Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease DOI Creative Commons
Ryan C. Chai, Mischa Lundberg, Bernard Freudenthal

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

Abstract Musculoskeletal diseases are a major global health burden. Development of new bone-active therapies is hindered by limited understanding the complex interactions between cells and genes that regulate skeleton. To unravel this complexity, we systematically annotated all in bone defined control their function at single-cell resolution. Integration with data from human gene-mapping studies rare skeletal disorders common disease traits identified novel genes, which validated functional analysis more than one thousand genetic mouse models. This multiscale approach expands repertoire to include endothelial vascular smooth muscle cells. also revealed hundreds disease-associated landscape as potential drug targets. The cellular mechanisms overcomes knowledge gaps helps accelerate development next generation treat diseases.

Language: Английский

Single-cell Transcriptomic Analysis Identifies Senescent Osteocytes that Trigger Bone Destruction in Breast Cancer Metastasis DOI
Japneet Kaur, Manish Adhikari, Hayley M. Sabol

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(23), P. 3936 - 3952

Published: Sept. 23, 2024

Breast cancer bone metastases increase fracture risk and are a major cause of morbidity mortality among women. Upon colonization by tumor cells, the microenvironment undergoes profound reprogramming to support progression, which disrupts balance between osteoclasts osteoblasts leads lesions. A deeper understanding processes mediating this could help develop interventions for treating patients with metastases. Here, we demonstrated that osteocytes (Ot) in established breast metastasis premature senescence distinctive senescence-associated secretory phenotype (SASP) favors destruction. Single-cell RNA sequencing identified Ots from mice enriched senescence, SASP markers, pro-osteoclastogenic genes. Multiplex situ hybridization artificial intelligence-assisted analysis depicted satellite distension, telomere dysfunction, p16Ink4a expression metastasis. cells promoted Ot enhanced their osteoclastogenic potential vitro ex vivo organ cultures. Clearance senescent senolytics suppressed resorption preserved mass These results demonstrate undergo pathological identify as an initiating event triggering lytic disease Significance: remodel promoting cellular osteocytes, can be targeted alleviate loss induced metastatic cancer. See related commentary Frieling Lynch, p. 3917.

Language: Английский

Citations

4
Fibrocartilage repair involves chronic cellular senescence in a rat model of bone marrow stimulation DOI Creative Commons

Luke Childress,

Landon B. Gatrell,

Hong Wu

et al.

Osteoarthritis and Cartilage Open, Journal Year: 2025, Volume and Issue: unknown, P. 100620 - 100620

Published: April 1, 2025

Language: Английский

Citations

0
Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect DOI Creative Commons
Bilal Mohamad El-Masri, Christina Møller Andreasen,

Kaja Søndergaard Laursen

et al.

Bone Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Oct. 18, 2024

Abstract Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases mass, and reduces fracture risk. discontinuation causes an extensive wave of rebound but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as direct approach to identify cells activate osteoclastogenesis through RANKL/OPG pathway. ISH was performed across species, skeletal sites, following recombinant OPG (OPG:Fc) parathyroid hormone 1–34 (PTH) treatment mice. OPG:Fc mice induced increased expression RANKL mRNA mainly trabecular, not endocortical surface cells. Additionally, decreased detected osteocytes both compartments. A similar more pronounced effect on seen one hour after PTH treatment. These findings suggest conjointly regulate activation osteoclastogenesis, induces local accumulation osteoclastogenic ready recruit osteoclasts upon discontinuation. Analysis publicly available single-cell RNA sequencing (scRNAseq) data from murine marrow stromal revealed Tnfsf11 + expressed high levels Mmp13 , Limch1 Wif1 confirming their osteoprogenitor status. confirmed co-expression vehicle- OPG:Fc-treated Under physiological conditions human/mouse bone, by osteoprogenitors proximate osteoclasts, while bone-forming osteoblasts.

Language: Английский

Citations

3
The Myofibroblast Fate of Therapeutic Mesenchymal Stromal Cells: Regeneration, Repair, or Despair? DOI Open Access
Fereshteh S. Younesi, Boris Hinz

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8712 - 8712

Published: Aug. 9, 2024

Mesenchymal stromal cells (MSCs) can be isolated from various tissues of healthy or patient donors to retransplanted in cell therapies. Because the number MSCs obtained biopsies is typically too low for direct clinical application, MSC expansion culture required. However, ex vivo amplification often reduces desired regenerative potential and enhances undesired traits, such as activation into fibrogenic myofibroblasts. Transiently activated myofibroblasts restore tissue integrity after organ injury by producing contracting extracellular matrix scar tissue. In contrast, persistent cause excessive scarring-called fibrosis-that destroys function. this review, we focus on relevance molecular mechanisms myofibroblast upon contact with stiff plastic recipient tissue, hypertrophic scars large skin burns. We discuss mechanoperception integrins stretch-activated channels, mechanotransduction through contractile actin cytoskeleton, conversion mechanical signals transcriptional programs via mechanosensitive co-transcription factors, YAP, TAZ, MRTF. further elaborate how prolonged stress create memory nucleus that evoke lasting epigenetic modifications at DNA level, histone methylation acetylation. conclude projecting mechanics modulated generate MSCs, which epigenetically protected against transport regeneration environment

Language: Английский

Citations

2
An integrated single-cell atlas of the limb skeleton from development through adulthood DOI Creative Commons
Tim Herpelinck, Liesbeth Ory, Tom Verbraeken

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: March 15, 2022

Abstract The recent growth of single-cell transcriptomics has turned RNA sequencing (scRNA-seq) into a near-routine experiment. Breakthroughs in improving scalability have led to the creation organism-wide transcriptomic datasets, aiming comprehensively profile cell types and states within an organism throughout its lifecycle. To date, however, skeleton remains majorly underrepresented organ system atlases. Considering how not only serves as central framework vertebrate body but is also home hematopoietic niche player major metabolic homeostatic processes, this presents deficit current reference atlas projects. address issue, we integrated ten separate scRNA-seq datasets containing limb skeletal cells their developmental precursors, generating 133 332 cells. This describes across mesenchymal lineage from induction adult bone encompasses 39 different states. Furthermore, expanding repertoire available time points single dataset allowed for more complete analyses cell-cell communication or silico perturbation studies. Taken together, present missing piece mapping efforts, which will be value researchers fields biology, hematopoiesis, metabolism regenerative medicine.

Language: Английский

Citations

10
Single-cell Transcriptome Analysis Identifies Senescent Osteocytes as Contributors to Bone Destruction in Breast Cancer Metastasis DOI Creative Commons
Jesús Delgado‐Calle, Manish Adhikari, Japneet Kaur

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: March 14, 2024

Breast cancer bone metastases increase fracture risk and are a major cause of morbidity mortality among women. Upon colonization by tumor cells, the microenvironment undergoes profound reprogramming to support progression that disrupts balance between osteoclasts osteoblasts, leading lesions. Whether such affects matrix-embedded osteocytes remains poorly understood. Here, we demonstrate in breast metastasis develop premature senescence distinctive senescence-associated secretory phenotype (SASP) favors destruction. Single-cell RNA sequencing identified from mice with enriched SASP markers pro-osteoclastogenic genes. Using multiplex

Language: Английский

Citations

1
CRISPR activation of Tfeb, a master regulator of autophagy and lysosomal biogenesis, in osteoblast lineage cells increases bone mass and strength DOI
A. Gordon James, James A. Hendrixson, Ilham Kadhim

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 26, 2024

Autophagy is a recycling pathway in which damaged or dysfunctional proteins, protein aggregates, and organelles are delivered to lysosomes for degradation. Insufficiency of autophagy thought contribute several age-related diseases including osteoporosis. Consistent with this, elimination from the osteoblast lineage reduces bone formation causes low mass. However, whether increasing would benefit health unknown. Here, we increased expression endogenous Transcription Factor EB gene (

Language: Английский

Citations

0
Voluntary exercise in mice triggers an anti-osteogenic and pro-tenogenic response in the ankle joint without affecting long bones DOI Creative Commons

Anne Briolay,

F. Duboeuf,

Séverine Delplace

et al.

Bone Reports, Journal Year: 2024, Volume and Issue: 23, P. 101810 - 101810

Published: Oct. 15, 2024

Language: Английский

Citations

0
Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease DOI Creative Commons
Ryan C. Chai, Mischa Lundberg, Bernard Freudenthal

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

Abstract Musculoskeletal diseases are a major global health burden. Development of new bone-active therapies is hindered by limited understanding the complex interactions between cells and genes that regulate skeleton. To unravel this complexity, we systematically annotated all in bone defined control their function at single-cell resolution. Integration with data from human gene-mapping studies rare skeletal disorders common disease traits identified novel genes, which validated functional analysis more than one thousand genetic mouse models. This multiscale approach expands repertoire to include endothelial vascular smooth muscle cells. also revealed hundreds disease-associated landscape as potential drug targets. The cellular mechanisms overcomes knowledge gaps helps accelerate development next generation treat diseases.

Language: Английский

Citations

0