Molecular and genetic predictors of impaired reparative regeneration of long bones

Abstract

The osteoinductive potential of the body and the activity of bone resorption / biosynthesis processes at the time of injury are determined by numerous factors, among which the most important are age, sex, the presence of metabolic disorders, immunological status, obliterating vascular diseases, etc [1, 6, 8]. In recent years, it has been established that hyperhomocysteinemia (HHcy) is one of the factors of vascular lesions and thrombosis, which is associated with the risk of osteoporosis, osteoporotic fractures and adversely affects reparative osteogenesis [1, 7, 12]. The toxic effect of high levels of homocysteine (Hcy) on bone tissue is mainly associated with activation of bone demineralization, collagen degradation, oxidative stress development, hypomelylation, genital destabilization and chemical modification of proteins [3, 4, 9, 10]. In the experimental conditions it was found [4, 6] that the negative effect of high levels of Hcy on the musculoskeletal system was largely realized through vascular mechanisms, by proatherogenic damage to the peripheral vessels, a violation of the vascular output of nitric oxide and increased fibroblastic expression of the transforming factor growth - β 1 (TGF-β1). Clinical studies have also proved [4, 12] that the violation of reparative osteogenesis of long bones, which leads to the formation of bone nonunion, is associated with metabolic disorders, namely: HHcy, atherogenic dyslipidemia, high levels of inflammatory mediators, and an imbalance in the nitric oxide system. It was established that the prevalence of these metabolic disorders as well as the mutations of the gene of the enzyme exchange of Hcy - methylene tetrahydrofolate reductase (MTHFR C677T) and the promoter of the synthase nitric oxide gene (eNOS T786C) is significantly higher than those with consolidated fractures [5, 11]. In this case, HHcy, atherogenic dyslipidemia, inflammatory syndrome, pathogenic genotypes MTHFR 677-TT and eNOS 786-CC, disorders of endothelial function prevail among patients with acute types of bone nonunion. However, it remains unclear which of the identified metabolic and genetic 25 factors can be used in predicting disorders of reparative osteogenesis and the formation of bone nonunion of long bones. Aim of the research. The purpose of the study: based on the methods of statistical analysis and forecasting was determined the independent metabolic and molecular genetic predictors of the violation of reparative osteogenesis and the formation of bone nonunion of long bones. Object and methods. The main monitoring group was 153 (26.11%) of 586 examined patients with bone nonunion of long bones at the level of diaphyseal who did not have established objective and iatrogenic factors of the disorders of reparative osteogenesis. The average age was 40.3±0.93 years. Male persons were - 118 (77,2%), female - 35 (22,8%). Duration of the disease from 7.5 to 126 months. According to the clinical-radiological characteristics of the bone nonunion, the normoplastic type is diagnosed in 27 (17,65%), hyperplastic – in 24 (15,69%), hypoplastic – in 50 (32,68%), atrophic – in 52 (33,98 %) of patients. Metabolic disorders in the form of HHcy were diagnosed in 125 (21.33%) patients, including its combination with dyslipidemia – in 61 (10.41%) and aberrant levels of interleukin-6 in 39 (6.65%) patients. Signs of dyslipidemia without an increase in the level of Hcy were found in 28 (4.78%) people.