Biology subjects

Reppe, S.

Publications and source records attributed to Reppe, S..

4 recordsLinked to original sources

bioRxiv2025

Endogenous retrotransposon reverse transcriptase supports osteocyte function: implications for antiretroviral therapy-associated bone loss

Retrotansposable elements such as LINE-1 and HERV-K encode endogenous reverse transcriptases (RTs) with emerging roles in human biology. People living with HIV, particularly those receiving nucleoside reverse transcriptase inhibitor (NRTI)-based therapy, have increased risk of low bone mineral density (BMD), but the underlying mechanisms remain unclear. Here we show that endogenous RT activity, estimated by L1-Ta and HERV-K DNA content, is enriched in human bone and markedly reduced in osteoporosis, where it correlates with BMD and osteocyte gene expression. In vitro, nucleoside reverse transcriptase inhibitors (NRTIs), widely used as antiretroviral drugs, impair osteocyte endocrine function, disrupting vitamin D3-induced FGF23 production and parathyroid hormone- mediated regulation of SOST. These findings identify endogenous RT activity as a regulator of osteocyte function and bone homeostasis, and suggest that its pharmacological inhibition may contribute to antiretroviral therapy-associated bone loss.

molecular biology↗

bioRxiv2023

Transcriptomic network analysis of brain and bone reveals shared molecular mechanisms underlyingAlzheimer's Disease and related dementias and Osteoporosis

Alzheimers disease and related dementias (ADRD) and Osteoporosis (OP) are two prevalent diseases of aging with numerous epidemiological associations, but the underlying molecular mechanisms contributing to this association are unknown. We used WGCNA (weighted gene co-expression network analysis) to develop transcriptomic networks in bone and brain tissue using two different studies to discover common molecular mechanisms. We used RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Memory and Aging Project), including a subset of 298 meeting criteria for inclusion in five ADRD categories and the full set in a secondary analysis, and RNA array data from transiliac bone in 84 participants from the Oslo study of postmenopausal women. After developing each network, we analyzed associations between modules (groups of co-expressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms. We discovered three modules in ROSMAP that showed significant associations with ADRD and bone related traits and four modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the two networks, most notably among those modules linked to canonical Wnt signaling and skeletal tissue homeostasis and development. These results were preserved with a network from the full ROSMAP cohort (n=629), which included a broader spectrum of participants. Our results require validation in experimental studies but show support for Wnt signaling as an important driver of pathology in OP and ADRD. We additionally show a strong link between Dementia with Lewy bodies and bone outcomes. These results have translational significance in the development of novel treatments and biomarkers for both ADRD and OP.

neuroscience↗

bioRxiv2023

MskAge - An Epigenetic Biomarker of Musculoskeletal Age Derived from a Genetic Algorithm Islands Model

BackgroundAge is a significant risk factor for functional decline and disease of the musculoskeletal system, yet few biomarkers exist to facilitate ageing research in musculoskeletal tissues. Multivariate models based on DNA methylation, termed epigenetic clocks, have shown promise as markers of biological age. However, the accuracy of existing epigenetic clocks in musculoskeletal tissues are no more, and often less accurate than a randomly sampled baseline model. ResultsWe developed a highly accurate epigenetic clock, Msk-Age, that is specific to tissues and cells of the musculoskeletal system. MskAge was built using a penalised genetic algorithm islands model that addresses multi-tissue clock bias. The final model was trained on the transformed principal components of CpGs selected by the genetic algorithm, which are significantly enriched for pathways terms related to the skeletal system and mesenchyme development. We show that MskAge tracks epigenetic ageing ex vivo and in vitro. Epigenetic age estimates are rejuvenated to zero with cellular reprogramming and are accelerated at a rate of 0.45 years per population doubling. Remarkably, MskAge explains more variance associated with in vitro ageing of fibroblasts than the purpose-developed skin and blood clock. ConclusionThe precision of MskAge and its ability to capture perturbations in biological ageing make it a promising research tool for musculoskeletal and ageing biologists.

cell biology↗

bioRxiv2018

Genome-wide mapping identifies beta-1,4-N-acetyl-galactosaminyl-transferase as a novel determinant of sclerostin levels and bone mineral density

In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two sample Mendelian Randomisation (MR). A genetic instrument for circulating sclerostin, derived from a genome wide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n= 32,744) in GEFOS, and estimated BMD by heel ultrasound (eBMD; n=426,824), and fracture risk (n=426,795), in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD)) change in sclerostin per A allele ({beta}=0.20, P=4.6x10-49), and GALNT1 ({beta}=0.11 per G allele, P=4.4x10-11). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two SNPs as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD ({beta}= -0.12, 95%CI= -0.20 to -0.05) and eBMD ({beta}= -0.12, 95%CI= -0.14 to -0.10), and a positive relationship with fracture risk ({beta}= 0.11, 95%CI= 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis.

genetics↗