Features of Bone Tissue Remodeling under Phagocyte Stimulation

The dissertation is devoted to the study of bone tissue remodeling mechanisms, with emphasis on the role of phagocytes — neutrophils and monocytes-macrophages — in the regulation of restorative processes. It examines the cellular basis of bone remodeling, systemic and local regulation of bone tissue homeostasis, as well as the involvement of the immune system in osteogenesis in the context of osteoimmunology. The research is aimed at solving urgent clinical tasks associated with bone fractures, osteoporosis, and other pathologies in which the balance between osteoclastic and osteoblastic processes is disrupted.

Relevance of the Problem. The study of bone tissue remodeling mechanisms is of fundamental importance for solving a range of problems in various branches of clinical medicine — in cases of bone fractures, osteoporosis, neoplasms, reconstructive surgery, congenital defects, periodontitis, and other conditions. This problem is highly topical in the field of regulation of restorative processes in bone tissue, as trauma remains one of the acute problems of healthcare, comparable in significance to cardiovascular diseases. In particular, annually 5–6 out of every 100 residents of Russia sustain injuries and require various forms of medical assistance. In the United States, up to 6.2 million bone fractures are registered annually [1, 2, 84, 111, 167]. Therefore, it can be confidently stated that the study of mechanisms regulating reparative osteogenesis and the development of new effective methods for treating fractures remain highly relevant. Certain progress has been achieved in this direction, associated with the implementation of effective medical technologies, including various types of osteosynthesis. They are based, in particular, on the compression-distraction osteosynthesis method developed by G.A. Ilizarov, on creating optimal conditions for regeneration of bone and other tissues of the musculoskeletal system, and allow increasing the length of a tubular bone by 50% of its original size [27, 62]. However, it should be noted that the possibilities of controlled regeneration of bone tissue are not exhausted. This necessitates further study of the mechanisms of bone tissue remodeling that determine the nature of restorative processes in bone.

Another pressing problem of the present era is osteoporosis [35]. Its basis is the disruption of bone tissue remodeling due to the predominance of osteoclastic processes over osteoblastic ones. The pathogenetic mechanisms of osteoporosis may be varied, most often associated with disruption of hormonal regulation of bone tissue density. In recent years, immunological mechanisms of activation of osteoresorptive processes have also been demonstrated [102, 107, 130, 177]. Overall, bone tissue remodeling is characterized by staged progression, complex regulatory mechanisms, and depends on numerous factors. Today, extensive material has been accumulated on the role of the neuroendocrine and immune systems in the regulation of osteogenesis [42, 49, 97, 150, 177]. Currently, concepts of immunoregulation of osteogenesis exist, attesting to the important role of T and B lymphocytes, monocytes-macrophages in the regulation of bone formation and the possibility of its immunostimulation [8, 25, 42, 52, 207], which constitutes the essence of a new interdisciplinary direction in science — osteoimmunology [163, 195, 197]. At the same time, the involvement of various phagocyte populations in the regulation of bone tissue remodeling requires detailed investigation. In particular, neutrophils were assigned a role only in the implementation of inflammation. Nevertheless, there are grounds for the hypothesis that affecting phagocytic activity may also stimulate osteogenesis. However, this assertion requires convincing evidence. Furthermore, in recent years, new pharmacological agents (cytokine preparations, granulocyte colony-stimulating factor — G-CSF) have emerged, possessing the ability to modulate the functional activity of phagocytes, but their effect on bone tissue homeostasis remains insufficiently studied. Thus, the study of mechanisms of immunological regulation of bone remodeling involving phagocyte cells: neutrophils and monocytes-macrophages, and on this basis the development of new methods for stimulating impaired osteogenesis, is a current medical-biological task that determines the necessity and appropriateness of conducting this research.

Aim of the Study — to investigate the relationship between the state of reparative processes in bone tissue and the activity of phagocytic cells. Research objectives:

1. To compare laboratory indicators of the state of phagocytic cells with the dynamics of bone tissue regeneration in closed tibial fractures.

2. To evaluate the effect of magnetolaser exposure on the state of phagocytic activity and the course of osteogenesis.

3. To study the effect of granulocyte colony-stimulating factor on bone tissue remodeling.

Scientific Novelty. The work presents, for the first time, a comprehensive comparison of morphofunctional characteristics of various phagocyte populations with the course of reparative osteogenesis. For the first time, the effects of G-CSF on bone remodeling have been demonstrated, and the cellular mechanism of magnetolaser exposure on regenerating bone tissue has been presented. The hypothesis regarding the polarization of neutrophil granulocyte functions during bone tissue remodeling has been substantiated.

Practical Significance of the Work and Ways of Its Implementation. The data obtained on the effect of magnetolaser therapy and G-CSF on bone tissue remodeling serve for the pathogenetic justification of using these factors in various categories of patients.

The developed experimental model of tibial bone fractures can be used in pathophysiological research for investigating the mechanisms of regulation of bone tissue homeostasis.

The results obtained have been implemented in the educational process at the departments of pathological physiology, clinical laboratory and microbiological diagnostics of the State Educational Institution of Higher Professional Education «Ural State Medical Academy of the Federal Agency for Health and Social Development» during the study of the section «Inflammation».

Work Review. The dissertation materials were presented at conferences dedicated to the 25th anniversary of the Central Scientific Research Laboratory of the Chelyabinsk Medical Academy (Chelyabinsk, 2006), at the XI All-Russian Scientific Forum «Immunology Days in St. Petersburg» (St. Petersburg, 2007), at scientific conferences of the Central Scientific Research Laboratory of the Ural State Medical Academy (Yekaterinburg, 2005, 2007), at the IV Joint Forum of Immunologists of Russia (St. Petersburg, 2008).

Publications. Nine works on the dissertation topic have been published, including three in publications recommended by the Higher Attestation Commission of the Russian Federation (VAK RF).

Structure and Scope of the Dissertation. The dissertation is presented in 110 pages of typescript. It consists of an introduction, a literature review, a chapter «Methodological Issues», two chapters of original research results, a conclusion, findings and practical recommendations. The reference list includes 65 domestic and 152 foreign sources.