA patients received a hand MRI, which was scored according to PsAMRIS method. miRNA analysis of serum samples was performed stepwise using RT-qPCR (TAmiRNA Vienna). In the discovery phase 192 miRNA assays were analyzed in 48 samples (N=16 each group). In the validation phase 17 miRNAs (Table 1) were selected and analyzed in 94 samples (N=35 PsA, N=24 PsO, N=35 HC) based on results of discovery phase and previous reports in literature. Results presented as mean±SD/median (IQR), p-values are adjusted for multiple testing.Table 1.miRNAsPsA vs HCPsO vs HCPsA vs PsODiscovery PhaseValidation PhaseDiscovery PhaseValidation PhaseDiscovery PhaseValidation Phasep-adj.p-adj.p-adj.p-adj.p-adj.p-adj.miR-93-5p0.0001<0.0010.0080.0050.0390.947miR-29b-3p0.0001<0.00010.0040.00020.1910.522miR-19b-3p0.0070.7080.00020.0200.1380.147miR-320d0.0010.619<0.00010.1350.9410.247miR-144-5p0.0030.0060.00010.1690.3500.444miR-188-5p0.0140.9900.9750.6470.0530.839let-7b-5p0.0250.00030.8890.0260.00030.472miR-92a-3p0.0430.0010.0050.773<0.00010.0005miR-324-3p0.1381.0000.2570.3920.8140.518miR-126-3p0.0140.1690.0130.5980.9220.654miR-223-3p0.1690.8720.6170.7460.5191.000miR-130a-3p0.0390.0350.5560.0090.0060.724miR-140-3p0.3500.0530.0020.0060.1180.683miR-155-5p0.1590.9950.1690.5490.9220.604miR-21-5p0.2970.9900.0030.1160.080.014miR-146a-5p0.7060.0040.8360.0380.9050.941miR-122-5p0.9600.7340.6950.7990.9050.444Results51 PsA patients (age: 51.3±11.4 years; 56.9% females), 40 PsO patients (51.4±11.0; 37.5%) and 50 HC (51.0±10.5; 52.9%) were assessed. Duration of psoriasis was 12(25) years in PsA and 15(22.8) years in PsO. Duration of joint disease in PsA was 1.0(4.8) year. 51% of PsA and 5% of PsO patients were on biological disease modifying drugs (bDMARDs), 49% vs. 10% on conventional DMARDs. The most frequent findings in the MRI were erosions (PsA 59.6%; PsO 40%) and synovitis (PsA 48.9%; PsO 42.5%). PsA patients had higher number of tenosynovitis compared to PsO (p=0.04). In discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared to HC, with an overlap of 33 miRNAs changed in PsA and PsO (p<0.05). Results of the selected 17 miRNAs are presented in Table 1. The top candidates to differentiate PsA and HC were miR-29b-3p (AUC=0.87), miR-93-5p (AUC=0.83) and let-7b-5p (AUC=0.79). For differentiating PsO and HC, they were miR-29b-3p (AUC=0.82), miR-140-3p (AUC=0.81) and miR-19b-3p (AUC=0.80) and for PsO vs. PsA miR-92a-3p (AUC=0.87), let-7b-5p (AUC=0.72) and miR-21-5p (AUC=0.70). miR-93-5p was lower in patients with erosions (p=0.01). miR-92a-3p, let-7b-5p and miR-21-5p were lower in patients with tenosynovitis, bone proliferations or erosions.ConclusionPsA and PsO patients show miRNA signatures different from HC. Top candidate miRNAs differentially regulated in PsA and PsO have been previously reported in alteration of bone metabolism and osteoarthritis indicating the intimate association of psoriatic inflammation with bone and cartilage changes.References[1]Faustini F et al. Ann Rheum Dis 2016 Dec;75(12):2068-2074[2]Hackl, M et al. Molecular and Cellular Endocrinology Elsevier Ireland Ltd 432, pp 83–95[3]Feichtinger X et al. Sci Rep 2018 Mar 20;8(1):4867Disclosure of InterestsNone declared
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