Publications
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Klein Hesselink MS, Nies M, Bocca G, et al., 2016, Pediatric Differentiated Thyroid Carcinoma in The Netherlands: A Nationwide Follow-Up Study, The Journal of Clinical Endocrinology & Metabolism, Vol: 101, Pages: 2031-2039, ISSN: 0021-972X
Introduction:Treatment for differentiated thyroid carcinoma (DTC) in pediatric patients is based mainly on evidence from adult series due to lack of data from pediatric cohorts. Our objective was to evaluate presentation, treatment-related complications, and long-term outcome in patients with pediatric DTC in the Netherlands.Patients and methods:In this nationwide study, presentation, complications and outcome of patients with pediatric DTC (age at diagnosis ≤18 years) treated in the Netherlands between 1970 and 2013 were assessed using medical records.Results:We identified 170 patients. Overall survival was 99.4% after median follow-up of 13.5 (range 0.3–44.7) years. Extensive follow-up data were available for 105 patients (83.8% women), treated in 39 hospitals. Median age at diagnosis was 15.6 (range 5.8–18.9) years. At initial diagnosis, 43.8% of the patients had cervical lymph node metastases; 13.3% had distant metastases. All patients underwent total thyroidectomy. Radioiodine was administered to 97.1%, with a median cumulative activity of 5.66 (range 0.74–35.15) GBq. Lifelong postoperative complications (permanent hypoparathyroidism and/or recurrent laryngeal nerve injury) were present in 32.4% of the patients. At last known follow-up, 8.6% of the patients had persistent disease and 7.6% experienced a recurrence. TSH suppression was not associated with recurrences (OR 2.00, 95% CI 0.78 to 5.17, P = 0.152).Conclusions:Survival of pediatric DTC is excellent. Therefore, minimizing treatment-related morbidity takes major priority. Our study shows a frequent occurrence of lifelong postoperative complications. Adverse effects may be reduced by centralization of care, which is crucial for children with DTC.
Bassett JH, Williams GR, 2016, Role of thyroid hormones in skeletal development and bone maintenance., Endocrine Reviews, Vol: 37, ISSN: 1945-7189
The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development, adulthood and in response to injury. Future analysis of T3 action in individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteoarthritis. This review provides a comprehensive analysis of the current state-of-the-art.
Taylor PN, Richmond R, Davies N, et al., 2016, Paradoxical Relationship Between Body Mass Index and Thyroid Hormone Levels: A Study Using Mendelian Randomization, Journal of Clinical Endocrinology & Metabolism, Vol: 101, Pages: 730-738, ISSN: 1945-7197
Context: Free T3 (FT3) has been positively associated with body mass index (BMI) in cross-sectionalstudies in healthy individuals. This is difficult to reconcile with clinical findings in pathologicalthyroid dysfunction.Objective: We aimed to investigate whether childhood adiposity influences FT3 levels.Design: Mendelian randomization using genetic variants robustly associated with BMI.Setting: Avon Longitudinal Study of Parents and Children, a population-based birth cohort.Participants: A total of 3014 children who had thyroid function measured at age 7, who alsounderwent dual x-ray absorptiometry scans at ages 9.9 and 15.5 years and have genetic dataavailable.Main Outcome Measures: FT3.Results: Observationally at age 7 years, BMI was positively associated with FT3: -standardized(-[std]) 0.12 (95% confidence interval [CI]: 0.08, 0.16), P 4.02 10 10; whereas FT4 wasnegatively associated with BMI: -(std) 0.08 (95% CI: 0.12, 0.04), P 3.00 10 5. Thesedifferences persisted after adjustment for age, sex, and early life environment. Genetic analysisindicated 1 allele change in BMI allelic score was associated with a 0.04 (95% CI: 0.03, 0.04) SDincrease in BMI (P 6.41 10 17). At age 7, a genetically determined increase in BMI of 1.89 kg/m2was associated with a 0.22 pmol/L (95% CI: 0.07, 0.36) increase in FT3 (P .004) but no substantialchange in FT4 0.01 mmol/L, (95% CI: 0.37, 0.40), P .96.Conclusion: Our analysis shows that children with a genetically higher BMI had higher FT3 but notFT4 levels, indicating that higher BMI/fat mass has a causal role in increasing FT3 levels. This mayexplain the paradoxical associations observed in observational analyses. Given rising childhoodobesity levels, this relationship merits closer scrutiny.
Duncan Bassett JH, van der Spek A, Logan JG, et al., 2015, Thyrostimulin regulates osteoblastic bone formation during early skeletal development., Endocrinology, Vol: 156, Pages: 3098-3113, ISSN: 1945-7170
The ancestral glycoprotein hormone thyrostimulin is a heterodimer of unique GPA2 and GPB5 subunits with high affinity for the thyrotropin receptor (TSHR). Transgenic over-expression of GPB5 in mice results in cranial abnormalities, but the role of thyrostimulin in bone remains unknown. We hypothesized that thyrostimulin exerts paracrine actions in bone and determined; (i) GPA2 and GPB5 expression in osteoblasts and osteoclasts, (ii) the skeletal consequences of thyrostimulin deficiency in GPB5KO mice and (iii) osteoblast and osteoclast responses to thyrostimulin treatment. Gpa2 and Gpb5 expression was identified in the newborn skeleton but declined rapidly thereafter. GPA2 and GPB5 mRNAs were also expressed in primary osteoblasts and osteoclasts at varying concentrations. Juvenile thyrostimulin-deficient mice had increased bone volume and mineralization as a result of increased osteoblastic bone formation. However, thyrostimulin failed to induce a canonical cAMP response or activate the non-canonical Akt, ERK or P38 signaling pathways in primary calvarial or bone marrow stromal cell-derived osteoblasts. Furthermore, thyrostimulin did not directly inhibit osteoblast proliferation, differentiation or mineralization in vitro. These studies identify thyrostimulin as a negative but indirect regulator of osteoblastic bone formation during skeletal development.
Blum MR, Bauer DC, Collet T-H, et al., 2015, Subclinical thyroid dysfunction and fracture risk: A meta-analysis, JAMA-Journal of the American Medical Association, Vol: 313, Pages: 2055-2065, ISSN: 1538-3598
Importance Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking.Objective To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures.Data Sources and Study Selection The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures.Data Extraction Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations.Main Outcome and Measures The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes.Results Among 70 298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762 401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56 471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25 901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21 722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20 328). Lower TSH was associated with higher fracture rates: for TSH of less t
Okosieme O, Gilbert J, Abraham P, et al., 2015, Management of Primary Hypothyroidism Statement by the British Thyroid Association Executive Committee., Clinical Endocrinology, Vol: 84, Pages: 799-808, ISSN: 1365-2265
Primary hypothyroidism is an insidious condition with a significant morbidity and often subtle and non-specific symptoms and clinical signs [1, 2]. The earliest biochemical abnormality is an increase in serum thyroid-stimulating hormone (thyrotrophin) (TSH) concentration associated with normal serum free thyroxine (T4) and triiodothyronine (T3) concentrations (subclinical hypothyroidism), followed by a decrease in serum free T4 concentration, at which stage most patients have symptoms and benefit from treatment (overt hypothyroidism) [1-3]. In the UK, the prevalence of spontaneous hypothyroidism is between 1% and 2%, and it is more common in older women and ten times more common in women than in men [4, 5]. The cause is either chronic autoimmune disease (atrophic autoimmune thyroiditis or goitrous autoimmune thyroiditis (Hashimoto's thyroiditis)) or destructive treatment for hyperthyroidism with either radioiodine or surgery which may account for up to one-third of cases of hypothyroidism in the community [6]. Less frequent causes include surgery and radioiodine ablation for benign nodular thyroid disease and thyroid cancer, external beam irradiation of malignant tumours of the head and neck and drugs including lithium, amiodarone and interferon [1]. Congenital hypothyroidism affects about one newborn in 3,500-4,000 births [7]. This article is protected by copyright. All rights reserved.
Waung JA, Bassett JHD, Williams GR, 2015, Adult Mice Lacking the Type 2 Iodothyronine Deiodinase Have Increased Subchondral Bone but Normal Articular Cartilage, THYROID, Vol: 25, Pages: 269-277, ISSN: 1050-7256
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- Citations: 19
Kang H, Kerloc'h A, Rotival M, et al., 2014, Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease, Cell Reports, Vol: 8, Pages: 1210-1224, ISSN: 2211-1247
Macrophages can fuse to form osteoclasts in boneor multinucleate giant cells (MGCs) as part of theimmune response. We use a systems geneticsapproach in rat macrophages to unravel their geneticdeterminants of multinucleation and investigate theirrole in both bone homeostasis and inflammatory disease.We identify a trans-regulated gene networkassociated with macrophage multinucleation andKcnn4 as being the most significantly trans-regulatedgene in the network and induced at the onsetof fusion. Kcnn4 is required for osteoclast andMGC formation in rodents and humans. Geneticdeletion of Kcnn4 reduces macrophage multinucleationthrough modulation of Ca2+ signaling, increasesbone mass, and improves clinical outcomein arthritis. Pharmacological blockade of Kcnn4reduces experimental glomerulonephritis. Our dataimplicate Kcnn4 in macrophage multinucleation,identifying it as a potential therapeutic target for inhibitionof bone resorption and chronic inflammation.
van Zeijl CJJ, Surovtseva OV, Kwakkel J, et al., 2014, Thyrostimulin deficiency does not alter peripheral responses to acute inflammation-induced nonthyroidal illness, American Journal of Physiology-Endocrinology and Metabolism, Vol: 307, Pages: E527-E537, ISSN: 1522-1555
Thyrostimulin deficiency does not alter peripheral responses to acuteinflammation-induced nonthyroidal illness. Am J Physiol EndocrinolMetab 307: E527–E537, 2014. First published August 12, 2014;doi:10.1152/ajpendo.00266.2014.—Thyrostimulin, a putative glycoproteinhormone, comprises the subunits GPA2 and GPB5 and activatesthe TSH receptor (TSHR). The observation that proinflammatorycytokines stimulate GPB5 transcription suggested a role forthyrostimulin in the pathogenesis of nonthyroidal illness syndrome(NTIS). In the present study, we induced acute inflammation by LPSadministration to GPB5/ and WT mice to evaluate the role ofthyrostimulin in peripheral thyroid hormone metabolism during NTIS.In addition to serum thyroid hormone concentrations, we studiedmRNA expression and activity of deiodinase types I, II, and III (D1,D2, and D3) in peripheral T3 target tissues, including liver, muscle,and white and brown adipose tissue (WAT and BAT), of which thelatter three express the TSHR. LPS decreased serum free (f)T4 and fT3indexes to a similar extent in GPB5/ and WT mice. Serum reverse(r)T3 did not change following LPS administration. LPS also inducedsignificant alterations in tissue D1, D2, and D3 mRNA and activitylevels, but only the LPS-induced increase in WAT D2 mRNA expressiondiffered between GPB5/ and WT mice. In conclusion, lackingGPB5 during acute illness does not affect the LPS-induced decreaseof serum thyroid hormones while resulting in subtle changes in tissueD2 expression that are unlikely to be mediated via the TSHR.
Williams GR, 2014, Role of thyroid hormone receptor-α1 in endochondral ossification, Endocrinology, Vol: 155, Pages: 2747-2750, ISSN: 1945-7170
Perros P, Boelaert K, Colley S, et al., 2014, Guidelines for the management of thyroid cancer, Clinical Endocrinology, Vol: 81, Pages: 1-136, ISSN: 0300-0664
Bassett JHD, Boyde A, Zikmund T, et al., 2014, Thyroid Hormone Receptor alpha Mutation Causes a Severe and Thyroxine-Resistant Skeletal Dysplasia in Female Mice, Endocrinology, Vol: 155, Pages: 3699-3712, ISSN: 1945-7170
A new genetic disorder has been identified that results from mutation of THRA, encoding thyroidhormone receptor 1 (TR1). Affected children have a high serum T3:T4 ratio and variable degreesof intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In anattempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients arereceiving varying doses and durations of T4 treatment, but responses have been inconsistent so far.Thra1PV/ mice express a similar potent dominant-negative mutant TR1 to affected individuals,and thus represent an excellent disease model.We hypothesized that Thra1PV/ mice could be usedto predict the skeletal outcome of human THRA mutations and determine whether prolongedtreatment with a supraphysiological dose of T4 ameliorates the skeletal abnormalities. Adult femaleThra1PV/ mice had short stature, grossly abnormal bone morphology but normal bonestrength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effecton skeletalmaturation, linear growth, or bonemineralization, thus demonstrating profound tissueresistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bonestiffness and strength, suggesting the potential for detrimental consequences in the long term. Ourstudies establish that TR1 has an essential role in the developing and adult skeleton and predictthat patients with different THRA mutations will display variable responses to T4 treatment, whichdepend on the severity of the causative mutation. (Endocri
Waung JA, Maynard SA, Gopal S, et al., 2014, Quantitative X-ray microradiography for high-throughput phenotyping of osteoarthritis in mice, Osteoarthritis and Cartilage, Vol: 22, Pages: 1396-1400, ISSN: 1522-9653
ObjectiveTo investigate and validate digital X-ray microradiography as a novel, high-throughput and cost-effective screening approach to identify abnormal joint phenotypes in mice.MethodDigital X-ray microradiography was used to quantify the subchondral bone mineral content (BMC) in the medial tibial plateau. Accuracy and reproducibility of the method were determined in 22 samples from C57BL/6(B6Brd;B6Dnk;B6N-Tyrc-Brd) wild-type mice. The method was then validated in wild-type mice that had undergone surgical destabilisation of medial meniscus (DMM) and in a genetically modified mouse strain with an established increase in trabecular bone mass.ResultsThe measurement of subchondral BMC by digital X-ray microradiography had a coefficient of variation of 3.6%. Digital X-ray microradiography was able to demonstrate significantly increased subchondral BMC in the medial tibial plateau of male mice 4 and 8 weeks after DMM surgery and in female mice 8 weeks after surgery. Furthermore, digital X-ray microradiography also detected the increase in subchondral BMC in a genetically modified mouse strain with high trabecular bone mass.ConclusionQuantitation of subchondral BMC by digital X-ray microradiography is a rapid, sensitive and cost-effective method to identify abnormal joint phenotypes in mice of both genders at several ages.
Gogakos A, Logan JG, Waung JA, et al., 2014, <i>THRA</i> and <i>DIO2</i> mutations are unlikely to be a common cause of increased bone mineral density in euthyroid post-menopausal women, EUROPEAN JOURNAL OF ENDOCRINOLOGY, Vol: 170, Pages: 637-644, ISSN: 0804-4643
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- Citations: 7
Blum MR, Bauer D, da Costa BR, et al., 2014, SUBCLINICAL THYROID DYSFUNCTION AND FRACTURE RISK: AN INDIVIDUAL PARTICIPANT DATA ANALYSIS OF PROSPECTIVE COHORTS, 37th Annual Meeting of the Society-General-Internal-Medicine, Publisher: SPRINGER, Pages: S212-S213, ISSN: 0884-8734
Refetoff S, Bassett JHD, Beck-Peccoz P, et al., 2014, Classification and Proposed Nomenclature for Inherited Defects of Thyroid Hormone Action, Cell Transport, and Metabolism, Journal of Clinical Endocrinology & Metabolism, Vol: 99, Pages: 768-770, ISSN: 1945-7197
Refetoff S, Bassett JHD, Beck-Peccoz P, et al., 2014, Classification and Proposed Nomenclature for Inherited Defects of Thyroid Hormone Action, Cell Transport, and Metabolism, THYROID, Vol: 24, Pages: 407-410, ISSN: 1050-7256
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- Citations: 37
van Rijn LE, Pop VJ, Williams GR, 2014, Low bone mineral density is related to high physiological levels of free thyroxine in peri-menopausal women, EUROPEAN JOURNAL OF ENDOCRINOLOGY, Vol: 170, Pages: 461-468, ISSN: 0804-4643
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- Citations: 33
Jones GN, Moschidou D, Abdulrazzak H, et al., 2014, Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta, STEM CELLS AND DEVELOPMENT, Vol: 23, Pages: 262-276, ISSN: 1547-3287
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- Citations: 29
Bianco AC, Anderson G, Forrest D, et al., 2014, American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models, THYROID, Vol: 24, Pages: 88-168, ISSN: 1050-7256
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- Citations: 136
Brassill MJ, Rahman SA, Boyde A, et al., 2013, Peptide YY Regulates Bone Mineral Content and Strength, IRISH JOURNAL OF MEDICAL SCIENCE, Vol: 182, Pages: S409-S409, ISSN: 0021-1265
Wojcicka A, Bassett JHD, Williams GR, 2013, Mechanisms of action of thyroid hormones in the skeleton, BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, Vol: 1830, Pages: 3979-3986, ISSN: 0304-4165
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- Citations: 66
Gogakos A, Hoeg A, Murphy E, et al., 2012, Bone Turnover and Bone Mineral Density Are Independently Related to Selenium Status in Healthy Euthyroid Postmenopausal Women., J Clin Endocrinol Metab
Context:Selenium status may have direct effects on bone and indirect effects through changes in thyroid hormone sensitivity.Objective:We hypothesized that variation in selenium status in healthy euthyroid postmenopausal women is associated with differences in bone turnover, bone mineral density (BMD) and fracture susceptibility.Design:The Osteoporosis and Ultrasound Study (OPUS) is a 6-yr prospective study of fracture-related factors.Setting:The study was comprised of a population-based cohort from five European cities.Participants:A total of 2374 postmenopausal women participated. Subjects with thyroid disease and nonthyroidal illness and those receiving drugs affecting thyroid status or bone metabolism were excluded, leaving a study population of 1144.Interventions:There were no interventions.Main Outcome Measures:We measured selenium (micrograms per liter); selenoprotein P (milligrams per liter); free T(4) (picomoles per liter); free T(3) (picomoles per liter); TSH (milliunits per liter); bone turnover markers; BMD; and vertebral, hip, and nonvertebral fractures.Results:Higher selenium levels were associated with higher hip BMD at study entry (β = 0.072, P = 0.004) and lower levels of bone formation (osteocalcin: β = -0.101, P < 0.001; procollagen type 1 N-terminal propeptide: β = -0.074, P = 0.013) and resorption markers (C-telopeptide of type 1 collagen: β = -0.058, P = 0.050; N-telopeptide of type 1 collagen: β = -0.095, P = 0.002). Higher selenoprotein P was associated with higher hip (β = 0.113, P < 0.001) and lumbar spine BMD (β = 0.088, P = 0.003) at study entry, higher hip BMD after the 6-yr follow-up (β = 0.106, P = 0.001) and lower osteocalcin (β = -0.077, P = 0.009), C-telopeptide of type 1 collagen (β = -0.075, P = 0.012), and N-telopeptide of type 1 collagen (β = -0.110, P < 0.001).Conclusion:Selenium status is inversely related to bone turnover and positively correlated with BMD in heal
Bassett JHD, Gogakos A, White JK, et al., 2012, Rapid-Throughput Skeletal Phenotyping of 100 Knockout Mice Identifies 9 New Genes That Determine Bone Strength, PLOS GENETICS, Vol: 8, ISSN: 1553-7404
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- Citations: 59
Bassett JHD, Logan JG, Boyde A, et al., 2012, Mice Lacking the Calcineurin Inhibitor Rcan2 Have an Isolated Defect of Osteoblast Function, ENDOCRINOLOGY, Vol: 153, Pages: 3537-3548, ISSN: 0013-7227
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- Citations: 19
Murray JR, Williams GR, Harrington KJ, et al., 2012, Rising thyroglobulin tumour marker during pregnancy in a thyroid cancer patient: no cause for alarm?, CLINICAL ENDOCRINOLOGY, Vol: 77, ISSN: 0300-0664
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- Citations: 5
Nicholls JJ, Brassill MJ, Williams GR, et al., 2012, The skeletal consequences of thyrotoxicosis, JOURNAL OF ENDOCRINOLOGY, Vol: 213, Pages: 209-221, ISSN: 0022-0795
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- Citations: 75
O'Shea PJ, Kim DW, Logan JG, et al., 2012, Advanced Bone Formation in Mice with a Dominant-negative Mutation in the Thyroid Hormone Receptor β Gene due to Activation of Wnt/β-Catenin Protein Signaling, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 17812-17822
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- Citations: 31
Xing W, Govoni KE, Donahue LR, et al., 2012, Genetic evidence that thyroid hormone is indispensable for prepubertal insulin-like growth factor-I expression and bone acquisition in mice, JOURNAL OF BONE AND MINERAL RESEARCH, Vol: 27, Pages: 1067-1079, ISSN: 0884-0431
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- Citations: 56
Karunaratne A, Esapa CR, Hiller J, et al., 2012, Significant Deterioration in Nanomechanical Quality Occurs Through Incomplete Extrafibrillar Mineralization in Rachitic Bone: Evidence From In-Situ Synchrotron X-ray Scattering and Backscattered Electron Imaging, JOURNAL OF BONE AND MINERAL RESEARCH, Vol: 27, Pages: 876-890, ISSN: 0884-0431
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- Citations: 50
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