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).

ETS transcription factor ELF3 (ESE-1) is a cell cycle regulator in benign and malignant prostate.

This study aimed to elucidate the role of ELF3, an ETS family member in normal prostate growth and prostate cancer. Silencing ELF3 in both benign prostate (BPH-1) and prostate cancer (PC3) cell lines resulted in decreased colony-forming ability, inhibition of cell migration and reduced cell viability due to cell cycle arrest, establishing ELF3 as a cell cycle regulator. Increased ELF3 expression in more advanced prostate tumours was shown by immunostaining of tissue microarrays and from analysis of gene expression and genetic alteration studies. This study indicates that ELF3 functions not only as a part of normal prostate epithelial growth but also as a potential oncogene in advanced prostate cancers.

Pharmacological Manipulation of Early Zebrafish Skeletal Development Shows an Important Role for Smad9 in Control of Skeletal Progenitor Populations.

Osteoporosis and other conditions associated with low bone density or quality are highly prevalent, are increasing as the population ages and with increased glucocorticoid use to treat conditions with elevated inflammation. There is an unmet need for therapeutics which can target skeletal precursors to induce osteoblast differentiation and osteogenesis. Genes associated with high bone mass represent interesting targets for manipulation, as they could offer ways to increase bone density. A damaging mutation in SMAD9 has recently been associated with high bone mass. Here we show that Smad9 labels groups of osteochondral precursor cells, which are not labelled by the other Regulatory Smads: Smad1 or Smad5. We show that Smad9+ cells are proliferative, and that the Smad9+ pocket expands following osteoblast ablation which induced osteoblast regeneration. We further show that treatment with retinoic acid, prednisolone, and dorsomorphin all alter Smad9 expression, consistent with the effects of these drugs on the skeletal system. Taken together these results demonstrate that Smad9+ cells represent an undifferentiated osteochondral precursor population, which can be manipulated by commonly used skeletal drugs. We conclude that Smad9 represents a target for future osteoanabolic therapies.

Incidence and Management of Hypertriglyceridemia-Associated Acute Pancreatitis: A Prospective Case Series in a Single Australian Tertiary Centre.

BACKGROUND: Hypertriglyceridemia-associated acute pancreatitis (HTGAP) has been linked with increased severity and morbidity. In this study, triglyceride levels were measured in all patients admitted with acute pancreatitis (AP) to establish the incidence of HTGAP in an Australian center. METHODS: A prospective cohort with AP was collated over an 18-month period in a single tertiary referral hospital. HTGAP was defined as AP with triglycerides ≥ 11.2 mmol/L (1000 mg/dL). Incidence, clinical co-morbidities, severity and management strategies were recorded. RESULTS: Of the 292 episodes of AP, 248 (85%) had triglycerides measured and were included. HTGAP was diagnosed in 10 of 248 (4%) AP cases. Type 2 diabetes, obesity, alcohol misuse and gallstones were common cofactors. The HTGAP group demonstrated severe hypertriglyceridemia compared to the non-HTGAP group (median 51 mmol/L vs. 1.3 mmol/L). Intensive care unit (ICU) admissions were significantly increased (odds ratio (OR) 16; 95% CI 4-62) in the HTGAP group (5/10 vs. 14/238 admissions, p < 0.001) and constituted 26% (5/19) of total ICU admissions for AP. Four patients received intravenous insulin with fasting and had a rapid reduction in triglyceride levels by 65-77% within 24 h; one patient had mild hypoglycemia secondary to therapy. CONCLUSION: HTGAP occurred in 4% of AP cases and was associated with higher risk of ICU admission. Intravenous insulin and fasting appear safe and efficacious for acutely lowering triglyceride levels in HTGAP.

A Systematic Review of Prophylactic Anticoagulation in Nephrotic Syndrome.

INTRODUCTION: Nephrotic syndrome is associated with an increased risk of venous and arterial thromboembolism, which can be as high as 40% depending on the severity and underlying cause of nephrotic syndrome. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend prophylactic anticoagulation only in idiopathic membranous nephropathy but acknowledge that existing data are limited and of low quality. There is a need for better identification of vulnerable patients in order to balance the risks of anticoagulation. METHODS: We undertook a systematic search of the topic in MEDLINE, EMBASE and COCHRANE databases, for relevant articles between 1990 and 2019. RESULTS: A total of 2381 articles were screened, with 51 full-text articles reviewed. In all, 28 articles were included in the final review. CONCLUSION: We discuss the key questions of whom to anticoagulate, when to anticoagulate, and how to prophylactically anticoagulate adults with nephrotic syndrome. Using available evidence, we expand upon current KDIGO guidelines and construct a clinical algorithm to aid decision making for prophylactic anticoagulation in nephrotic syndrome.