© Borgis - Postępy Nauk Medycznych 10/2016, s. 787-794
*Dariusz Boroń1, Małgorzata Kasprzyk-Żyszczyńska2, Krzysztof Januszyk1, Bogusław Czerny3, Adam Kamiński4, Agnieszka Seremak-Mrozikiewicz5, 6, Andrzej Klejewski7, 8
The role of inflammatory factors in pathogenesis of postmenopausal osteoporosis
Rola czynników zapalnych w patogenezie postmenopauzalnej osteoporozy
1High School of Strategic Planning in Dąbrowa Górnicza
Head of High School: Professor Janusz Bohosiewicz, MD, PhD
2Department Lung Diseases and Rehabilitation, Regional Hospital of Lung Diseases and Rehabilitation in Jaroszowiec
Head of Department: Krzysztof Barczyk, MD, PhD
3Department of General Pharmacology and Pharmacoeconomics, Pomeranian Medical University in Szczecin
Head of High School: Professor Bogusław Czerny, MD, PhD
4Department of Pediatric Orthopaedics and Traumatology, Independent Public Teaching Hospital No 1. Pomeranian Medical University in Szczecin
Head of Department: Professor Maciej Kołban, MD, PhD
5Division of Perinatology and Women’s Diseases, Poznań University of Medical Sciences
Head of Division: Professor Krzysztof Drews, MD, PhD
6Department of Pharmacology and Phytochemistry, Institute of Natural Fibers and Medicinal Plants, Poznań
Head of Department: Professor Bogusław Czerny, MD, PhD
7Department of Nursing, Poznań University of Medical Sciences
Head of Department: Professor Jacek Brązert, MD, PhD
8Department of Obstetrics and Women’s Diseases, Poznań University of Medical Sciences
Head of Department: Professor Jacek Brązert, MD, PhD
Streszczenie
Osteoporoza jest chorobą metaboliczną polegającą na postępującym ubytku masy kostnej, spowodowanym utratą związków wapnia, powiązanym ze zmianami hormonalnymi oraz czynnikami genetycznymi. Osteoporoza trzykrotnie częściej występuje u kobiet, co jest związane ze zmianami hormonalnymi towarzyszącymi okresowi menopauzy. Obniżanie się masy szkieletu kostnego podczas starzenia się organizmu spowodowane jest między innymi: zaburzeniem jelitowej absorpcji wapnia, spadkiem poziomu aktywnej witaminy D, wzrostem poziomu parathormonu, wzrostem aktywności osteoklastów oraz obniżeniem poziomu estrogenów, co aktywuje proces resorpcji kości. Osteoporoza rozwija się pod wpływem interakcji pomiędzy czynnikami środowiskowymi, hormonalnymi i genetycznymi, które oddziałują na wartość BMD (gęstość mineralna kości) oraz wpływają na ryzyko złamań. Środowiskowymi czynnikami ryzyka rozwoju tej choroby są czynniki żywieniowe: niedożywienie, niedostateczna podaż wapnia czy witaminy D, styl życia, w tym brak aktywności fizycznej, stosowanie używek, liczba przebytych ciąż, przebyte choroby, zaburzenia dotyczące szpiku kostnego, przebyte stany zapalne czy zażywane leki. Odkrycie trzech podstawowych cząsteczek, które sterują pracą osteoklastów, a tym samym wpływają na osteoporozę i inne choroby kości, było punktem zwrotnym, który rozpoczął nową erę w medycynie. Te cząsteczki to aktywator receptora jądrowego czynnika κB (RANK), jego ligand RANKL oraz naturalny receptor pułapka dla RANKL, czyli osteoprotegeryna (OPG).
Wiadomo, że osteoporoza jest chorobą uwarunkowaną występowaniem licznych polimorfizmów tzw. „genów kandydujących” do jej rozwoju. W badaniach na ten temat ocenia się zmienność tych genów w populacjach ludzkich, opierając się przy tym na identyfikacji polimorfizmów pojedynczego nukleotydu (SNP). Polimorfizmy te mogą wpływać na zmienność takich cech, jak gęstość mineralna kości.
Wśród regulatorów szlaku sygnalizacyjnego przemiany kostnej podkreśla się rolę cytokin, które mogą wspierać lub hamować resorpcję kości. Interleukina IL-17 czy TNF-α zwiększają ekspresję RANKL i dlatego uznaje się je za czynniki proresorpcyjne, stymulujący osteoklastogenezę.
Summary
Osteoporosis is a metabolic disease where progressing loss of the bone mass effects from the loss of calcium compounds, associated with hormonal changes and genetic factors. Osteoporosis is three times more frequent in women which is associated with hormonal changes throughout the menopausal period. Reduced mass of the bone skeleton during ageing is caused, among other, by impaired intestinal absorption of calcium, decreased level of active vitamin D, elevated parathormone, increased activity of osteoclasts and reduced level of estrogens which activates bone resorption. Osteoporosis develops as the result of interaction between the environmental, hormonal and genetic factors which affect the bone mineral density and has a role in the risk of fracture. The environmental risk factors include the nutritional patterns: undernutrition, insufficient supply of calcium or vitamin D, lifestyle, including lack of physical activity, the use of substances, the number of pregnancies, the diseases suffered from, disorders of the bone marrow, any past inflammatory conditions or the drugs taken. Discovery of three major particles controlling osteoblasts, therefore influencing osteoporosis and other bone conditions was a turning point to start a new era of medicine. The particles are activators of the receptor of nuclear factor κB (RANK), its ligand RANKL and the natural receptor trap for RANKL, i.e. osteoprotegerin (OPG). Osteoporosis is known to be conditioned by a number of polymorphisms, the so-called “candidate genes” for its development. The studies of the condition evaluate variability of such genes across populations, based on identification of polymorphisms of a single nucleotide (SNP). The polymorphisms may influence variability of such traits, e.g. bone mineral density. Among regulators of the signaling pathways of bone remodeling, the role of cytokines has been emphasized for their capacity to enhance or to inhibit bone resorption. Interleukin IL-17 or TNF-α increase RANKL expression, therefore they are regarded as proresorptive factors, stimulating osteoclastogenesis.
Osteoporosis is a metabolic disease where progressing loss of the bone mass effects from the loss of calcium compounds, associated with hormonal changes and genetic factors. It is characterized by impairments of bone microarchitecture and the osseous tissue metabolism. Misdiagnosing and delayed treatment, both contribute to frequent fractures bringing dangerous consequences. Osteoporosis appears as a growing social issue, therefore it has been classified by the World Health Organisation as a civilization disease.
Today WHO defines the condition as a generalized metabolic disease of bones, characterized by low bone mass, impaired microarchitecture of bones, and in consequence, increased fragility and susceptibility to fractures. The definition of osteoporosis has been complemented by the value of T-score (SD – standard deviation from the average scores for the peak bone mass at the age 20-29 years). It has been accepted that the T-score value indicative of osteoporosis is below 2.5 SD from the average scores for the peak bone mass at the age 20-29 years (1).
The present number of inhabitants of Europe and the United States affected by osteoporosis exceeds 75 million, contributing to more than 2.5 million bone fractures each year. Contrary to Caucasian population, the prevalence of the condition in Afro-Americans is much lower. Osteoporosis is three times more frequent in women which is associated with hormonal changes throughout the menopausal period. Men show the bone mass higher than women, therefore significant loss of the bone mass in them is less frequent. Statistical data on osteoporotic fractures are alarming. Fractures of the hip bone in white women at advanced age have been estimated at least at 3% in year (2).
Defining the ageing process one should observe that it is characterized by reduced general physiological efficiency of the body, where katabolic changes predominate the anabolic ones and susceptibility to illness grows for both, acute and chronic conditions (3).
Ageing is also associated with structural changes within a bone, both a dense and a spongy one. Reduced mass of the bone skeleton during ageing is caused, among other, by impaired intestinal absorption of calcium, decreased level of active vitamin D, elevated parathormone, increased activity of osteoclasts and reduced level of estrogens which activates bone resorption (4).
A breakthrough in woman’s life is the perimenopausal period and the menopause itself. This time is defined as a stage characterized by gradual extinction and eventual exclusion of the ovarian function and regression of menstruation. Throughout that time the female body adapts to altered conditions associated with the lack of hormonal activity of the ovaries, the deficiency of estrogens and failure to secrete such hormones as gonadoliberin (GnRH), the foliculothropic hormone (FSH) and the luteinizing hormone (LH) (5). Reduced production of estrogens contributes not only to impaired metabolism of the osseous tissue and development of osteoporosis, but also to the growing risk of neoplastic diseases. Abrupt loss of the bone mass is experienced during a few years following the menopause. Beyond the age of 65, the loss of the bone mass reaches approximately 25% of the maximum bone mass, while during the following years the decrease is remarkably lower (6).
Osteoporosis develops as the result of interaction between the environmental, hormonal and genetic factors which affect the bone mineral density and has a role in the risk of fracture. The environmental risk factors include the nutritional patterns: undernutrition, insufficient supply of calcium or vitamin D, lifestyle, including lack of physical activity, the use of substances, the number of pregnancies, the diseases suffered from, disorders of the bone marrow, any past inflammatory conditions or the drugs taken.
The bones change throughout the human life, where the process comprise bone resorption by osteoclasts and synthesis of the matrix by osteoblasts. It is estimated that the whole human skeleton in replaced every 10-25 years. This is necessary to adapt to the changing pressures on the skeleton throughout daily routines and to repair any microfractures or microdamages. Impaired balance between the osteoclasts and the osteoblasts may effect from hormonal changes or increased production of inflammatory cytokines or growth factors which results in reduced bone mass (osteoporosis) or the increased one (osteopetrosis). While osteopetrosis is a heterogenic group of rare hereditary diseases, osteoporosis, or the bone loss, is a common condition observed in numerous diseases, such as chronic infections, parodontosis, rheumatoid arthritis, leukaemia, postmenopausal osteoporosis or lytic bone metastases. Recently, it has become apparent that the immunological cells may have a role in bone physiology which gave birth to a new scientific discipline, named osteoimmunology.
Osteoclasts originate from the line of monocytes/macrophages are specialized cells responsible for bone decay (7). In normal bone remodeling the resorptive function of osteoclasts is coupled with formation of osteoblasts (8, 9). Bone remodeling is the basic process indispensable to preserve appropriate condition of the osseous tissue. The course of the process in physiological conditions in upon inflammation is presented in figure 1a, b.
Fig. 1a, b. Bone remodeling under physiological conditions (homeostasis) (10) (a) and bone remodeling in chronic inflammation (10) (b).
a) Bone remodeling involves several types of cells: osteoblasts (OBs) which form the organic bone matrix; the bone marrow stromal cells and osteoclasts (OCs) resorbing a bone. Osteoblasts originate from the mesenchymal matrix cells. An important role in induction of osteoblastogenic transcription factors Runx2, Dlx5 and osterix is played by the pathways Wnt10 and LRP5. Osteoclasts are formed from the myeloid precursors influenced by RANK pathway and several transcription factors, e.g. NFκB i AP-1 (c-fos). RANK is activated by RANKL, member of TFN superfamily, which is a key osteoclastogenic cytokine, produced mainly by bone marrow cells and osteoblasts. RANKL activity is inhibited by osteoprotegerin, which is a soluble decoy receptor for RANKL. Bone homeostasis is regulated by the balanced resorptive activity of RANKL and the protective one of OPG.
b) Active lymphocytes T produce RANKL and its soluble form, therefore have a direct role in bone loss through induction and activation of OCs via RANKL. The quantity of RANKL exceeds the protective capacity of OPG. In addition, the proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α, promote osteoclastogenesis and bone resorption, cooperating with RANKL. Gamma interferon (IFN-γ) promoted indirectly the bone decay through its capacity to trigger antigene presentation and activation of lymphocytes T through gene presenting cells
Numerous studies carried out throughout the recent years have significantly extended our knowledge of mechanisms underlying bone mass loss. Understanding of such processes is needed to design new therapeutic methods, which would slow down the disease progression in patients with bone mass loss. Discovery of three major particles controlling osteoblasts, therefore influencing osteoporosis and other bone conditions was a turning point to start a new era of medicine. A diagram showing their role in bone physiology is presented in figure 2 and the mechanism regulating osteoclastogenesis is illustrated in figure 3.
Fig. 2. The mechanism of OPG, RANKL and RANK activity (11). RANKL is expressed by osteoblasts, bone marrow stromal cells and other cells, affected by a number of proresorptive growth factors, hormones and cytokines. Osteoblasts and stromal cells express OPG which, binding with RANKL, inhibits its activity. The main binding complex is most probably a single OPG homodimer effecting at high affinity upon RANKL single homodimer. At the absence of OPG, RANKL activates its receptor RANK on osteoclasts and their precursors. Such activity of RANK-RANKL effects in:
– recruitment of preosteoclasts and their fusion into multinuclear osteoclasts,
– activation of osteoclasts,
– survival of osteoclasts.
Each of the responses may be inhibited by OPG
Fig. 3. Regulation of osteoclastogenesis (18). Differentiation of osteoclasts is regulated by osteoblasts. The process involves membrane-bound RANKL and soluble V-CSF. Expression of RANKL by osteoblasts is supported by the hormones, e.g. parathormone or cytokines, such as IL-6 and parathormone related protein (PTHrP) and reduced by estrogens. OPG is inhibited by glucocorticoids or PTH. (s)RANKL is also expressed by active lymphocytes T. TNF-α stimulates M-CSF and release of RANKL from osteoblasts which enhances osteoclastogenesis in inflammatory conditions. RANKL and IL-1 affect osteoclasts preventing their apoptosis. RANKL-RANK interaction (circled) may be therapeutically interfered by specific monoclonal antibodies of RANKL
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