About 20 years ago osteoimmunology was identified as new field of scientific knowledge. It studies patterns of immune and bone system interactions in normal and pathological conditions. The osteoimmunology achievements have fundamentally changed our ideas about the pathogenesis of human skeleton diseases, including osteoporosis. This review presents cytokines key role in physiological and pathological bone remodeling. The issues of interaction between cytokines, osteoblasts and osteoclasts are described in detail. The crucial role of proinflammatory cytokines increased production by immunocompetent cells in the postmenopausal osteoporosis development has been characterized. Pubmed, Scopus, Web of Science, MedLine, eLIBRARY.RU databases were used for systematic literature search.
Significant successes in the study of physiological and pathophysiological patterns of bone remodeling in recent years have highlighted immune factors important role in bone tissue pathology and significantly revised our ideas about postmenopausal osteoporosis development mechanisms. Advanced osteoimmunology and evidence of immune mechanisms key role in bone remodeling disorders gave us possibility for identification of osteoporosis as chronic immune-mediated disease. Moreover, instead of the term “Osteoporosis”, the term “Immunoporosis” was reasonably used. Bone tissue is constantly in state of continuous renewal (remodeling), which is balanced by formation and resorption processes and is achieved through the coordinated functioning of the three main bone cells types. Constant and active interaction between osteocytes, osteoblasts and osteoclasts is ensured by cytokines (RANKL, osteoprotegerin, macrophage colony-stimulating factor, vascular endothelial growth factor, etc) secretion. Moreover, predominantly, bone remodeling regulation is limited by Osteocyte-Osteoblast-Osteoclast system. With pathological changes in immune reactivity, which may be caused by deficiency of estrogen, vitamin D, calcium, inflammatory diseases, etc., various types of immunocompetent cells are activated. This is accompanied with increased RANKL production by leukocyte cells, which potentiates processes of maturation, differentiation of osteoclasts, and increase in their activity. In addition to RANKL secretion, activated leukocytes, including T lymphocytes, enhance other osteoclastogenic cytokines production. IL-1, IL-6, IL-17, TNF and TGF-β are main mediators of accelerated bone loss in postmenopausal women.
Pharmacogenetic testing, that is promising technology for personalized medicine, is already being introduced into clinical practice. Pharmacogenetic approach is especially necessary when prescribing treatment for patients with osteoporosis, because anti-osteoporotic drugs effect can be assessed only after 12 months or more after therapy start. On this basis, aim of study was to estimate alendronic acid effectiveness in women with postmenopausal osteoporosis depending on rs2234693 polymorphism of estrogen receptor type 1 gene (ESR1). Material and methods. 136 patients were included to research. The studies in women were performed twice - before and 12 months after osteoporosis treatment, that included alendronic acid standard doses. Evaluation of 12-month therapy effectiveness was carried out according to bone mineral density increase based on X-ray osteodensitometry. Genotype of rs2234693 polymorphism of ESR1 gene was determined by real-time PCR. Results. Women with postmenopausal osteoporosis after alendronic acid 12-month course demonstrated significant (p<0.001) mineral density increase in various parts of skeleton - lumbar vertebrae L1-L4 (4.26% [1.00; 6.95]), left proximal region and femoral neck (2.76% [0.00; 5.95] and 2.42% [-1.41; 5.53], respectively) and right ones (3.76%[-0.20; 6.65] and 3.27% [0.00; 7.18], respectively). Patients with TT genotype of ESR1 gene rs2234693 polymorphism had lower (p<0.05) increase in mineral density of lumbar vertebrae L1-L4 (2.53% [-0.28; 5.54]) compared to all other patients (4.71% [1.75; 8.08]) or to women with CC genotype (5.52% [1.66; 9.12]). Conclusion. rs2234693 polymorphism of ESR1 gene testing in patients with postmenopausal osteoporosis before antiosteoporotic drugs prescription should be used for individualization of treatment regimens and therapy effectiveness enhancement.
The aim of work was to study blood serum concentrations of tumor necrosis factor alpha (TNF-α), interleukins (IL) -1β, -6, -10, -17A, osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) in dynamics of alendronic acid-based treatment in women with postmenopausal osteoporosis with. 136 women with postmeno- pausal osteoporosis were examined in dynamics of treatment with alendronate. Treatment duration was 12 months. TNF-α, IL-1β, IL-6, IL-10, IL-17A, OPG and RANKL serum concentrations were studied in all patients before and after treatment. Molecular genetic studies included real-time PCR testing of ESR1 gene rs2234693 polymorphisms and IL-6 gene rs1800795 one. Women with postmenopausal osteoporosis had increased serum IL-1β and IL-6 concentra- tions before and after therapy (p<0.05), as well as RANKL before treatment (p=0.033). The dynamics of OPG content (p=0.013), as well as OPG/RANKL index (p=0.010) decrease was noted during the therapy course. TT genotype of rs2234693 polymorphism of ESR1 gene in women with postmenopausal osteoporosis is associated with increased RANKL production and decreased OPG/RANKL ratio both before and after treatment (p<0.05). Women with GG geno- type of rs1800795 polymorphism of IL-6 gene are characterized by consistently increased levels of IL-6 (before and after treatment), as well as IL-17A before starting therapy (p<0.05). It is reasonable to use the obtained results for development of postmenopausal osteoporosis personalized treatment regimens development.
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