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Osteoclasts and their circulating precursors in rheumatoid arthritis: Relationships with disease activity and bone erosions.

ABSTRACT: Patients with rheumatoid arthritis (RA) have very different outcomes, particularly with regard to bone erosions. Since osteoclasts are responsible for bone destruction adjacent to rheumatoid synovium, profiling osteoclasts from circulating precursors in RA could help identify patients at risk for bone destruction. In this study, we sought to determine whether the functional characteristics of osteoclasts generated from their blood precursors were modified by RA activity or were intrinsic to osteoclasts and associated with the RA phenotype (erosive or not). Osteoclasts were generated in vitro from peripheral blood mononuclear cells (PBMCs) of subjects with RA (n = 140), as well as sex- and age-matched healthy controls (n = 101). Osteoclastic parameters were analyzed at baseline and during the follow-up for up to 4 years, with regular assessment of RA activity, bone erosions, and bone mineral density (BMD). As a validation cohort, we examined RA patients from the Early Undifferentiated PolyArthritis (EUPA) study (n = 163). The proportion of CD14+ PBMC was higher in RA than in control subjects, but inversely correlated with the 28-joint disease activity score (DAS28). Also surprisingly, in osteoclast cultures from PBMCs, active RA was associated with lower osteoclastogenic capacity, while in vitro bone resorption per osteoclast and resistance to apoptosis were similar in both active and quiescent RA. In a small subgroup analysis, osteoclasts from subjects with recent RA that had progressed at four years to an erosive RA exhibited at baseline greater resistance to apoptosis than those from patients remaining non-erosive. Our findings establish that when RA is active, circulating monocytes have a reduced potential to generate osteoclasts from PBMCs in vitro. In addition, osteoclasts associated with erosive disease had resistance to apoptosis from the start of RA.

SUBMITTER: Allard-Chamard H

PROVIDER: S-EPMC7251539 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBlood metabolites serve as pivotal indicators in identifying and predicting the course of rheumatoid arthritis (RA). However, empirical substantiation of a direct causal link between these serum biomarkers and the development of RA is still lacking comprehensive support.MethodIn pursuit of a thorough exploration of the causal links between circulating blood metabolites and RA, we deployed a two-sample Mendelian randomization (MR) approach during our initial investigative phase. This method was utilized to examine the potential connections between 249 distinct circulating metabolites and the prevalence of RA. In the validation phase, we conducted replication analyses with a new metabolic dataset consisting of 123 metabolites. Furthermore, we employed the Mendelian randomization based on Bayesian model averaging (MR-BMA) technique to pinpoint key metabolic characteristics that have significant causal implications.ResultsIn our primary analysis, we found that acetate, acetoacetate and pyruvate exhibited a consistent protective causal association with rheumatoid arthritis, while lactate demonstrated a positive correlation with rheumatoid arthritis risk. It is also noteworthy that a substantial subset of traits related to both saturated and unsaturated fatty acids showed causal influences. Subsequent secondary analyses substantiated these observations, revealing that traits associated with the average number of methylene groups in a fatty acid chain exhibited protective effects. Ultimately, our MR-BMA analyses unveiled that the ratio of polyunsaturated fatty acids (PUFAs) to total fatty acids assumes a paramount role in increasing the susceptibility to rheumatoid arthritis.ConclusionsBy employing systemic MR analyses, our study has successfully generated an all-encompassing atlas elucidating the intricate connections between circulating metabolites and the susceptibility to rheumatoid arthritis. Our results indicate the high unsaturation degree is a dominant risk factors correlated with rheumatoid arthritis.

Project description:ObjectiveActivation of osteoclastogenesis at the bone site in rheumatoid arthritis (RA) is well established. The mechanisms by which circulating osteoclast precursors contribute are still unclear. Peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?) is implicated in transcriptional regulation of osteoclastogenesis in mouse models. This study was undertaken to investigate the contribution of PGC-1? to circulating osteoclast precursors and its link to bone destruction in RA.MethodsPGC-1? expression in RA peripheral blood CD14+ monocytes was increased and showed correlation with joint destruction shown on radiographs. Cells from RA patients or healthy controls were transfected with a lentivirus vector for PGC-1? gene silencing or overexpression and cultured with macrophage colony-stimulating factor and RANKL. Bone resorption activity, bone-degrading enzymes, and signaling molecules were measured in these mature osteoclasts.ResultsIncreased nuclear accumulation of PGC-1? was observed in RA peripheral blood CD14+ monocytes, and these cells had stronger osteoclastogenesis than in healthy controls. PGC-1? protein expression was positively correlated with radiographic joint destruction (r = 0.396-0.413; all P < 0.05). PGC-1? knockdown suppressed (51-82% reduction) the expression of cathepsin K, tartrate-resistant acid phosphatase (TRAP), and matrix metalloproteinase 9 (MMP-9), as well as osteoclast differentiation and bone resorption activity. Conversely, PGC-1? overexpression increased these markers (by 1.5-1.8-fold) and osteoclastogenesis. VIVIT, an inhibitor of NFATc1 activation, inhibited the effect of overexpressed PGC-1? by reducing cathepsin K, TRAP, and MMP-9 expression. Chromatin immunoprecipitation assay and dual-luciferase reporter gene assay showed PGC-1? bound to NFATc1 promoter, leading to transcriptional activation.ConclusionActivation of the PGC-1?/NFATc1 pathway in circulating osteoclast precursors was associated with bone destruction in RA. This may represent a new treatment target.

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Osteoclasts and their circulating precursors in rheumatoid arthritis: Relationships with disease activity and bone erosions.

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