Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism.

Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C > T, p.Arg553Trp) in GALNT3, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831 T > A, p.Asp277Glu) within the same gene. In silico protein modeling predicted that p.Arg553Trp would disrupt salt-bridge interactions, causing instability of GALNT3, and that p.Asp277Glu would disrupt manganese binding and consequently GALNT3 catalytic function. Bi-allelic loss-of-function GALNT3 mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the GALNT3 locus show genome-wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at loci coding for FGF23, its receptor FGFR1, or coreceptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and genome-wide association studies data from UK Biobank, suggested increased expression of GALNT3 reduces total body, lumbar spine, and femoral neck BMD but has no effect on phosphate concentrations. In conclusion, rare heterozygous loss-of-function variants in GALNT3 may cause HBM without altering phosphate concentration. These findings suggest that GALNT3 may affect BMD through pathways other than FGF23 regulation, the identification of which may yield novel anabolic drug targets for osteoporosis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

High Bone Mass Disorders: New Insights From Connecting the Clinic and the Bench.

Monogenic high bone mass (HBM) disorders are characterized by an increased amount of bone in general, or at specific sites in the skeleton. Here, we describe 59 HBM disorders with 50 known disease-causing genes from the literature, and we provide an overview of the signaling pathways and mechanisms involved in the pathogenesis of these disorders. Based on this, we classify the known HBM genes into HBM (sub)groups according to uniform Gene Ontology (GO) terminology. This classification system may aid in hypothesis generation, for both wet lab experimental design and clinical genetic screening strategies. We discuss how functional genomics can shape discovery of novel HBM genes and/or mechanisms in the future, through implementation of omics assessments in existing and future model systems. Finally, we address strategies to improve gene identification in unsolved HBM cases and highlight the importance for cross-laboratory collaborations encompassing multidisciplinary efforts to transfer knowledge generated at the bench to the clinic. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Gender equity in academic rheumatology, current status and potential for improvement: a cross-sectional study to inform an EULAR task force.

OBJECTIVES: Evidence on the current status of gender equity in academic rheumatology in Europe and potential for its improvement is limited. The EULAR convened a task force to obtain empirical evidence on the potential unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology. METHODS: This cross-sectional study comprised three web-based surveys conducted in 2020 among: (1) EULAR scientific member society leaders, (2) EULAR and Emerging EULAR Network (EMEUNET) members and (3) EULAR Council members. Statistics were descriptive with significance testing for male/female responses assessed by χ2 test and t-test. RESULTS: Data from EULAR scientific member societies in 13 countries indicated that there were disproportionately fewer women in academic rheumatology than in clinical rheumatology, and they tended to be under-represented in senior academic roles. From 324 responses of EULAR and EMEUNET members (24 countries), we detected no gender differences in leadership aspirations, self-efficacy in career advancement and work-life integration as well as the share of time spent on research, but there were gender differences in working hours and the levels of perceived gender discrimination and sexual harassment. There were gender differences in the ranking of 7 of 26 factors impacting career advancement and of 8 of 24 potential interventions to aid career advancement. CONCLUSIONS: There are gender differences in career advancement in academic rheumatology. The study informs a EULAR task force developing a framework of potential interventions to accelerate gender-equitable career advancement in academic rheumatology.

Gender equity in academic rheumatology: is there a gender gap at European rheumatology conferences?

OBJECTIVES: To obtain an overview of gender equity at European rheumatology conferences. METHODS: The proportion of women invited as either moderators or speakers to the European Alliance of Associations for Rheumatology (EULAR) annual congresses and national conferences in Europe was calculated from the published congress materials from EULAR annual congresses (2015-2019) and the 2019 national conferences of France, Germany, Italy, Spain and the UK. Data from EULAR congresses were further categorised by type of session. Significance testing was conducted using χ2 tests with the level of statistical significance set at p<0.05. RESULTS: The proportion of combined women moderators and speakers at EULAR varied from 40% to 43% between 2015 and 2019 with no obvious trend over time. There were higher proportions of women in the Health Professionals in Rheumatology and People with Arthritis and Rheumatism sessions (>50% consistently). However, these sessions represent <25% of EULAR congress invitations. Representation of women at the EULAR congress in 2019 (39.6%) was significantly higher than at the national congresses in France (28.6%) and Germany (29.6%) but similar to that observed in Italy (33.7%), Spain (41.7%) and the UK (42%). CONCLUSION: Women account for less than half of invited moderators and speakers at the conferences reviewed. Compared with historical EULAR data in 2003 (16%) and in 2004 (19%), the gender gap at EULAR congresses has narrowed considerably, but there remains a need to monitor and improve women's representation.

Anabolic treatments for osteoporosis in postmenopausal women.

Antiresorptive agents are generally recommended as first-line treatment for osteoporosis in postmenopausal women. These drugs suppress bone resorption but do not rebuild bone, limiting their efficacy. Antiresorptive use is further hampered by concerns over rare side effects, including atypical femoral fractures and osteonecrosis of the jaw. Anabolic treatments overcome limitations of antiresorptive treatment by stimulating new bone formation, reducing the risk of fracture with greater efficacy. This review summarises the latest trial data for the three anabolic agents currently available for the treatment of osteoporosis in postmenopausal women: teriparatide, abaloparatide, and romosozumab. Data from head-to-head studies comparing anabolic and antiresorptive treatments are reviewed. At present, anabolic treatments are generally reserved for use in patients with severe osteoporosis at very high fracture risk; the factors limiting their more widespread use are discussed together with how this may change in the future.

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.

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.

Prevalence and predictors of asymmetric hypertensive heart disease: insights from cardiac and aortic function with cardiovascular magnetic resonance.

AIMS: We sought to determine the prevalence of asymmetric hypertensive heart disease (HHD) overlapping morphologically with hypertrophic cardiomyopathy (HCM) and to determine predictors of this pattern of hypertensive remodelling. METHODS AND RESULTS: One hundred and fifty hypertensive patients underwent 1.5 T cardiovascular magnetic resonance imaging. Twenty-one patients were excluded due to concomitant cardiac pathology that may confound the hypertrophic response, e.g. myocardial infarction, moderate-severe valvular disease, or other cardiomyopathy. Asymmetric HHD was defined as a segmental wall thickness of ≥15 mm and >1.5-fold the opposing wall in ≥1 myocardial segments, measured from short-axis cine stack at end-diastole. Ambulatory blood pressure, myocardial replacement fibrosis, aortic distensibility and aortoseptal angle were investigated as predictors of asymmetric HHD by multivariate logistic regression. Out of 129 hypertensive subjects (age: 51 ± 15 years, 50% male, systolic blood pressure: 170 ± 30 mmHg, diastolic blood pressure: 97 ± 16 mmHg), asymmetric HHD occurred in 21%. Where present, maximal end-diastolic wall thickness (EDWT) was 17.8 ± 1.9 mm and located exclusively in the basal or mid septum. In asymmetric HHD, aortoseptal angle (114 ± 10° vs. 125 ± 9° vs. 123 ± 12°, P < 0.05, respectively) was significantly reduced compared to concentric left ventricular hypertrophy (LVH) and compared to no LVH, respectively. Aortic distensibility in asymmetric HHD (1.01 ± 0.60 vs. 1.83 ± 1.65 mm2/mmHg × 103, P < 0.05, respectively) was significantly reduced compared to subjects with no LVH. Age (odds ratio [95th confidence interval]: 1.10 [1.02-1.18], P < 0.05) and indexed LV mass (1.09 [0.98-1.28], P < 0.0001) were significant, independent predictors of asymmetric HDD. CONCLUSIONS: Asymmetric HHD morphologically overlapping with HCM, according to the current ESC guidelines, is common. Postulating a diagnosis of HCM on the basis of EDWT of ≥15 mm should be made with caution in the presence of arterial hypertension particular in male subjects with elevated LV mass.

Physician-based ultrasound-guided biopsy for diagnosing pleural disease.

BACKGROUND: Definitive diagnosis of pleural disease (particularly malignancy) depends upon histologic proof obtained via pleural biopsy or positive pleural fluid cytology. Image-guided sampling is now standard practice. Local anesthetic thoracoscopy has a high diagnostic yield for malignant and nonmalignant disease, but is not always possible in frail patients, if pleural fluid is heavily loculated, or where the lung is adherent to the chest wall. Such cases can be converted during the same procedure as attempted thoracoscopy to cutting-needle biopsy. This study aimed to determine the diagnostic yield of a physician-led service in both planned biopsies and cases of failed thoracoscopy. METHODS: This study was a retrospective review of all ultrasound-guided, cutting-needle biopsies performed at the Oxford Centre for Respiratory Medicine between January 2010 and July 2013. Histologic results were assessed for the yield of pleural tissue, final diagnosis, and clinical follow-up in nonmalignant cases. RESULTS: Fifty ultrasound-guided biopsies were undertaken. Overall, 47 (94.0%) successfully obtained sufficient tissue for histologic diagnosis. Of the 50 biopsy procedures, 13 were conducted after failed thoracoscopy (5.2% of 252 attempted thoracoscopies over the same time period); of these 13, 11 (84.6%) obtained sufficient tissue. Thirteen of 50 biopsy specimens (26.0%) demonstrated pleural malignancy on histology (despite previous negative pleural fluid cytology), while 34 specimens (68.0%) were diagnosed as benign. Of the benign cases, 10 were pleural TB, two were sarcoidosis, and 22 were benign pleural thickening. There was one "false negative" of mesothelioma (median follow-up, 16 months). CONCLUSIONS: Within this population, physician-based, ultrasound-guided, cutting-needle pleural biopsy obtained pleural tissue successfully in a high proportion of cases, including those of failed thoracoscopy.