Biology subjects

Geurts, J.

Publications and source records attributed to Geurts, J..

4 recordsLinked to original sources

bioRxiv2026

Subchondral bone remodeling in knee osteoarthritis is coupled to lipid mobilization from bone marrow adipocytes

Objective Pathological bone formation requires energy derived from metabolic substrates including glucose, amino acids, and fatty acids. As bone marrow adipose tissue (BMAT) is a rich local source of fatty acids and is progressively depleted in osteoarthritic subchondral bone, we investigated whether lipolytic lipid mobilization is associated with osteogenic activity in sclerotic regions and whether this process is pharmacologically modifiable. Design Human knee osteoarthritis subchondral bone samples (n = 23) were analyzed using transcriptomic, histological, and ex vivo explant approaches. Associations between lipolytic and bone formation markers were assessed, with particular focus on PNPLA2, encoding adipose triglyceride lipase (ATGL), and alkaline phosphatase (ALP). Immunohistochemistry was used to localize lipolytic activation in relation to sclerotic bone regions. Ex vivo explants were used to assess adipocyte morphology, secretion of lipolysis products, including free fatty acids (FFA) and glycerol, and bone formation markers including ALP and P1NP. Pharmacological modulation of lipolysis was performed using forskolin to stimulate and metformin to inhibit lipid mobilization. Results Transcriptomic analysis revealed a strong association between ALPL expression and PNPLA2, suggesting a link between bone formation and lipolytic activity. Histological analysis confirmed local activation of ATGL in sclerotic subchondral bone regions. In explant cultures, reduced adipocyte size was accompanied by increased release of free fatty acids and glycerol, together with elevated ALP and P1NP levels. FFA secretion strongly correlated with ALP, supporting a relationship between BMAT lipid mobilization and osteogenic activity. PLIN1, a marker of lipid droplet integrity, was downregulated in isolated BMAT adipocytes but upregulated in paired stromal-vascular cells, suggesting transfer or utilization of BMAT-derived lipids by neighboring bone-forming cells. Pharmacological modulation confirmed that BMAT lipolysis is dynamically regulated: forskolin enhanced free fatty acid release, whereas metformin reduced it. However, short-term modulation did not significantly alter bone formation indices. Conclusion These findings identify BMAT lipolysis as a metabolic feature of subchondral bone sclerosis in knee OA. Mobilization of lipids from marrow adipocytes may provide energetic substrates that support osteoblast activity and pathological bone formation. BMAT lipolysis therefore represents a potentially modifiable metabolic pathway within the OA subchondral bone niche.

physiology↗

bioRxiv2026

Modeling cis-regulatory variation in human brain enhancers across a large Parkinson's Disease cohort

Genome-wide association studies (GWAS) have linked more than a hundred non-coding genomic loci to Parkinsons disease (PD) risk. Deciphering their functional impact on gene regulation requires cell type-aware modeling approaches to assess the effects of sequence variation on enhancer function and target gene expression. To address this challenge, we generated a comprehensive matched dataset from 190 human donors (115 controls and 75 PD), comprising long-read whole-genome sequencing alongside single nucleus multiome atlases (snATAC-seq and snRNA-seq for 3.1 and 1.1 million nuclei respectively) of the anterior cingulate cortex and substantia nigra. By integrating chromatin accessibility quantitative trait loci (caQTL), DNA methylation QTL (meQTL), and allele-specific chromatin accessibility (ASCA), we identified 53,841 high-confidence cis-acting genetic variants that modulate cell type-specific enhancer accessibility in one or both brain regions. We further demonstrate that sequence-to-function models can accurately predict the impact of these variants directly from the genomic sequence. Novel explainability approaches allowed stratifying these variants according to their regulatory function, with the majority disrupting specific transcription factor binding sites in a cell type specific manner. Integrating these "enhancer variants" (EV) with eQTL mapping and gene locus modeling linked a subset of EVs to their target genes. Finally, we applied these models to prioritize regulatory variants at known PD GWAS loci, bypassing statistical limitations in rare disease-relevant populations like dopaminergic neurons. All together, we establish a unique resource and new sequence modeling strategies to interpret functional non-coding variation in the human brain.

genomics↗

bioRxiv2024

Subchondral bone marrow adipose tissue lipolysis regulates bone formation in hand osteoarthritis

ObjectiveBone marrow adipose tissue (BMAT) is emerging as an important regulator of bone formation and energy metabolism. Lipolysis of BMAT releases glycerol and fatty acid substrates that are catabolized by osteoblasts. Here, we investigated whether BMAT lipolysis is involved in subchondral bone formation in hand osteoarthritis (OA). MethodsSubchondral BMAT lipolysis and bone marrow adipocyte (BMAd) morphology were studied in clinical specimens of carpo-metacarpal (CMC1) ans distal interphalangeal joint (DIP) OA. BMAd size, osteoblast numbers and expression of lipolysis enzymes (ATGL, phospho-HSL, MGLL) were compared between regions of low and high bone formation. Free fatty acids, glycerol and bone biomarkers were measured in osteochondral explants. ResultsSubchondral BMAd size was positively correlated with BMI and reduced in regions of high bone formation. Osteoblast numbers were negatively correlated with BMAd size. ATGL, phoshpo-HSL and MGLL were expressed in both in BMAds and activated osteoblasts and increased in regions of high bone formation. Secreted glycerol levels, but not free fatty acids, were correlated with bone formation markers pro-collagen type I and alkaline phosphatase. ConclusionOur findings reveal a previously unrecognized role of BMAT lipolysis in regulating bone formation in hand OA, which may be modulated by BMI.

pathology↗

bioRxiv2017

Progression of regional grey matter atrophy in multiple sclerosis

Grey matter atrophy is present from the earliest clinical stages of multiple sclerosis (MS), but the temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in MS, and its association with disability accumulation.\n\nIn this longitudinal study, we included 1,417 subjects: 253 with clinically-isolated syndrome (CIS), 708 relapsing-remitting MS (RRMS), 128 secondary-progressive MS (SPMS), 125 primary-progressive MS (PPMS), and 203 healthy controls from 7 European centres. Subjects underwent repeated MRI scanning (total number of scans 3,604); the mean follow-up for patients was 2.41yrs (SD{+/-}1.97). Disability was scored using the Expanded Disability Status Scale (EDSS). We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template. We used an established data-driven event-based model (EBM) to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific EBM stage, based on the number of their atrophic regions. We used nested linear mixed-effects regression models to explore the associations between the rate of increase in the EBM stages over time, disease duration and annual rate of EDSS gain.\n\nThe first regions to become atrophic in CIS and relapse-onset MS patients (RRMS and SPMS) were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. The sequence of atrophy in PPMS showed a similar involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse-onset MS and late atrophy in PPMS. Patients with SPMS showed the highest EBM stages (highest number of atrophic regions, all p<0.001) at study entry. Rates of increase in EBM stages were significantly different from healthy controls in all MS phenotypes, except for CIS. The increase in the number of atrophic regions (EBM stage) was associated with disease duration in all patients. EBM stage was associated with disability accumulation in RRMS independent of disease duration (p<0.0001).\n\nThis data-driven staging of atrophy progression in a large MS sample demonstrates that grey matter atrophy spreads to involve more regions over time. The sequence in which regions become atrophic is reasonably consistent across MS phenotypes. The spread of atrophy was associated with disease duration, and disability accumulation in RRMS.\n\nAbbreviations

neuroscience↗