Biology subjects

Olmer, M.

Publications and source records attributed to Olmer, M..

3 recordsLinked to original sources

bioRxiv2026

Single-nucleus multiome profiling reveals osteocyte-centered remodeling of human subchondral bone across osteoarthritis severity

Objective: Subchondral bone remodeling is a hallmark of osteoarthritis (OA), but osteocytes, the principal regulators of bone homeostasis, have been inaccessible to single-cell studies because they are embedded in mineralized matrix. We aimed to define the cellular, transcriptional and chromatin changes of human subchondral bone across OA severity, osteocytes included, and to identify candidate signals between cartilage and bone. Design: Subchondral bone from the medial femoral condyle of human knees graded by the Outerbridge system was analyzed by bulk RNA sequencing (89 knees) and by single-nucleus multiome sequencing of gene expression and chromatin accessibility after mechanical nuclear isolation (16 donors). Three hypotheses were prespecified: with increasing OA severity, (1) the osteoprogenitor fraction increases, (2) the osteocyte fraction increases, and (3) osteocyte SMAD2/3 motif activity increases. Results: With OA severity, bulk expression shifted toward extracellular matrix and ossification programs. The atlas resolved 26 cell states among 61,570 nuclei, including 906 osteocytes. Osteoprogenitors (p = 0.003) and osteocytes (p = 0.036) increased in share along an osteogenic continuum that starts from CXCL12-abundant reticular cells. Chondrocytes at the osteochondral junction upregulated FN1, FGF1, FGF2 and TNFSF11 without increased hypertrophic gene expression, and their share of the inferred FN1 signal received by osteocytes rose from 4% in normal knees to 33% in severe OA. Osteocyte SMAD2/3 motif activity increased with severity (rho = 0.70, p = 0.003), and all three hypotheses remained significant after Holm correction. Across the osteogenic lineage, SMAD2/3 activity correlated with junction chondrocyte FN1 (rho = 0.63, p = 0.017), and in osteocytes it was accompanied by TGF-{beta}-responsive matrix genes and perilacunar-remodeling genes. Conclusions: This osteocyte-inclusive atlas of human OA subchondral bone shows expansion of the osteogenic compartment and a rise of osteocyte SMAD2/3-linked matrix remodeling with disease, and identifies chondrocyte-derived FN1 as a candidate contributor to cartilage-bone communication associated with osteocyte TGF-{beta}/SMAD2/3 signaling.

molecular biology↗

bioRxiv2026

3'tRNAAsp(GTC)-derived fragment links inflammation to post-transcriptional reprogramming in chondrocytes during osteoarthritis.

ObjectiveTransfer RNA-derived fragments (tRFs) belong to an emerging class of small non-coding RNAs that dynamically respond to metabolic stressors and drive different pathological processes, yet their role in osteoarthritis (OA) remains poorly explored. We aimed to define the tRF landscape in OA and investigate the function of 3tRFAsp(GTC) in chondrocyte stress adaptation and translational control. MethodsEx vivo, cartilage specimens from OA patients (n=6) and healthy donors (n=7) were analyzed by small RNA sequencing to define disease-associated tRF signatures. In vitro, primary chondrocytes derived from OA patients were treated with lipopolysaccharide (LPS) to mimic inflammatory environment of OA, used for small RNA sequencing (n=3) and validation analysis (n=6). Functional studies in C28/I2 chondrocytes included antisense oligonucleotide-mediated 3tRFAsp(GTC) inhibition, AGO2-RNA immunoprecipitation (RIP), polysome profiling, stress granule (SG) immunofluorescence, and differential protein analysis. Computational target prediction and pathway enrichment were used to explore tRF-mediated regulatory networks. ResultsBoth OA cartilage and LPS-treated chondrocytes displayed upregulation of 3tRFAsp(GTC) and 5tRFGlu(CTC), indicating a shared inflammatory tRF signature. Predicted targets of upregulated tRFs were enriched in stress-adaptive, proteostasis, and translational control pathways, whereas downregulated tRFs modulated mitochondrial processes. Silencing 3tRFAsp(GTC) inhibited LPS-induced COX2 and MMP13 expression, prevented ER stress, and blocked SG assembly. RIP confirmed selective recruitment of 3tRFAsp(GTC) into AGO2 complexes. Polysome profiling revealed association with 40S ribosomal subunit, mediating translational arrest and influencing selective mRNA expression. Conclusion3tRFAsp(GTC) emerges as a regulator linking inflammation to translational control and SG dynamics in OA. tRFs thus could represent novel therapeutic targets in OA disease.

biochemistry↗

bioRxiv2018

Characterization of osteoarthritis phenotypes by global metabolomic profiling of human synovial fluid

ObjectiveOsteoarthritis (OA) is a multifactorial disease with etiological heterogeneity. The objective of this study was to classify OA subgroups by generating metabolic phenotypes of OA from human synovial fluid.\n\nDesignPost mortem synovial fluids (n=75) were analyzed by high performance-liquid chromatography mass spectrometry (HPLC-MS) to measure changes in the global metabolome. Comparisons of healthy (grade 0), early OA (grades I-II), and late OA (grades III-IV) donor populations were considered to reveal phenotypes throughout disease progression.\n\nResultsGlobal metabolomic profiles in synovial fluid were distinct between healthy, early OA, and late OA donors. Pathways differentially activated among these groups included structural deterioration, glycerophospholipid metabolism, inflammation, central energy metabolism, oxidative stress, and vitamin metabolism. Within disease states (early and late OA), subgroups of donors revealed distinct phenotypes. Phenotypes of OA exhibited increased inflammation (early and late OA), oxidative stress (late OA), or structural deterioration (early and late OA) in the synovial fluid.\n\nConclusionThese results revealed distinct metabolic phenotypes of OA in human synovial fluid, provide insight into pathogenesis, represent novel biomarkers and assist in developing personalized interventions for subgroups of OA patients.

pathology↗