Pathophysiological unity of development of osteoporosis and arteriosclerosis of blood vessels

In the structure of mortality in the developed countries, the leading role belongs to diseases of the circulatory system. Cardiovascular diseases (arterial hypertension, ischemic heart disease, myocardial infarction), based on atherosclerosis, are rightly called the XXI century epidemic.

According to the WHO, in the world, more than 17 million people die from cardiovascular diseases per year and by 2015 the number of deaths will increase to 20 million. Along with this, one of the leading causes of functional insufficiency and disability in the adult population is osteoporosis (OP) the most known and often occurring in the world disease of the bone system with age-associated prevalence. Osteoporosis is a multifactorial polygenic disease of the skeleton, which is the most common form of metabolic osteopathy. The disease is characterized by a loss of bone mass, a violation of their microarchitectonics (destruction of trabeculae), a decrease in strength and is accompanied by a high risk of fractures.

It is the fractures, of which the most severe fractures of the neck of the femur and radius in the lower third of the forearm, determine the medical and medico-social significance of the disease, including increased mortality and associated significant economic losses. The peculiarity of osteoporosis lies in the fact that this disease affects mostly elderly and senile people. The significant increase in the incidence of osteoporosis, observed from the second half of the 20th century, naturally reflects the demographic changes that occur in the population and are manifested by the aging of the population in all industrialized countries of the world. Numerous epidemiological studies, conducted recently in the world and in Europe, indicate a positive correlation between cardiovascular diseases and pathologies of the bone system. At the same time, many authors associate osteoporosis with the progression of atherosclerosis, including the calcification of the walls of the vessels. In women with osteoporotic fractures, there is an increase in the frequency of calcification of the aorta and coronary arteries, the severity of which correlates with a decrease in bone mineral density (BMD).

Studies S. O. Song et al. A relationship was found between the decrease in the BMD of the spine and the proximal femur and the increase in the calcium content in the coronary arteries according to electron-beam computed tomography. M. Naves et al. Found that in women with postmenopausal osteoporosis, a decrease in BMD by one standard deviation from peak bone mass was associated with an increase in the risk of overall mortality by 43% and premature death from cardiovascular disease. In other studies, it was also found that in patients with a decrease in BMD, lipid concentrations in the blood are more often observed, more severe coronary atherosclerosis develops, the risk of developing a stroke and myocardial infarction is significantly increased. These data suggest that the increase in the frequency of osteoporosis, ectopic calcification and atherosclerosis in the same patients has a common pathogenetic basis. The concept that cardiovascular diseases and osteoporosis are linked through markers that simultaneously affect vascular and bone cells has been confirmed in extensive experimental studies.

Applicant for the role of this marker is the newly discovered protein osteoprotegerin (OPG), belonging to the family of receptors of tumor necrosis factor and included in the RANKL-RANK-OPG-cytokine system.

[1], [2]

Remodeling of the bone and the role of rankl-rank-opg-system

Osteoporosis is a disease that is based on the processes of bone remodeling disorders with an increase in bone resorption and a decrease in bone synthesis. Both processes of bone tissue formation are closely interrelated and result from the cellular interaction of osteoblasts (OB) and osteoclasts (OC) originating from the precursors of different cell lines: osteoblasts from mesenchymal stem cells, osteoclasts from macrophage-monocyte cells of the bone marrow. Osteoblasts are a mononuclear cell that participates in the process of bone formation and mineralization of bone matrix cells. Osteoblasts play a fundamental role in modulating bone remodeling and regulating the metabolic activity of other bone cells. They secrete a number of biologically active substances through which they affect the maturation process of the osteoclast precursor cell, turning it into a large multinucleate cell capable of participating in resorption, that is, resorption of bone tissue, acting only on the mineralized bone without altering the bone matrix itself .

Maturation and differentiation of osteoblasts are influenced by various specific factors affecting the transcription process, the most important of which is the protein Cbfal (also known as runt related transcription factor 2; RUNX2). In mice with Cbfal / RUNX2 insufficiency, there is a significant slowdown in the process of bone formation, and the maturation of OB cells is not observed. In contrast, the introduction of recombinant Cbfal into animals induces the expression of genes inherent in osteoblasts in neosteogenic cells. The significant role played by Cbfal / RUNX2 in the differentiation and maturation of osteoblasts is also manifested in the ability of the protein to regulate the function of many genes involved in the synthesis of bone proteins: collagen type 1, osteopontin (OPN), osteocalcin and sialoprotein. Paracrine and / or autocrine factors regulating the activity of intranuclear transcription processes, the synthesis of OPN and osteocalcin also affect the growth and functional capacity of the OB. These include a number of cell growth factors, modulators of cytokines, hormonal biologically active substances. The assumption that the activation and regulation of bone remodeling is a consequence of the interaction of osteoblasts and osteoclasts has been confirmed in numerous research papers. Significant progress in understanding the processes of bone remodeling was achieved with the discovery of the cytokine RANKL-RANK-OPG system, which plays a key role in the formation, differentiation and activity of osteoclasts. The discovery of this system has become a cornerstone for understanding the pathogenesis of osteoporosis, osteoclastogenesis and regulation of bone resorption, as well as other processes involved in local bone remodeling. Regulation of osteoclastogenesis is carried out mainly with the help of two cytokines: the receptor-activator of nuclear factor kappa-B (RANKL) and OPG against the background of the permissive effect of macrophage colony-stimulating factor (M-CSF).

RANKL is a glycoprotein produced by cells of the osteoblastic series, activated by T lymphocytes, which belongs to the superfamily of tumor necrosis factor (TNF) ligands and is the main stimulus of maturation of osteoclasts. The molecular basis of intercellular interaction involving the RANKL-RANK-OPG system can be represented as follows: RANKL, expressed on the surface of osteoblasts, binds to the RANK receptor located on the membranes of the precursor cells of the OC, and induces the process of differentiation and activation of osteoclasts. At the same time, bone marrow stem cells and OB release M-CSF. This polypeptide growth factor, interacting with its high affinity transmembrane receptor (c-fms), activates intracellular tyrosine kinase, stimulating the proliferation and differentiation of the osteoclast precursor cell. The proliferative activity of M-CSF is significantly increased when exposed to OB parathyroid hormone, vitamin D3, interleukin 1 (IL-1), TNF and, conversely, decreases under the influence of estrogens and OPG. Estrogens, interacting with intracellular OB receptors, increase the proliferative and functional activity of the cell, while simultaneously lowering the function of osteoclasts by stimulating the production with OPG osteoblast. OPG is a soluble receptor for RANKL, synthesized and released by osteoblastic cells, as well as stroma cells, endothelial vascular cells and B lymphocytes. OPG acts as an endogenous receptor-trap for RANKL, blocking its interaction with its own receptor (RANK), and thus inhibits the formation of mature multinucleated osteoclast cells, disrupting the process of osteoclastogenesis, decreasing the activity of bone resorption. The RANKL synthesized and released by OB cells is a specific factor necessary for the development and functioning of OK. RANKL interacts with the RANK receptor tropic to it on the membrane of the precursor cell OK (a common precursor for osteoclasts and monocytes / macrophages), leading to intracellular cascade genomic trans-formations. RANK acts on the nuclear factor kappa-B (NF-kB) via the receptor-conjugated protein TRAF6, which activates and translates NF-kB from the cytoplasm into the cell nucleus.

Accumulation of activated NF-kB increases the expression of the NFATcl protein, which is a specific trigger triggering the transcription of intracellular genes that form the process of osteoclastogenesis. The differentiated osteoclast takes a definite position on the surface of the bone and develops a specialized cytoskeleton that allows it to create an isolated cavity of resorption, a micro environment between osteoclasts and bone. The OK membrane, which is turned into a cavity formed by the cell, forms a plurality of folds, acquires a corrugated appearance, which considerably increases the resorbing surface. The microenvironment of the created cavity of resorption is acidified by electrogenic pumping of protons into it. The intracellular pH OK is maintained with the participation of carbonic anhydrase II by exchange of HCO3 / Cl ions through the antiresorptive membrane of the cell. Ionized chlorine through the anion channels of the corrugated resorptive membrane penetrates into the microcavity of resorption, as a result of which the pH in the cavity reaches values of 4.2-4.5. Acidic environment creates conditions for the mobilization of the bone mineral phase and forms optimal conditions for degradation of the organic matrix of bone tissue with the participation of cathepsin K, an enzyme synthesized and released into the resorption cavity by "acidic vesicles" OK. Increasing RANKL expression directly leads to activation of bone resorption and a decrease in the BMD of the skeleton. The introduction of recombinant RANKL by the end of the first day led to the development of hypercalcemia, and by the end of the third - a significant loss of bone mass and a decrease in the MIC. The balance between RANKL and OPG actually determines the amount of resorbed bone and the degree of change in BMD. In animal experiments, it was found that increased expression of OPG in mice leads to an increase in bone mass, osteopetrosis and is characterized by a decrease in the number and activity of osteoclasts. On the contrary, when the OPG gene is switched off, a decrease in BMD is observed, a significant increase in the number of mature, multinucleated osteoclasts, a decrease in bone density, and the occurrence of spontaneous vertebral fractures.

Subcutaneous administration to mice of recombinant OPG at a dose of 4 mg / kg / day during the week restored the MIC. In the model of adjuvant arthritis in rats, the administration of OPG (2.5 and 10 mg / kg / day) for 9 days in the initial stage of the pathological process blocked the RANKL function and prevented the loss of bone and cartilage tissue mass. The conducted experiments indicate that the OPG function basically consists in reducing or significantly "switching off" the effects caused by RANKL. It has now become apparent that maintaining the relationship between RANKL and OPG is an important condition for maintaining a balance between resorption and bone formation. Conjugacy of these two processes, relative concentrations of RANKL and OPG in bone tissue determine the main determinants of bone mass and strength. Since the discovery of the RANKL-RAMK-OPG system as the final pathway for the formation and differentiation of osteoclasts, many researchers have confirmed the leading role of this cellular-molecular mechanism of the pathogenesis of osteoporosis.

The role of the rankl-rank-opg-cytokine system in the process of vasodilation of vessels

The assumption that there is a common pathogenetic basis for osteoporosis and atherosclerosis, a certain similarity between the mechanisms of osteoporosis development and vascular calcification is confirmed in many experimental and clinical observations. It has been demonstrated that bone and vascular tissues have many identical properties at both the cellular and molecular levels. Bone tissue and bone marrow contain endothelial cells, preosteoblasts and osteoclasts - derivatives of monocytes, all of which are also normal components of the cellular populations of the vascular wall. Both bone tissue and the wall of arterial vessels under the conditions of an atherosclerotic process contain OPN, osteocalcin, morphogenetic bone protein, matrix Gla protein, collagen type I, and matrix vesicles. In the pathogenesis of atherosclerosis and OP, monocytes with differentiation into macrophages with a foamy cytoplasm within the vascular wall and into osteoclasts in bone tissue are involved. In the vascular wall there are cellular elements that differentiate into osteoblasts in accordance with the stages of formation of bone OM, producing a mineral component of bone.

Of fundamental importance is the fact that the RANKL-RANK-OPG-cytokine system that initiates osteoblasto- and osteoclastogenesis in bone tissue induces, among other things, the differentiation of osteoblasts and OK, as well as the process of mineralization of the vessel wall. Among the components of this system, directly indicating the existence of the relationship between osteoporosis and atherosclerosis, OPG attracts the greatest attention of researchers. It is known that OPG is expressed not only by bone cells, but also by cells of the cardiovascular system: myocardiocytes, smooth muscle cells of arteries and veins, endothelial cells of blood vessels. OPG is a modulator of vessel calcification, which was confirmed in the experimental work of S.Mogopa et al., Performed in intact mice and animals with a violation / absence of a gene providing OPG expression. It was found that in mice with impaired ability to synthesize OPG (OPG - / -), in contrast to the control group of animals, activation of the calcification of the arteries in combination with the development of osteoporosis and multiple bone fractures was noted. In contrast, the administration to animals with insufficient expression of OPG of a gene synthesizing it promoted inhibition of both bone resorption and vessel calcification.

Inflammation plays a key role in all stages of development of atherosclerosis, accompanied by a significant increase in plasma concentrations of inflammatory markers - cytokines (interleukin-1, a-TNF), which in turn induce bone resorption. According to the inflammatory nature of the development of atherosclerosis, the expression and release into the blood stream and surrounding OPG tissues by endothelial cells and smooth muscle cells of the vessel walls are carried out under the influence of these proinflammatory factors. Unlike stromal cells, endothelial cells and smooth muscle tissue of vessels do not react with increased synthesis and release of OPG to change the content of vitamin D3 or parathyroid hormone (PTH) in the blood plasma. OPG prevents vitamin D3-induced ectopic calcification in vessels, while simultaneously increasing the OPN, the main non-collagen matrix bone protein that acts as an inhibitor of vascular mineralization and as a trigger for the synthesis and release of endothelial and smooth muscle OPG cells. OPN, inhibiting the formation of hydroxyapatite matrix (in vitro) and vascular calcification (in vivo), in sufficiently high concentrations is synthesized and released by smooth muscle cells of the vascular wall and macrophages of the intima. Synthesis of OPN is carried out in places with a predominant mineralization of the vascular wall and is regulated by pro-inflammatory and osteogenic factors. Together with the aux3 integrin synthesized by endothelial cells in the sites of atherogenesis, OPN causes the NF-kB-dependent effect of OPG on the preservation of endothelial cell integrity. Thus, an increase in plasma and blood vessel concentrations of OPG seen in cardiovascular diseases may be due to the activity of endothelial cells, both under the influence of inflammation markers and as a result of the effect of the OPN / avb3-HHTerpnHOBoro mechanism.

Activation of NF-kB in macrophages of the arterial wall and in the OC is also one of the important mechanisms linking osteoporosis and atherosclerosis. The increase in NF-kB activity is due to the effect of cytokines released by activated T cells in the intima of the vessels, which increases the activity of serine / threonine kinase (Akt, protein kinase B), an important factor for the function, primarily of endothelial vascular cells.

It was found that as a result of the increase in the activity of protein kinase B, stimulation of eNOS and an increase in the synthesis of nitric oxide (NO) involved in the mechanism of preservation of endothelial cell integrity are observed. Like OPG, the synthesis and release of RANKL by endothelial cells is effected by cytokines of inflammation, but not by exposure to vitamin D3 or PTH, which are capable of increasing the concentration of RANKL in OB or stromal cells.

The increase in the concentration of RANKL in arterial and venous vessels is also effected as a result of the inhibitory effect of the transforming growth factor (TGF-Pj) on the OPG expression process, the content of which significantly decreases under the influence of this factor has a multidirectional effect on the RANKL content in bone and vessels: in bone tissue TGF -Pj promotes the expression of OPG OB and, as a result, OPG, binding RANKL, lowers its concentration and osteoclastogenesis activity. In the walls of the vessels, TGF-Pj increases the RANKL / OPG ratio and, as a consequence, the RANKL content, interacting with its RANK receptor on the membrane surface of the endothelial cells with the participation of intracellular signaling systems, stimulates the osteogenesis of vascular cells, activates the process of calcification, cell proliferation and migration, remodeling matrix. The result of the new concept is the synthesis of a new generation drug - denosumab, based on the modern concept of the cellular-molecular mechanism of bone remodeling development in osteoporosis and atherosclerosis process, and the elucidation of the leading role of the cytokine RANKL-RANK-OPG system in the implementation of these diseases. Denosumab (Prolia; Amgen Incorporation) is a specific human monoclonal antibody with a high degree of tropism to RANKL blocking the function of this protein. Numerous laboratory and clinical studies have shown that denosumab, exhibiting a high ability to lower RANKL activity, significantly slows down and weakens the degree of bone resorption. Currently, denosumab is used as a first-line preparation, along with bisphosphonates, in patients with systemic osteoporosis to prevent fractures of bones. Simultaneously, S. Helas et al. Established the inhibitory effect of denosumab on the ability of RANKL to realize the process of vascular calcification. Thus, the data obtained opens up new opportunities for slowing the progression of osteoporosis and atherosclerosis of the vessels, preventing the development of cardiovascular complications in osteoporosis, and preserving the health and life of patients.

S. Sagalovsky, Richter. Pathophysiological unity of development of osteoporosis and arteriosclerosis of vessels // International Medical Journal - №4 - 2012