Publications
123 results found
Loisay L, Ebri DK, Kaci N, et al., 2022, Fgfr3 gain-of-function mutation impacts bone homeostasis in hypochondroplasia mouse model., Annual Meeting of the American-Society-for-Bone-and-Mineral-Research (ASBMR), Publisher: WILEY, Pages: 29-30, ISSN: 0884-0431
Loisay L, Ebri DK, Kaci N, et al., 2022, Fgfr3 gain-of-function mutation impacts bone homeostasis in hypochondroplasia mouse model., Annual Meeting of the American-Society-for-Bone-and-Mineral-Research (ASBMR), Publisher: WILEY, Pages: 250-250, ISSN: 0884-0431
Lademann F, Mayerl S, Tsourdi E, et al., 2022, The Thyroid Hormone Transporter MCT10 Is a Novel Regulator of Trabecular Bone Mass and Bone Turnover in Male Mice, ENDOCRINOLOGY, Vol: 163, ISSN: 0013-7227
Foessl I, Bassett JHD, Bjornerem A, et al., 2021, Bone phenotyping approaches in human, mice and zebrafish - expert overview of the EU cost action GEMSTONE ("GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork"), Frontiers in Endocrinology, Vol: 12, Pages: 1-32, ISSN: 1664-2392
A synoptic overview of scientific methods applied in bone and associated research fields across species has yet to be published. Experts from the EU Cost Action GEMSTONE (“GEnomics of MusculoSkeletal Traits translational Network”) Working Group 2 present an overview of the routine techniques as well as clinical and research approaches employed to characterize bone phenotypes in humans and selected animal models (mice and zebrafish) of health and disease. The goal is consolidation of knowledge and a map for future research. This expert paper provides a comprehensive overview of state-of-the-art technologies to investigate bone properties in humans and animals – including their strengths and weaknesses. New research methodologies are outlined and future strategies are discussed to combine phenotypic with rapidly developing –omics data in order to advance musculoskeletal research and move towards “personalised medicine”.
Youlten SE, Kemp JP, Logan JG, et al., 2021, Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease, Nature Communications, Vol: 12, Pages: 1-21, ISSN: 2041-1723
Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
Dennis EP, Brito FMJDS, Pearson RD, et al., 2021, Asporin is important in bone development but not in cartilage homeostasis, Publisher: WILEY, Pages: A8-A9, ISSN: 0959-9673
Formosa MM, Bergen DJM, Gregson CL, et al., 2021, A Roadmap to gene discoveries and novel therapies in monogenic low and high bone mass disorders, Frontiers in Endocrinology, Vol: 12, Pages: 1-24, ISSN: 1664-2392
Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.
Makitie RE, Henning P, Jiu Y, et al., 2021, An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility, JBMR PLUS, Vol: 5
Butterfield NC, Curry KF, Steinberg J, et al., 2021, Accelerating functional gene discovery in osteoarthritis (vol 12, 467, 2021), NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723
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- Citations: 2
McDonald MM, Khoo WH, Ng PY, et al., 2021, Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption., Cell, Vol: 184
McDonald MM, Khoo WH, Ng PY, et al., 2021, Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption, Cell, Vol: 184, Pages: 1330-1347.e13, ISSN: 0092-8674
Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases.
Steinberg J, Southam L, Roumeliotis T, et al., 2021, A molecular quantitative trait locus map for osteoarthritis, Nature Communications, Vol: 12, Pages: 1-11, ISSN: 2041-1723
Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.
Tobias JH, Duncan EL, Kague E, et al., 2021, Opportunities and challenges in functional genomics research in osteoporosis: report from a workshop held by the causes working group of the osteoporosis and bone research academy of the Royal Osteoporosis Society on October 5th 2020, Frontiers in Endocrinology, Vol: 11, Pages: 1-11, ISSN: 1664-2392
The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by “multi-omics” database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the “osteocyte signature”, by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.
Bassett J, Williams GR, 2021, Accelerating functional gene discovery in osteoarthritis, Nature Communications, Vol: 12, Pages: 1-18, ISSN: 2041-1723
Osteoarthritis causes debilitating pain and disability, resulting in a considerablesocioeconomic burden, yet no drugs are available that prevent disease onset or progression.Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormaljoint phenotypes in randomly selected mutant mice generated by the International KnockoutMouse Consortium. We identify 14 genes with functional involvement in osteoarthritispathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidatehuman osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods byidentifying age-related degenerative joint damage in wild-type mice. Finally, we phenotypepreviously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onsetwith public health implications. This expanding resource of mutant mice will acceleratefunctional gene discovery in osteoarthritis and offer drug discovery opportunities for thiscommon, incapacitating chronic disease.
Freudenthal B, Watts L, Bassett JHD, et al., 2021, Thyroid hormone, thyroid medication, and the skeleton, Marcus and Feldman's Osteoporosis (Fifth Edition)
Thyroid hormone is an essential systemic regulator of development and metabolism and has important effects on bone that are mediated principally by thyroid hormone receptor α. In children, hypothyroidism causes growth retardation and delayed bone age, whereas hyperthyroidism accelerates linear growth and advances skeletal maturation. In adults, hyperthyroidism causes high bone turnover osteoporosis and an increased risk of fracture. Overt thyrotoxicosis, subclinical hyperthyroidism, and overtreatment of hypothyroid patients with thyroxine can all result in reduced bone mineral density and an increased susceptibility to fracture. Thyroid hormones are thus essential for normal skeletal development and the normal maintenance of adult bone. When treating patients with thyroid disorders, it is important to consider the potential for detrimental consequences to the skeleton.
Swan AL, Schuett C, Rozman J, et al., 2020, Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density, PLoS Genetics, Vol: 16, Pages: 1-27, ISSN: 1553-7390
The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.
Manousaki D, Forgetta V, Keller-Baruch J, et al., 2020, A Polygenic Risk Score as a Risk Factor for Medication-Associated Fractures, JOURNAL OF BONE AND MINERAL RESEARCH, Vol: 35, Pages: 1935-1941, ISSN: 0884-0431
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- Citations: 3
Pereira M, Ko J-H, Logan J, et al., 2020, A trans-eQTL network regulates osteoclast multinucleation and bone mass, eLife, Vol: 9, ISSN: 2050-084X
Functional characterisation of cell-type-specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans-regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (Pik3cb-/-, Atp8b2+/-, Igsf8-/-, Eml1-/-, Appl2-/-, Deptor-/-) and myeloid-specific Slc40a1 knockout mice displayed abnormal bone phenotypes. We report opposing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast multinucleation and bone mass.
Freudenthal B, Makitie R, Logan J, et al., 2020, A mouse model of juvenile onset X-linked osteoporosis, Bone Research Society BRS Online Rare Bone Disease 2020
Joustra SD, Roelfsema F, van Trotsenburg ASP, et al., 2020, IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 105, Pages: E70-E84, ISSN: 0021-972X
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- Citations: 12
Leitch VD, Bassett JHD, Williams GR, 2020, Role of thyroid hormones in craniofacial development, NATURE REVIEWS ENDOCRINOLOGY, Vol: 16, Pages: 147-164, ISSN: 1759-5029
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- Citations: 20
Freudenthal B, Watts L, Williams G, et al., 2020, The skeletal system in thyrotoxicosis, Werner & Ingbar's The Thyroid
Watts L, Freudenthal B, Bassett J, et al., 2020, The skeletal system in hypothyroidism, Werner & Ingbar's The Thyroid
Leitch VD, Brassill MJ, Rahman S, et al., 2019, PYY is a negative regulator of bone mass and strength, Bone, Vol: 127, Pages: 427-435, ISSN: 8756-3282
ObjectiveBone loss in anorexia nervosa and following bariatric surgery is associated with an elevated circulating concentration of the gastrointestinal, anorexigenic hormone, peptide YY (PYY). Selective deletion of the PYY receptor Y1R in osteoblasts or Y2R in the hypothalamus results in high bone mass, but deletion of PYY in mice has resulted in conflicting skeletal phenotypes leading to uncertainty regarding its role in the regulation of bone mass. As PYY analogs are under development for treatment of obesity, we aimed to clarify the relationship between PYY and bone mass.MethodsThe skeletal phenotype of Pyy knockout (KO) mice was investigated during growth (postnatal day P14) and adulthood (P70 and P186) using X-ray microradiography, micro-CT, back-scattered electron scanning electron microscopy (BSE-SEM), histomorphometry and biomechanical testing.ResultsBones from juvenile and Pyy KO mice were longer (P < 0.001), with decreased bone mineral content (P < 0.001). Whereas, bones from adult Pyy KO mice had increased bone mineral content (P < 0.05) with increased mineralisation of both cortical (P < 0.001) and trabecular (P < 0.001) compartments. Long bones from adult Pyy KO mice were stronger (maximum load P < 0.001), with increased stiffness (P < 0.01) and toughness (P < 0.05) compared to wild-type (WT) control mice despite increased cortical vascularity and porosity (P < 0.001). The increased bone mass and strength in Pyy KO mice resulted from increases in trabecular (P < 0.01) and cortical bone formation (P < 0.05).ConclusionsThese findings demonstrate that PYY acts as a negative regulator of osteoblastic bone formation, implicating increased PYY levels in the pathogenesis of bone loss during anorexia or following bariatric surgery.
Beck-Cormier S, Lelliott CJ, Logan JG, et al., 2019, Slc20a2, encoding the phosphate transporter PiT2, is a novel genetic determinant of bone quality and strength, Journal of Bone and Mineral Research, Vol: 34, Pages: 1101-1114, ISSN: 1523-4681
Osteoporosis is characterized by low bone mineral density (BMD) and fragility fracture and affects over 200 million people worldwide. Bone quality describes the material properties that contribute to strength independently of BMD, and its quantitative analysis is a major priority in osteoporosis research. Tissue mineralization is a fundamental process requiring calcium and phosphate transporters. Here we identify impaired bone quality and strength in Slc20a2–/– mice lacking the phosphate transporter SLC20A2. Juveniles had abnormal endochondral and intramembranous ossification, decreased mineral accrual, and short stature. Adults exhibited only small reductions in bone mass and mineralization but a profound impairment of bone strength. Bone quality was severely impaired in Slc20a2–/– mice: yield load (–2.3 SD), maximum load (–1.7 SD), and stiffness (–2.7 SD) were all below values predicted from their bone mineral content as determined in a cohort of 320 wild‐type controls. These studies identify Slc20a2 as a physiological regulator of tissue mineralization and highlight its critical role in the determination of bone quality and strength.
Freudenthal B, Shetty S, Butterfield NC, et al., 2019, Genetic and pharmacological targeting of transcriptional repression in resistance to thyroid hormone alpha, Thyroid, Vol: 29, ISSN: 1050-7256
Background Thyroid hormones act in bone and cartilage via thyroid hormone receptor α (TRα). In the absence of T3, TRα interacts with co-repressors, including nuclear receptor co-repressor-1 (NCoR1), which recruit histone deacetylases (HDACs) and mediate transcriptional repression. Dominant-negative mutations of TRα cause resistance to thyroid hormone α (RTHα; OMIM 614450), characterized by excessive repression of T3 target genes leading to delayed skeletal development, growth retardation and bone dysplasia. Treatment with thyroxine has been of limited benefit even in mildly affected individuals and there is a need for new therapeutic strategies. We hypothesized that (i) the skeletal manifestations of RTHα are mediated by the persistent TRα/NCoR1/HDAC repressor complex containing mutant TRα, and (ii) treatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would ameliorate these manifestations. Methods We determined the skeletal phenotypes of (i) Thra1PV/+ mice, a well characterized model of RTHα, (ii) Ncor1ΔID/ΔID mice, which express an NCoR1 mutant that fails to interact with TRα, and (iii) Thra1PV/+Ncor1ΔID/ΔID double mutant adult mice. Wild-type, Thra1PV/+, Ncor1ΔID/ΔID, and Thra1PV/+Ncor1ΔID/ΔID double mutant mice were also treated with SAHA to determine whether HDAC inhibition results in amelioration of skeletal abnormalities. Results Thra1PV/+ mice had a severe skeletal dysplasia characterized by short stature, abnormal bone morphology and increased bone mineral content. Despite normal bone length, Ncor1ΔID/ΔID mice displayed increased cortical bone mass, mineralization and strength. Thra1PV/+Ncor1ΔID/ΔID double mutant mice displayed only a small improvement of skeletal abnormalities compared to Thra1PV/+ mice. Treatment with SAHA to inhibit histone deacetylation had no beneficial or detrimental effects on bo
Rauner M, Baschant U, Roetto A, et al., 2019, Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signaling (vol 1, pg 111, 2019), NATURE METABOLISM, Vol: 1, Pages: 584-584
Morris JA, Kemp JP, Youlten SE, et al., 2019, Author Correction: An atlas of genetic influences on osteoporosis in humans and mice., Nat Genet
In the version of this article initially published, in Fig. 5a, the data in the right column of 'DAAM2 gRNA1' were incorrectly plotted as circles indicating 'untreated' rather than as squares indicating 'treated'. The error has been corrected in the HTML and PDF versions of the article.
Butterfield NC, Logan JG, Waung J, et al., 2019, Quantitative X-Ray Imaging of Mouse Bone by Faxitron., Methods Mol Biol, Vol: 1914, Pages: 559-569
This chapter describes the use of point projection digital microradiography for rapid imaging and quantitation of bone mineral content in mice.
Morris JA, Kemp JP, Youlten SE, et al., 2019, An atlas of genetic influences on osteoporosis in humans and mice, Nature Genetics, Vol: 51, Pages: 258-266, ISSN: 1061-4036
Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10−75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
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