Dataset Information

Molecular insights into an ancient form of Paget disease of bone

ABSTRACT: Paget disease of bone (PDB) is a chronic skeletal disorder with contemporary cases characterised by one or a few affected bones in individuals over 55 years of age. PDB-like changes have been noted in archaeological remains as old as Roman although accurate diagnoses and knowledge of the natural history of ancient forms of the disease are lacking. Previous macroscopic and radiographic analyses of six skeletons from a collection of 130 excavated at Norton Priory in Cheshire, UK, and dating to late Medieval times, noted unusually extensive pathological changes resembling PDB affecting up to 75% of individual skeletons. Here we report the prevalence of the disease in the collection is also remarkably high (at least 15.8% of the adult sample) with age-at-death estimations as low as 35 years. Despite these profound phenotypic differences paleoproteomic analyses identified SQSTM1/p62 (p62), a protein central to the pathological milieu of classical PDB, as one of the few non-collagenous human sequences preserved in skeletal samples, indicating that the disorder was likely an ancient precursor of contemporary PDB. Western blotting indicated abnormal migration of ancient p62 protein, with subsequent targeted proteomic analyses detecting more than 60% of the p62 primary sequence and directing sequencing analyses of ancient DNA that excluded contemporary PDB-associated SQSTM1 mutations. Together our observations indicate the ancient p62 protein is likely modified within its C-terminal ubiquitin-associated (UBA) domain. Ancient miRNAs were also remarkably well preserved in an osteosarcoma from a skeleton with extensive disease, with miR-16 expression changes consistent with that reported in contemporary PDB-associated bone tumours. Our work demonstrates the potential of proteomics to inform diagnoses of ancient disease and supports the proposal that Medieval Norton Priory was a ‘hotspot’ for an ancient form of PDB, with unusual features presumably potentiated by as yet unidentified environmental or genetic factors.

OTHER RELATED OMICS DATASETS IN: GSE118540

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Bone Tissue, Bone

DISEASE(S): Bone Osteosarcoma

SUBMITTER: Roman Fischer

LAB HEAD: Roman Fischer

PROVIDER: PXD011743 | Pride | 2019-04-09

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	FL0389_MSQ885_RobLayfield_071216_p62.mgf	Mgf
	FL0389_MSQ885_RobLayfield_071216_p62.pride.mgf.gz	Mgf
	FL0389_MSQ885_RobLayfield_071216_p62.raw	Raw
	peptides_1_1_0.mzid.gz	Mzid
	peptides_1_1_0.pride.mztab.gz	Mztab

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Publications

Molecular insights into an ancient form of Paget's disease of bone.

Shaw Barry B Burrell Carla L CL Green Darrell D Navarro-Martinez Ana A Scott Daniel D Daroszewska Anna A van 't Hof Rob R Smith Lynn L Hargrave Frank F Mistry Sharad S Bottrill Andrew A Kessler Benedikt M BM Fischer Roman R Singh Archana A Dalmay Tamas T Fraser William D WD Henneberger Kirstin K King Turi T Gonzalez Silvia S Layfield Robert R

Proceedings of the National Academy of Sciences of the United States of America 20190429 21

Paget's disease of bone (PDB) is a chronic skeletal disorder that can affect one or several bones in individuals older than 55 y of age. PDB-like changes have been reported in archaeological remains as old as Roman, although accurate diagnosis and natural history of the disease is lacking. Six skeletons from a collection of 130 excavated at Norton Priory in the North West of England, which dates to medieval times, show atypical and extensive pathological changes resembling contemporary PDB affec ...[more]

PMID: 31036632

Similar Datasets

Project description:Paget’s disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over the age of 60. PDB is inherited as an autosomal dominant trait with genetic heterogeneity. SQSTM1/p62 UBA domain mutation (p62P392L) is widely identified in PDB and has been shown to increase osteoclastogenesis. Further, environmental factors such as paramyxovirus are implicated in PDB and MVNP has been shown to induce Pagetic phenotype in osteoclasts. However, the molecular mechanisms underlying p62P392L and MVNP stimulation of osteoclast differentiation in PDB are unclear. We therefore determined MVNP regulated gene expression profiling during osteoclast differentiation. We identified 8.4% of genes were upregulated (> 4-fold) in MVNP transduced cells. MVNP increased integrin β3 (63 fold), NFAT activating protein (6.5 fold), OSCAR (5.5 fold), TRAF5 (8.5 fold) mRNA expression compared to empty vector (EV) transduced cells. MVNP also elevated gene expression of cytokines/growth factors such as IL-17 (18 fold), IL-1F7 (10 fold), IL-17R (4.5 fold) and IL-11 (7 fold). Interestingly, MVNP transduced cells demonstrated high level expression of signal regulatory protein beta 1 (SIRPβ1) (353 fold). SIRPβ1 has been shown to interact with DAP 12, an ITAM containing adaptor protein which plays an important role in osteoclast differentiation. Real-time PCR analysis of total RNA isolated from normal human peripheral blood monocytes transduced with MVNP confirmed upregulation of SIRPβ1 mRNA expression in the absence of RANKL stimulation. In contrast, RANKL stimulation did not alter SIRPβ1 expression in these cells. Furthermore, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPβ1 mRNA expression compared to normal subjects. Thus, MVNP regulated gene expression profiling during osteoclast differentiation provides new insights into molecular mechanisms and therapeutic targets to control elevated osteoclast activity in PDB. Total RNA isolated from normal human bone marrow mononuclear cells transduced with EV, MVNP retroviral expression vectors and stimulated with M-CSF and RANKL for 48 h were subjected to Agilent microarray (~26,000 genes) analysis. One replicate per treatment was hybridized.

Project description:How does environmental change drive phenotypic evolution? We addressed this question using Daphnia genotypes separated by ~1600-years of evolution in a Minnesota lake using methods in resurrection ecology (i.e., reviving dormant eggs from sediments) and found substantial genetic and physiological differentiation. These shifts are highly correlated with anthropogenic environmental change, specifically phosphorus (P)-driven eutrophication. Here, we explore transcriptomic changes that may underlie the observed shifts in P use physiology (see poster by Fricsh et al for a detailed explanation). We compared the transcriptomes of two ancient and two contemporary genotypes in ancient (i.e., low P; LP) and contemporary (i.e., high P; HP) conditions using an 11000-gene microarray. Ancient and contemporary genotypes differed in the number of differentially expressed genes in the HP (mean ± SD; 645 ± 112.95) and LP (1071 ± 211.63) treatments. These results indicate considerable transcriptomic variation between ancient and contemporary genotypes in both dietary treatments, with stressful (LP) conditions invoking differential expression of more genes (t= -2.51; P= 0.04). Moreover, ancient and contemporary genotypes exhibited markedly different transcriptomic responses to dietary treatments. Contemporary genotypes upregulated 84.5 ± 28.99 while ancient genotypes upregulated 413.5 ± 26.16 genes (t= 164.5; P= 0.003). Similarly, ancient (127.5 ± 101.1) and contemporary (316 ± 98.99) genotypes differed significantly in the number of genes downregulated between the HP and LP treatments (t= 125.66; P= 0.005). These results indicate substantial regulatory shifts may underlie the striking physiological differences observed. Further analyses of gene families that were differentially expressed (DE) between ancient and contemporary genotypes revealed several gene families already known to be important in mitigating stoichiometric imbalances driven by P availability. Agglomerative hierarchical cluster analyses of DE loci between ancient and contemporary genotypes indicating age-based clustering will be presented. Together, our theoretical framework based on elemental supply, and unique model system enabled a millennial-scale exploration of the environmental contribution to phenotypic evolution.

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