Publications
227 results found
Williams GR, 2024, Year in thyroidology: basic science, Thyroid, Vol: 34, Pages: 10-13, ISSN: 1050-7256
The Centenary of the American Thyroid Association (ATA) was celebrated in 2023, and I was honored to present the “Year in Thyroidology: Basic Science” Lecture at the 92nd Annual Meeting of the ATA in Washington, DC. All basic science papers in the fields of thyroid gland development and function, thyroid autoimmunity, thyroid cancer, and thyroid hormone action published between September 1st, 2022 and August 31st, 2023 were considered. Searches of PubMed® (https://pubmed.ncbi.nlm.nih.gov) and bioRxiv (https://www.biorxiv.org) identified over 2500 articles. Initially, 100 of those considered to be the most impactful were selected based on their novelty, scientific rigor, general interest, and application of cross disciplinary, state-of-the-art methods. Forty-five papers were selected for in-depth scrutiny. Ultimately, 5 were highlighted in the presentation and a further 10 were discussed (Table 1).
Loisay L, Komla-Ebri D, Morice A, et al., 2023, Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice, JCI Insight, Vol: 8, Pages: 1-21, ISSN: 2379-3708
Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge. Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. The appendicular and axial skeletons were both severely affected and we demonstrated an important role of FGFR3 in regulation of cortical and trabecular bone structure. Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. The present findings emphasize the detrimental effect of gain-of-function mutations in the Fgfr3 gene on long bone modeling during both developmental and aging processes, with potential implications for the management of elderly patients with hypochondroplasia and osteoporosis.
Kooblall KG, Stevenson M, Stewart M, et al., 2023, A mouse model with a frameshift mutation in the nuclear factor I/X (NFIX) gene has phenotypic features of Marshall-Smith syndrome, JBMR Plus, Vol: 7, ISSN: 2473-4039
The nuclear factor I/X (NFIX) gene encodes a ubiquitously expressed transcription factor whose mutations lead to two allelic disorders characterized by developmental, skeletal, and neural abnormalities, namely, Malan syndrome (MAL) and Marshall–Smith syndrome (MSS). NFIX mutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense-mediated decay (NMD) leading to NFIX haploinsufficiency, whereas NFIX mutations associated with MSS are clustered in exons 6–10 and escape NMD and result in the production of dominant-negative mutant NFIX proteins. Thus, different NFIX mutations have distinct consequences on NFIX expression. To elucidate the in vivo effects of MSS-associated NFIX exon 7 mutations, we used CRISPR-Cas9 to generate mouse models with exon 7 deletions that comprised: a frameshift deletion of two nucleotides (Nfix Del2); in-frame deletion of 24 nucleotides (Nfix Del24); and deletion of 140 nucleotides (Nfix Del140). Nfix+/Del2, Nfix+/Del24, Nfix+/Del140, NfixDel24/Del24, and NfixDel140/Del140 mice were viable, normal, and fertile, with no skeletal abnormalities, but NfixDel2/Del2 mice had significantly reduced viability (p < 0.002) and died at 2–3 weeks of age. Nfix Del2 was not cleared by NMD, and NfixDel2/Del2 mice, when compared to Nfix+/+ and Nfix+/Del2 mice, had: growth retardation; short stature with kyphosis; reduced skull length; marked porosity of the vertebrae with decreased vertebral and femoral bone mineral content; and reduced caudal vertebrae height and femur length. Plasma biochemistry analysis revealed NfixDel2/Del2 mice to have increased total alkaline phosphatase activity but decreased C-terminal telopeptide and procollagen-type-1-N-terminal propeptide concentrations compared to Nfix+/+ and Nfix+/Del2 mice. NfixDel2/Del2 mice were also found to have enlarged cerebral cortices and ventricular areas but smaller dentate gyrus compared to Nfix+/+ mice. Thus, NfixDel2/Del2 mice provide
Behmoaras J, 2023, Multinucleation resets human macrophages for specialized functions at the expense of their identity, EMBO Reports, Vol: 24, Pages: 1-19, ISSN: 1469-221X
Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. How multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrate comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced downregulation of macrophage identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, human LGCs preferentially express B7-H3 (CD276) and can form granuloma-like clusters in vitro, suggesting that their multinucleation potentiates T cell activation. These findings demonstrate how cell–cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC-specific functionality.
Perros P, Basu A, Boelaert K, et al., 2022, Postradioiodine graves' management: The PRAGMA study, Clinical Endocrinology, Vol: 97, Pages: 664-675, ISSN: 0300-0664
ObjectiveThyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post-RI and compare effectiveness of common management strategies.DesignRetrospective, multicentre and observational study.PatientsAdult patients with Graves' disease treated with RI with 12 months' follow-up.MeasurementsEuthyroidism was defined as both serum thyrotropin (thyroid-stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4.ResultsOf 812 patients studied post-RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post-RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%–28.7%). No negative outcomes (new-onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres.ConclusionsDysthyroidism in the 12 months post-RI was common. Differences between post-RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism.
Ruggiero C, Durand N, Jarjat M, et al., 2022, The secreted protein augurin is a novel modulator of canonical Wnt signalling involved in osteoblast differentiation, Clinical and Translational Discovery, Vol: 2, Pages: 1-14, ISSN: 2768-0622
BackgroundECRG4/C2ORF40 is a tumour suppressor gene downregulated in several cancer types, which encodes the secreted protein augurin. A wide number of functions in health and disease have been assigned to augurin, but the signalling pathways it regulates are still poorly characterized. Augurin expression is strongly upregulated during in vitro differentiation of neonatal mouse osteoblasts.MethodsIn vitro differentiation assays of calvarial osteoblasts isolated from Ecrg4 -/- and wild-type mice; transient transfection assays using reporters activated by Wnt signalling and other signal transduction pathways; Real-time quantitative polymerase chain reaction for measurement of gene expression; protein expression in Chinese hamster ovary cells and Escherichia coli; in situ binding assays of proteins expressed as fusions to alkaline phosphatase with cells expressing various membrane receptors.ResultsOsteoblasts from Ecrg4 -/- mice have an accelerated differentiation compared to wild-type and upregulation of Wnt markers. Augurin is a specific repressor of Wnt-stimulated transcriptional activity, both when coexpressed together with the reporter and when added to the culture medium as a soluble protein. We confirmed the previously described binding of augurin to LOX1, a scavenger receptor, but an inhibitor of this molecule did not impair augurin repression of Wnt-stimulated transcription specifically. Genome-wide association studies showed an association of ECRG4 genomic variation with body height and osteoarthritis.ConclusionsOur study sheds new light on the wide spectrum of functions previously ascribed to augurin in brain function, stem cell biology, inflammation/immunity and cancer. Furthermore, our discovery paves the way to further characterization of the mechanisms involved in augurin repression of Wnt signalling and the development of agonists and antagonists for this protein, which have a wide array of potential applications in the clinic.
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.
Dekker BL, Kobold ACM, Brouwers AH, et al., 2021, Bone Mineral Density in Adult Survivors of Pediatric Differentiated Thyroid Carcinoma: A Longitudinal Follow-Up Study, THYROID, Vol: 31, Pages: 1707-1714, ISSN: 1050-7256
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, ISSN: 2473-4039
Ras homologous guanosine triphosphatases (RhoGTPases) control several cellular functions, including cytoskeletal actin remodeling and cell migration. Their activities are downregulated by GTPase-activating proteins (GAPs). Although RhoGTPases are implicated in bone remodeling and osteoclast and osteoblast function, their significance in human bone health and disease remains elusive. Here, we report defective RhoGTPase regulation as a cause of severe, early-onset, autosomal-dominant skeletal fragility in a three-generation Finnish family. Affected individuals (n = 13) presented with multiple low-energy peripheral and vertebral fractures despite normal bone mineral density (BMD). Bone histomorphometry suggested reduced bone volume, low surface area covered by osteoblasts and osteoclasts, and low bone turnover. Exome sequencing identified a novel heterozygous missense variant c.652G>A (p.G218R) in ARHGAP25, encoding a GAP for Rho-family GTPase Rac1. Variants in the ARHGAP25 5′ untranslated region (UTR) also associated with BMD and fracture risk in the general population, across multiple genomewide association study (GWAS) meta-analyses (lead variant rs10048745). ARHGAP25 messenger RNA (mRNA) was expressed in macrophage colony-stimulating factor (M-CSF)–stimulated human monocytes and mouse osteoblasts, indicating a possible role for ARHGAP25 in osteoclast and osteoblast differentiation and activity. Studies on subject-derived osteoclasts from peripheral blood mononuclear cells did not reveal robust defects in mature osteoclast formation or resorptive activity. However, analysis of osteosarcoma cells overexpressing the ARHGAP25 G218R-mutant, combined with structural modeling, confirmed that the mutant protein had decreased GAP-activity against Rac1, resulting in elevated Rac1 activity, increased cell spreading, and membrane ruffling. Our findings indicate that mutated ARHGAP25 causes aberrant Rac1 function and consequently abnormal bone metabolism, highlig
Butterfield NC, Curry KF, Steinberg J, et al., 2021, Publisher Correction: Accelerating functional gene discovery in osteoarthritis, Nature Communications, Vol: 12, ISSN: 2041-1723
Walsh JS, Jacques R, Schomburg L, et al., 2021, Selenium supplementation to improve bone health in postmenopausal women: the SeMS three-arm RCT, Efficacy and Mechanism Evaluation, Vol: 8, Pages: 1-37, ISSN: 2050-4365
BackgroundObservational and pre-clinical studies have reported an association between selenium status, bone density, bone turnover and fracture risk. Selenium is an anti-oxidant, so we hypothesised that selenium could reduce the pro-resorptive action of reactive oxygen species on osteoclasts. Population mortality data suggest that the optimum range for serum selenium is 120–150 µg/l. Most adults in Europe are relatively selenium insufficient compared with adults in the USA and other geographical areas.ObjectivesThe objectives of the study were to determine if selenium supplementation in postmenopausal women with osteopenia decreased bone turnover, improved physical function or decreased markers of oxidative stress and inflammation.DesignWe conducted a 6-month double-blind, randomised, placebo-controlled trial.SettingThis was a single-centre study in Sheffield, UK.ParticipantsWe recruited 120 postmenopausal women with osteopenia or osteoporosis. One hundred and fifteen women completed follow-up and were included in the intention-to-treat analysis.InterventionsThe interventions were sodium selenite as Selenase 200 µg/day, Selenase 50 µg/day (biosyn, Germany) and placebo.Main outcome measuresThe primary end point was urine N–terminal cross-linking telopeptide of type I collagen/Cr (NTX/Cr) at 26 weeks. Groups were compared with an analysis of covariance, through the use of Hochberg testing. Secondary end points were other biochemical markers of bone turnover, bone mineral density by dual-energy X-ray absorptiometry and physical function scores (short physical performance battery and grip strength). The mechanistic end points were markers of inflammation and anti-oxidant activity (glutathione peroxidase, highly sensitive C-reactive protein and interleukin 6).ResultsIn the 200 µg/day group, mean serum selenium increased from 78.8 µg/l (95% confidence interval 73.5 to 84.2 µg/l) to 1
Walsh JS, Jacques RM, Schomburg L, et al., 2021, Effect of selenium supplementation on musculoskeletal health in older women: a randomised, double-blind, placebo-controlled trial, The Lancet Healthy Longevity, Vol: 2, Pages: e212-e221, ISSN: 2666-7568
BackgroundObservational and preclinical studies show associations between selenium status, bone health, and physical function. Most adults in Europe have serum selenium below the optimum range. We hypothesised that selenium supplementation could reduce pro-resorptive actions of reactive oxygen species on osteoclasts and improve physical function.MethodsWe completed a 6-month randomised, double-blind, placebo-controlled trial. We recruited postmenopausal women older than 55 years with osteopenia or osteoporosis at the Northern General Hospital, Sheffield, UK. Participants were randomly assigned 1:1:1 to receive selenite 200 μg, 50 μg, or placebo orally once per day. Medication was supplied to the site blinded and numbered by a block randomisation sequence with a block size of 18, and participants were allocated medication in numerical order. All participants and study team were masked to treatment allocation. The primary endpoint was urine N-terminal cross-linking telopeptide of type I collagen (NTx, expressed as ratio to creatinine) at 26 weeks. Analysis included all randomly assigned participants who completed follow-up. Groups were compared with analysis of covariance with Hochberg testing. Secondary endpoints were other biochemical markers of bone turnover, bone mineral density, short physical performance battery, and grip strength. Mechanistic endpoints were glutathione peroxidase, highly sensitive C-reactive protein, and interleukin-6. This trial is registered with EU clinical trials, EudraCT 2016-002964-15, and ClinicalTrials.gov, NCT02832648, and is complete.Findings120 participants were recruited between Jan 23, 2017, and April 11, 2018, and randomly assigned to selenite 200 μg, 50 μg, or placebo (n=40 per group). 115 (96%) of 120 participants completed follow-up and were included in the primary analysis (200 μg [n=39], 50 μg [n=39], placebo [n=37]). Median follow-up was 25·0 weeks (IQR 24·7–26·0). In the 200 μ
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
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 TI, et al., 2021, A molecular quantitative trait locus map for osteoarthritis., Nat Commun, Vol: 12
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.
Butterfield NC, Curry KF, Steinberg J, et al., 2021, Accelerating functional gene discovery in osteoarthritis., Nat Commun, Vol: 12
Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, 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.
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.
Joustra SD, Roelfsema F, van Trotsenburg ASP, et al., 2020, Response to Letter to the Editor: "IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction", JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 105, Pages: E2315-E2316, ISSN: 0021-972X
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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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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Pereira M, Ko J-H, Logan J, et al., 2020, A trans-eQTL network regulates osteoclast multinucleation and bone mass
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>in vivo</jats:italic> phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a <jats:italic>trans</jats:italic>-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 <jats:italic>Bcat1</jats:italic> and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (<jats:italic>Pik3cb</jats:italic><jats:sup>−/−</jats:sup>, <jats:italic>Atp8b2</jats:italic><jats:sup>+/−</jats:sup>, <jats:italic>Igsf8</jats:italic><jats:sup>−/−</jats:sup>, <jats:italic>Eml1</jats:italic><jats:sup>−/−</jats:sup>, <jats:italic>Appl2</jats:italic><jats:sup>−/−</jats:sup>, <jats:italic>Deptor</jats:italic><jats:sup>−/−</jats:sup>) and myeloid-specific <jats:italic>Slc40a1<jats:sup>ΔLysMCre</jats:sup></jats:italic> knockout mice displayed abnormal bone phenotypes. We report antagonizing 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 fusion and bone mass.</jats:p><jats:sec><jats:title>Impact statement</jats:title><jats:p>We took advantage of the osteoclast w
Freudenthal B, Watts L, Williams G, et al., 2020, The skeletal system in thyrotoxicosis, Werner & Ingbar's The Thyroid
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