Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease

Youlten, Scott E.; Kemp, John P.; Logan, John G.; Ghirardello, Elena J.; Sergio, C. Marcelo; Dack, Michael R.G.; Guilfoyle, Siobhan E.; Leitch, Victoria; Butterfield, Natalie C.; Komla-Ebri, Davide; Chai, Ryan C.; Corr, Alexander; Smith, James; Mohanty, Sindhu T.; Morris, John; McDonald, Michelle M.; Quinn, Julian M.W.; McGlade, Amelia; Bartoniček, Nenad; Jansson, Matt; Hatzikotoulas, Konstantinos; Irving, Melita; Beleza-Meireles, Ana; Rivadeneira, Fernando; Duncan, Emma L.; Richards, J. Brent; Adams, David J.; Lelliott, Christopher J.; Brink, Robert; Phan, Tri Giang; Eisman, John A.; Evans, David M.; Zeggini, Eleftheria; Baldock, Paul A.; Bassett, J. H. Duncan; Williams, Graham R.; Croucher, Peter I.

doi:10.1038/s41467-021-22517-1

Cited by 74 publications

(89 citation statements)

References 122 publications

(103 reference statements)

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“…The osteocyte network in bone bears similarity to the network of intercellular connections between neurons 9 . In addition, osteocytes have been reported to express certain neuronal transcripts; 28 , 29 however, the molecular mechanisms used by osteocytes to acquire this gene expression program are unknown. RNA-seq in Sp7-deficient and overexpressing Ocy454 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

et al. 2021

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Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during “osteocytogenesis” is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates defects in osteocyte maturation in the absence of Sp7. Sp7-dependent osteocyte gene networks are associated with human skeletal diseases. Moreover, humans with a SP7R316C mutation show defective osteocyte morphology. Sp7-dependent genes that mark osteocytes are enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. These findings reveal a role for Sp7 and its target gene Osteocrin in osteocytogenesis, revealing that pathways that control osteocyte development influence human bone diseases.

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Section: Resultsmentioning

confidence: 99%

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

et al. 2021

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“…Despite some limitations, this model allowed for novel achievements in the specification of the non-canonical FasL signalling related to osteogenesis. Recently, more evidence has accumulated for the role of osteocytes in bone signalling [ 36 ], and their transcriptome signature is being deciphered [ 57 ] to understand the role of these cells in skeletal homeostasis and disease. Simultaneously, 3D culture systems (including IDG-SW3 cells) are being developed to examine particular points in vitro, which would overcome certain difficulties with the isolation, culturing, and differentiation of osteocytes [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of FasL Stimulation on Sclerostin Expression and Osteogenic Profile in IDG-SW3 Osteocytes

Kratochvílová

Ramesova

Veselá

et al. 2021

Biology

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The Fas ligand (FasL) is known from programmed cell death, the immune system, and recently also from bone homeostasis. As such, Fas signalling is a potential target of anti-osteoporotic treatment based on the induction of osteoclastic cell death. Less attention has been paid to osteocytes, although they represent the majority of cells within the mature bone and are the key regulators. To determine the impact of FasL stimulation on osteocytes, differentiated IDG-SW3 cells were challenged by FasL, and their osteogenic expression profiles were evaluated by a pre-designed PCR array. Notably, the most downregulated gene was the one for sclerostin, which is the major marker of osteocytes and a negative regulator of bone formation. FasL stimulation also led to significant changes (over 10-fold) in the expression of other osteogenic markers: Gdf10, Gli1, Ihh, Mmp10, and Phex. To determine whether these alterations involved caspase-dependent or caspase-independent mechanisms, the IDG-SW3 cells were stimulated by FasL with and without a caspase inhibitor: Q-VD-OPh. The alterations were also detected in the samples treated by FasL along with Q-VD-OPh, pointing to the caspase-independent impact of FasL stimulation. These results contribute to an understanding of the recently emerging pleiotropic effects of Fas/FasL signalling and specify its functions in bone cells.

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“…Studies utilizing same methodologies, but integrating gene expression data obtained from blood-derived cells showed vastly different results, highlighting the need for tissue specificity (68). Recently, Youlten et al integrated a strategy wherein matched intra-sample controls were used to distinguish genes enriched for osteocyte expression compared to other tissues (138). Whilst this approach controls for possible tissue contamination, it may be monetarily prohibitive since it warrants repeat analyses of the samples.…”

Section: Transcriptomicsmentioning

confidence: 99%

“…Recently, Youlten et al. integrated a strategy wherein matched intra-sample controls were used to distinguish genes enriched for osteocyte expression compared to other tissues ( 138 ). Whilst this approach controls for possible tissue contamination, it may be monetarily prohibitive since it warrants repeat analyses of the samples.…”

Section: Overview Of -Omics Technologies For Skeletal Diseases: Transcriptomics Epigenomics Proteomics and Metabolomicsmentioning

confidence: 99%

Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques

Rauner¹,

Foessl

Formosa

et al. 2021

Front. Endocrinol.

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The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits (“endophenotypes”), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets.

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Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease

Cited by 74 publications

References 122 publications

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

Impact of FasL Stimulation on Sclerostin Expression and Osteogenic Profile in IDG-SW3 Osteocytes

Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques

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