Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2

Mechanisms leading to osteoporosis are incompletely understood. Genetic disorders with skeletal fragility provide insight into metabolic pathways contributing to bone strength. We evaluated 6 families with rare skeletal phenotypes and osteoporosis by next-generation sequencing. In all the families, we identified a heterozygous variant in SGMS2, a gene prominently expressed in cortical bone and encoding the plasma membrane-resident sphingomyelin synthase SMS2. Four unrelated families shared the same nonsense variant, c.148C>T (p.Arg50*), whereas the other families had a missense variant, c.185T>G (p.IIe62Ser) or c.191T>G (p.Met64Arg). Subjects with p.Arg50* presented with childhood-onset osteoporosis with or without cranial sclerosis. Patients with p.IIe62Ser or p.Met64Arg had a more severe presentation, with neonatal fractures, severe short stature, and spondylometaphyseal dysplasial Several subjects had experienced peripheral facial nerve palsy or other neurological manifestations. Bone biopsies showed markedly altered bone material characteristics, including defective bone mineralization. Osteoclast formation and function in vitro was normal. While the p.Arg50* mutation yielded a catalytically inactive enzyme, p.IIe62Ser and p.Met64Arg each enhanced the rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum. SGMS2 pathogenic variants underlie a spectrum of skeletal conditions, ranging from isolated osteoporosis to complex skeletal dysplasia, suggesting a critical role for plasma membrane-bound sphingomyelin metabolism in skeletal homeostasis.Peer reviewe

FTIR microspectroscopic analysis: future perspectives

It is widely accepted that bone strength depends on both its structural and material properties. The latter, although important, are difficult to establish until fairly recently. The new generation of infrared microspectroscopic and imaging instruments offers a unique tool in determining the material properties of bone as they allow the study of thin tissue sections and the determination of important parameters such as mineral maturity/crystallinity and collagen cross-links ratio in a spatially resolved manner, thus enabling the correlation with bone turnover. Despite the fact that the utility of such techniques as mass screening tools is currently debated since a biopsy is required, studies employing this technology have advanced our knowledge of the underlying mechanism of bone disease and the course of action of various therapeutic protocols

Effect of hormone replacement therapy on bone formation quality and mineralization regulation mechanisms in early postmenopausal women

Post-menopausal osteoporosis is characterized by a negative imbalance between bone formation and bone resorption resulting in a net bone loss, increasing the risk of fracture. One of the earliest interventions to protect against this was hormonal replacement therapy (HRT). Bone strength depends on both the amount and quality of bone, the latter including compositional / material and structural properties. Bone compositional / material properties are greatly dependent on both patient-, and tissue-age. Raman spectroscopy is an analytical tool ideally suited for the determination of bone compositional / material properties as a function of tissue age as it is capable of analyzing areas ~1 × 1 μm2 in tetracycline labeled bone forming areas. Using such analysis of humeri from an ovariectomized primate animal model, we reported that loss of estrogen results in alteration in the mineralization regulation mechanisms by osteoid organic matrix attributes at actively forming bone surfaces. In the present work, we used Raman microspectroscopic techniques to compare osteoid and youngest mineralized tissue composition, as well as relationships between osteoid organic matrix quality and quality attributes of the earliest mineralized tissue in paired iliac crest biopsies obtained from early postmenopausal women before and after two years of HRT therapy. Significant correlations between osteoid proteoglycans, sulfated proteoglycans, pyridinoline, and earliest mineralized tissue mineral content were observed, suggesting that in addition to changes in bone turnover rates, HRT affects the osteoid composition, mineralization regulation mechanisms, and potentially fibrillogenesis

The digital aqueous humor outflow meter: an alternative tool for screening of the human eye outflow facility

Vassilios P Kozobolis, Eleftherios I Paschalis, Nikitas C Foudoulakis, Stavrenia C Koukoula, Georgios LabirisDepartment of Ophthalmology and Eye Institute of Thrace, Democritus University of Thrace, Alexandroupolis, GreecePurpose: To develop, characterize, and validate a prototype digital aqueous humor outflow tonographer (DAHOM).Material and methods: The DAHOM was developed, characterized, and validated in three phases. Phase 1 involved construction of the sensor. This was broadly based on the fundamental design of a typical Schiotz tonographer with a series of improvements, including corneal indentation, which was converted to an electrical signal via a linear variable differential transducer, an analog signal which was converted to digital via ADC circuitry, and digital data acquisition and processing which was made possible by a serial port interface. Phase 2 comprised development of software for automated assessment of the outflow facility. Automated outflow facility assessment incorporated a series of fundamental improvements in comparison with traditional techniques, including software-based filtering of ripple noise and extreme variations, rigidity impact analysis, and evaluation of the impact of patient age, central corneal thickness, and ocular axial length. Phase 3 comprised characterization and validation of DAHOM, for which we developed an experimental setup using porcine cadaver eyes. DAHOM’s repeatability was evaluated by means of Cronbach’s alpha and intraclass correlation coefficient. The level of agreement with a standard Schiotz tonographer was evaluated by means of paired t-tests and Bland-Altman analysis in human eyes.Results: The experimental setup provided the necessary data for the characterization of DAHOM. A fourth order polynomial equation provided excellent fit (R square >0.999). DAHOM demonstrated high repeatability (Cronbach’s alpha ≥0.997; intraclass correlation coefficient ≥0.987) and an adequate level of agreement with a standard Schiotz tonographer.Conclusions: This study presents the development, characterization, and validation of a prototype digital tonographer. DAHOM demonstrates high repeatability and a sufficient level of agreement with a typical Schiotz tonographer, while its digital design remedies known vulnerabilities of conventional tonographers.Keywords: glaucoma, tonography, pressure, outflow facility, aqueous humo

Effects of Three Years Treatment With Once-Yearly Zoledronic Acid on the Kinetics of Bone Matrix Maturation in Osteoporotic Patients

ABSTRACT: INTRODUCTION: Yearly 5-mg infusions of Zolendronic acid (ZOL) for 3 years have shown pronounced antifracture efficacy. The purpose of the present study was to test whether ZOL affects the kinetics of forming bone material properties maturation. METHODS: Iliac crest biopsies obtained during the HORIZON-PFT clinical trial were analysed by Raman microspectroscopy in the area of actively bone forming surfaces as a function of tissue age (ZOL = 23, placebo (PLC) = 47)) in trabecular and osteonal bone, to determine ZOL’s effect on bone material quality indices (mineral / matrix, relative proteoglycan content, mineral crystallinity) maturation kinetics. RESULTS: Mineral / matrix ratio increased in both groups as a function of tissue age, at both osteonal and trabecular bone forming surfaces, ZOL exhibiting the greatest increase in the trabecular surfaces only. The relative proteoglycan content showed a dependency on tissue age in both trabecular and osteonal surfaces, with the ZOL receiving patients exhibiting significantly lower values in the tissue age 8-22 days in the trabecular surfaces. Mineral crystallinity (both crystallite length and thickness) showed a dependence on tissue age, with ZOL-treated patients exhibiting lower crystallite length compared to PLC only in the 8-22 day old tissue at trabecular surfaces, while crystal thickness was lower in the 1-5 day old tissue at both osteonal and trabecular surfaces. CONCLUSIONS: The results of the present study suggest that once-yearly administration of intravenous ZOL for 3 years in humans does not exert any deleterious effects on the evolution of intrinsic bone material properties at actively forming osteonal and trabecular surfaces, while it may have a beneficial effect on the progression of the mineral to matrix ratio and mineral maturity / crystallinity bone quality indices

Annual intraveneous zoledronic acid for three years increased cancellous bone matrix mineralization beyond normal values in the HORIZON biopsy cohort

The efficacy of 3 years’ annual intravenous administration of zoledronic acid (ZOL) in reducing vertebral and non-vertebral fractures in postmenopausal osteoporosis has been shown by the HORIZON pivotal fracture trial. Histomorphometric analysis of transiliac bone biopsies from the HORIZON participants revealed significantly improved trabecular architecture and reduced bone remodelling for the ZOL versus placebo treated patients. The aim of our study was to evaluate the cancellous and cortical bone mineralization density distribution (BMDD) in these biopsies by quantitative backscattered electron imaging (qBEI). The study cohort comprised 82 patients on active treatment (ZOL, yearly doses of 5mg), 70 treated with placebo and all received adequate Ca and VitD supplementation. Comparison of ZOL vs. placebo treated cancellous (Cn.) and cortical (Ct.) BMDD derived variables resulted in significantly higher average (Cn.CaMean +3.2%, Ct.CaMean +2.7%) and mode calcium concentrations (Cn.CaPeak +2.1%. Ct.CaPeak +1.5%), increased percentages of high mineralized bone areas (Cn.CaHigh +64%, Ct.CaHigh +31%), lower heterogeneity of mineralization (Cn.CaWidth -14%, Ct.CaWidth -13%), and decreased percentages of low mineralized bone areas (Cn.CaLow -22%, Ct.CaLow -26%) versus placebo (all p<0.001). Cn. BMDD from the patients on active treatment revealed also a statistically significant shift to higher calcium concentrations when compared to a historical normal reference BMDD. These differences in BMDD from ZOL patients compared to the other groups were in line with the correlation of BMDD variables with previously determined cancellous mineralizing surface per bone surface (Cn. MS/BS, a primary histomorphometric index for bone turnover), showing that those with lower Cn.MS/BS had higher degree of bone matrix mineralization. However, the differences in BMDD variables between the study groups remained when adjusted for Cn. MS/BS suggesting that other factors in addition to reduced bone turnover might contribute to the higher bone matrix mineralization after ZOL treatment

Correction: Advanced Glycation Endproducts and Bone Material Properties in Type 1 Diabetic Mice.

[This corrects the article DOI: 10.1371/journal.pone.0154700.]

Bone Quality determined by Fourier Transform Infrared Imaging Analysis in Mild Primary Hyperparathyroidism

Context: Mild primary hyperparathyroidism (PHPT) is characterized by asymptomatic hypercalcemia, most commonly in the absence of classical signs and symptoms. Hence, there is need to characterize this disorder with particular attention to the skeleton