Epigenetic regulation of bone remodeling and its role in the pathogenesis of primary osteoporosis

Discovery of molecular mechanisms of primary osteoporosis development is fundamental to understand the pathogenesis of musculoskeletal diseases in general and for identifying key links in the genetic and epigenetic regulation of bone remodelling genes. The number of identified molecular genetic markers for osteoporosis is increasing but there is a need to describe their functional interactions. These interactions have been determined to be associated with the control of expression of a number of transcription factors and the differentiation of mesenchymal stem cells through the pathway of osteoblastogenesis or adipogenesis, and monocytic precursors through the pathway of osteoclastogenesis. The results of epigenetic studies have significantly increased the understanding of the role of post-translational modifications of histones, DNA methylation and RNA interference in the osteoporosis pathogenesis and in bone remodelling. However, the knowledge should be systematised and generalised according to the results of research on the role of epigenetic modifiers in the development of osteoporosis, and the influence of each epigenetic mechanism on the individual links of bone remodelling during ontogenesis of humans in general, including the elderly, should be described. Understanding which mechanisms and systems are involved in the development of this nosology is of interest for the development of targeted therapies, as the possibility of using microRNAs to regulate genes is now being considered. Systematisation of these data is important to investigate the differences in epigenetic marker arrays by race and ethnicity. The review article analyses references to relevant reviews and original articles, classifies information on current advances in the study of epigenetic mechanisms in osteoporosis and reviews the results of studies of epigenetic mechanisms on individual links of bone remodelling

Modern classification and molecular-genetic aspects of osteogenesis imperfecta

Osteogenesis imperfecta (imperfect osteogenesis in the Russian literature) is the most common hereditary form of bone fragility, it is a genetically and clinically heterogeneous disease with a wide range of clinical severity, often leading to disability from early childhood. It is based on genetic disorders leading to a violation of the structure of bone tissue, which leads to frequent fractures, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, renal impairment, hearing loss. Osteogenesis imperfecta occurs in both men and women, the disease is inherited in both autosomal dominant and autosomal recessive types, there are sporadic cases of the disease due to de novomutations, as well as X-linked forms. The term “osteogenesis imperfecta” was coined by W. Vrolick in the 1840s. The first classification of the disease was made in 1979 and has been repeatedly reviewed due to the identification of the molecular cause of the disease and the discovery of new mechanisms for the development of osteogenesis imperfecta. In the early 1980s, mutations in two genes of collagen type I (COL1A1and COL1A2) were first associated with an autosomal dominant inheritance type of osteogenesis imperfecta. Since then, 18 more genes have been identified whose products are involved in the formation and mineralization of bone tissue.  The degree of genetic heterogeneity of the disease has not yet been determined, researchers continue to identify new genes involved in its pathogenesis, the number of which has reached 20. In the last decade, it has become  known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes, encoding  proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells, cause imperfect  osteogenesis. A large number of causative genes complicated the classical classification of the disease and, due to new advances in the molecular basis of the disease, the classification of the disease is constantly being improved.  In this review, we systematized and summarized information on the results of studies in the field of clinical and genetic aspects of osteogenesis imperfecta and reflected the current state of the classification criteria for diagnosing the disease

Clinical, genetic aspects and molecular pathogenesis of osteopetrosis

Osteopetrosis (“marble bone”, ICD-10-78.2) includes a group of hereditary bone disorders distinguished by clinical variability and genetic heterogeneity. The name “osteopetrosis” comes from the Greek language: ‘osteo’ means ‘bone’ and ‘petrosis’ means ‘stone’, which characterizes the main feature of the disease: increased bone density caused by imbalances in bone formation and remodeling, leading to structural changes in bone tissue, predisposition to fractures, skeletal deformities. These defects, in turn, affect other important organs and tissues, especially bone marrow and the nervous system. The disease can be autosomal recessive, autosomal dominant, X-linked or sporadic. Autosomal dominant osteopetrosis has an incidence of 1 in 20,000 newborns and autosomal recessive one has 1 in 250,000. To date, 23 genes have been described, structural changes in which lead to the development of osteopetrosis. Clinical symptoms in osteopetrosis vary greatly in their presentation and severity. The mildest skeletal abnormalities are observed in adulthood and occur in the autosomal dominant form of osteopetrosis. Severe forms, being autosomal recessive and manifesting in early childhood, are characterized by fractures, mental retardation, skin lesions, immune system disorders, renal tubular acidosis. Clinical examination and review of radiographs, bone biopsy and genetic testing provide the bases for clinical diagnosis. The early and accurate detection and treatment of the disease are important to prevent hematologic abnormalities and disease progression to irreversible neurologic consequences. Most patients die within the first decade due to secondary infections, bone marrow suppression and/or bleeding. This article summarizes the current state of the art in this field, including clinical and genetic aspects, and the molecular pathogenesis of the osteopetrosis

Reactions of phosphorylated allenes with dithiocarbamates

The addition of morpholino-, piperidino-, and N,N-diethyldithiocarbamate anions to 1,2-propadiene- and 1,2-butadienephosphonates proceeds on the electrophilic 1,2-double bond of the allene system with the formation of linear dithioesters. 1-Vinylallenylphosphonates add dithiocarbamate anions on the 1,3-conjugated system of multiple bonds, forming a mixture of stereoisomeric dithioesters with a diene structure. © 1990 Plenum Publishing Corporation

The role of DNA methylation in the disorders of bone metabolism

Osteoporosis is one of multifactorial diseases, it develops from interactions between the genetic component and the environment. However, the universal epigenetic markers of osteoporosis are not yet defined. Finding the risk factors will predict the risk of osteoporosis at the preclinical stage, help define the course and severity of the disease, and develop preventive measures based on them to reduce the risk of fractures. Expanding knowledge in the field of bone biology, especially in the genetics of osteoporosis and osteoimmunology, showed that osteoporosis is a disease that occurs not only due to hormonal or mechanical disorders, but also as a clinically and genetically heterogeneous disease, and there are still unknown pathogenetic links in its structure. Decreases in bone mass and matrix mineralization as well as changes in bone microarchitecture can have different pathogenetic patterns of development and, moreover, there are unknown links of the pathogenesis of osteoporosis. It is possible that DNA methylation is one of these links and a mechanism for epigenetic regulation of gene expression. Evidence exists that this mechanism alongside regulatory miRNAs and post-translational modifications makes a significant contribution to the central processes of bone remodeling; however, the results of various studies vary greatly, and, therefore, there is a need to understand the significance of the accumulated data and to make them consistent. The purpose of this review is to compile and systematize data on the role of DNA methylation in bone metabolism in normal and pathological conditions, in the formation of osteoporosis, and to assess achievements and trends in this field of research and technologies for studying DNA methylation

Reactions of allenylphosphonates with 2-aminoethanol and amines

Dialkyl 3-methyl-1,2-butadienylphosphonates take up 2-aminoethanol, butylamine, diethylamine, and morpholine in such a way that the amino nitrogen atom adds at the central carbon of the allene triad. The reactions with primary amines lead to the corresponding 1-phosphoryl-2-amino-1-butenes and isomeric 1-phosphoryl-2-iminobutanes, while secondary amines give rise to 1,2- and 2,3-enamines. © 2005 Pleiades Publishing, Inc

Reactions of diethyl 3-methylbuta-1,2-dienylphosphonate with 2-aminobenzothiazole

A reaction of diethyl 3-methylbuta-1,2-dienylphosphonate with 2-aminobenzothiazole afforded 1-diethoxyphosphoryl-2-(2-imino-2,3- dihydrobenzothiazol-3-yl)-3-methylbut-2-ene. © 2005 Springer Science+Business Media, Inc

Reaction of 2-acetyl-5-methyl-2H-1,2,3-diazaphosphole with butane-2,3-diol

The reaction of 2-acetyl-5-methyl-2H-1,2,3-diazaphosphole with (rac)-butane-2,3-diol at temperatures below 0 °C leads to the formation of a hydrospirophosphorane containing both a diazaphospholene and a dioxaphospholane ring system and a β-hydroxy-alkoxy-1,2,3-diazaphospholene. On heating, these products form a hydrospirotetraoxaphosphorane, its tautomeric monocyclic β-hydroxyalkylphosphite and N-acetyl-N'-isopropylidene-hydrazine

Association of vascular endothelial growth factor B (VEGFВ) gene polymorphisms with intracranial aneurysms

Intracranial aneurysm (IA) is a complex disease resulting in subarachnoid hemorrhage (SAH) due to a rupture. The average worldwide prevalence of this disease is about 2–5 %, with 50 % of them ending in death or neurological disorders of varying severity, with a high probability of recurrence of hemorrhage during the frst half of the year after rupture. Subarachnoid hemorrhage is annually registered in at least 18 thousand people in Russia. Associations of polymorphic variants rs594942 and rs11603042 of the VEGFB gene in intracranial aneurysm development in the Volga-Ural region of the Russian Federation with the presence of the symptom complex of undifferentiated connective tissue dysplasia (uDST) and arterial hypertension (AH) were investigated. The C* allele rs594942 and rs11603042 of the VEGFB gene is a marker of an increased risk of IA as a whole (p = 0.025; χ2 = 5.052; OR = 1.32) in women as a whole (p = 0.001; χ2 = 10.124; OR = 1.70) and in comorbid state with uDCT (p = 0.002; χ2 = 9.501; OR = 2.34) and AG (p = 0.006; χ2 = 7.385; OR = 2.109). We found that the genotype *C*C of locus rs594942 of the VEGFB gene is a marker of an increased risk of intracranial aneurysm in general (p = 0.017; χ2 = 5.702; OR = 1.49) and among women in general (p = 0.0005; χ2 = 12.078; OR = 2.25) and with the symptomatic complex uCTD (p = 0.007; χ2 = 7.173; OR = 2.67) and AH (p = 0.010; χ2 = 6.471; OR = 2.51). We have obtained new results on the role of polymorphic variants of the VEGFB gene in the formation of intracranial aneurysm, taking into account the presence of the symptom complex uDCT and AH among the residents of the Volga-Ural region of Russia. A burdened comorbid background and the presence of undifferentiated connective tissue dysplasia and arterial hypertension can contribute to an increased risk of intracranial aneurysm, as evidenced by the results of our study