Biology subjects

Lotz, M.

Publications and source records attributed to Lotz, M..

4 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

Synovial transcriptional clusters link cartilage degeneration to cell-type-specific gene expression in knee osteoarthritis

ObjectivesTo identify synovial transcriptional clusters in human knee osteoarthritis (OA) and determine how these relate to synovial histologic features, cell-type-associated gene expression, and cartilage degeneration severity. MethodsBulk RNA sequencing (RNA-seq) of synovial tissue from n = 135 patients with knee OA was analyzed using consensus clustering. Clusters were compared by clinical and histologic features, including cartilage degeneration severity (OARSI score). Single-cell RNA-seq (n = 18) and spatial transcriptomics were used to relate cartilage degeneration-associated gene expression patterns to synovial cell populations. ResultsFour synovial transcriptional clusters that differed in synovial histologic features and cartilage degeneration severity were identified. Greater cartilage degeneration was associated with enrichment of lining fibroblast- and inflammatory myeloid-associated gene expression, whereas lesser cartilage degeneration was associated with enrichment of sublining fibroblast, endothelial, mural cell, and adipocyte-associated gene expression. ConclusionsHuman knee OA synovium segregates into transcriptional clusters associated with cartilage degeneration severity. Synovial transcriptional heterogeneity corresponds to cell-type-associated gene expression. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIOsteoarthritis synovium exhibits marked histologic and molecular heterogeneity. C_LIO_LISynovial inflammation detected by MRI correlates with cartilage degeneration and predicts progressive cartilage loss in knee OA. C_LIO_LIPrior transcriptomic studies have identified molecular subsets of OA synovium, but their relationship to cartilage degeneration severity remains unclear. C_LI What this study addsO_LIOA synovium segregates into four transcriptional clusters: Sublining (C1), Lymphomyeloid (C2), Myeloid (C3), and Major trauma (C4). C_LIO_LIGreater cartilage degeneration is associated with enrichment of inflammatory myeloid and lining fibroblast gene expression, whereas lesser degeneration is associated with enrichment of adipocyte, sublining fibroblast, endothelial, and mural cell-associated gene expression. C_LI How this study might affect research, practice or policyO_LIProvides a framework for a clinically relevant biological stratification of OA patients based on synovial molecular features. C_LIO_LIInforms future efforts to link synovial biology with OA prognosis, cartilage degeneration, treatment allocation, and development of targeted therapeutic strategies. C_LI

genomics↗

bioRxiv2019

Biological sex and age shape melanoma tumour evolution

Many cancer types display sex and age disparity in incidence and outcome. Here, we establish a mathematical approach using cancer mutational data to analyze how sex and age shape the tumour genome. We model how age-related (clock-like) somatic mutations that arise during cell division, and extrinsic (environmental) mutations accumulate in cancer genomes. As a proof-of-concept, we apply our approach to melanoma, a cancer driven by cell-intrinsic age-related mutations and extrinsic ultraviolet light-induced mutations, and show these mutation types differ in magnitude, chronology and by sex in the distinct molecular melanoma subtypes.\n\nOur model confirms age and sex are determinants of cellular mutation rate, shaping the final mutation composition. We show mathematically for the first time how, similar to non-cancer tissues, melanoma genomes reflect a decline in cell division during ageing. We find clock-like mutations strongly correlate with the acquisition of ultraviolet light-induced mutations, but critically, males present a higher number and rate of cell division-linked mutations. These data indicate the contribution of environmental damage to melanoma likely extends beyond genetic damage to affect cell division.

cancer biology↗

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↗