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Osteoporosis in the View of Osteoimmunology: Common Feature Underlined by Different Pathogenic Mechanisms

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Osteoporosis in the View of Osteoimmunology: Common Feature Underlined by Different Pathogenic Mechanisms PERIODICUM BIOLOGORUM UDC 57:61 VOL. 117, No 1, 35–43, 2015 CODEN PDBIAD ISSN 0031-5362 Osteoporosis in the view of osteoimmunology: common feature underlined by different pathogenic mechanisms Abstract DARJA FLEGAR1,2 ALAN ŠUĆUR1,2 Osteoporosis is a skeletal disorder characterized by low bone mineral ANTONIO MARKOTIĆ1,2,3 2,4 density and microarchitectural changes with increased susceptibility to frac- NATAŠA KOVAČIĆ tures, resulting in significant morbidity and mortality. Although it pre- DANKA GRČEVIĆ1,2 dominantly affects postmenopausal women, it is now well known that sys- 1Department of Physiology and Immunology, temic bone loss is a common underlying feature of different metabolic, University of Zagreb School of Medicine, [alata 3b, endocrine and inflammatory diseases. Investigations of osteoporosis as a com- Zagreb-HR 10000, Croatia plication of chronic inflammatory conditions revealed immune mechanisms 2Laboratory for Molecular Immunology, University of behind the increased osteoclast bone resorption and impaired osteoblast bone Zagreb School of Medicine, formation. This concept was particularly emphasized after the research field [alata 12, Zagreb-HR 10000, Croatia of osteoimmunology emerged, focusing on the interaction between the im- 3Department of Physiology, University of Mostar mune system and bone. It is increasingly becoming evident that immune cells School of Medicine, Bijeli Brijeg bb, 88000 Mostar, and mediators critically regulate osteoclast and osteoblast development, func- Bosnia and Herzegovina tion and coupling activity. Among other mediators, receptor activator of 4Department of Anatomy, University of Zagreb School nuclear factor-kB ligand (RANKL), receptor activator of nuclear factor-kB of Medicine, [alata 3b, (RANK) and soluble decoy receptor osteoprotegerin (OPG) form a key func- Zagreb-HR 10000, Croatia tional link between the immune system and bone, regulating both osteoclast Correspondence: formation and activity as well as immune cell functions. Excessive produc- Danka Gr~evi} tion of inflammatory mediators exerts autocrine, paracrine and endocrine Department of Physiology and Immunology signaling effects on bone remodeling with the net increase in bone resorption University of Zagreb School of Medicine locally, in diseases primarily affecting joints, bones or surrounding tissues, [alata 3, 10000 Zagreb, Croatia and systemically, causing osteoporosis in various chronic inflammatory E-mail address: [email protected] Abbreviations: BMD – bone mineral density BME – bone marrow edema DKK-1 – Dickkopf-1 IL – interleukin M-CSF – macrophage colony-stimulating factor MRI – magnetic resonance imaging ODF – osteoclast differentiation factor OPG – osteoprotegerin PGE2 – prostaglandin E2 RANK – receptor activator of nuclear factor – kB RANKL – receptor activator of nuclear factor – kB ligand TNF – tumor necrosis factor TNFSF11 – tumor necrosis factor (ligand) superfamily, member 11 TNFRSF11A – tumor necrosis factor receptor superfamily, member 11 TRAIL – TNF-related ligand TRANCE – TNF-related activation-induced cytokine Received April 8, 2015. TRAP – tartrate-resistant acid phosphatase Darja Flegar et al. Osteoporosis in the view of osteoimmunology diseases. This brief review particularly focuses on bone pathol- bone mechanical properties and its response to metabolic ogy in rheumatoid arthritis, as one of the most extensively needs. Hence, it is regulated by numerous factors like studied conditions accompanied by local and systemic inflam- hormones, cytokines, chemokines and biochemical stim- mation-induced bone loss. uli, and therefore easily disrupted in different pathological conditions (5, 12). Well-coordinated differentiation and activation as well as synchronized function of two bone 1. INTRODUCTION cell types, osteoclasts and osteoblasts, is crucial for bone steoporosis is a systemic skeletal disease which af- homeostasis maintenance. fects more than 200 million people and is one of the O Osteoblasts are mature, cuboidal, non-proliferating major public health problems (1). It is characterized by cells that synthesize and mineralize bone matrix, and in- low bone mass and microarchitectural changes, both fluence osteoclast differentiation(13, 14). Osteoblast pro- leading to enhanced susceptibility to bone fractures and genitors arise from mesenchymal stem cells found in increased mortality risk (2, 3). Estimated occurrence of periosteum, bone marrow and circulation, which along- osteoporosis is 1 in 3 women and 1 in 12 men over the side of osteoblasts can produce a variety of lineages such age of 50 worldwide, being one of the main risk factors for pathologic fractures, mostly involving the lumbar ver- as adipocytes, chondrocytes, myocytes and hematopoiesis tebrae, hip, and wrist (4). Primary osteoporosis affects supporting cells (15-19). Osteoblastogenesis includes pro- postmenopausal women due to estrogen deficiency, and liferation and differentiation of osteoblast progenitors elderly women and men through vitamin D insufficiency through series of maturational stages to functional, bone and secondary hyperparathyroidism which contribute to matrix-secreting osteoblasts. By producing macrophage bone loss (3). On the other hand, secondary osteoporosis colony-stimulating factor (M-CSF), receptor activator of k is outlined as low bone mineral density (BMD) with in- nuclear factor- B ligand (RANKL) and osteoprotegerin creased risk of fractures caused by various factors other (OPG), osteoblasts regulate osteoclast progenitor pool than aging or postmenopause (5). Therefore, it affects men size, their differentiation and bone-resorbing activity(14, and premenopausal women who have not been typically 20). considered at high risk for primary osteoporosis (6). In- Osteoclasts are large, multinucleated, tartrate-resistant creased understanding of bone metabolism and factors acid phosphatase (TRAP)-positive, unique bone-resorb- that influence bone turnover leads to a better characteriza- ing cells (21-26). They originate from hematopoietic stem tion of diseases, disorders, treatments and medications that cells found in bone marrow and circulation. Belonging to decrease bone quality in women and men of all ages (2, myeloid monocyte/macrophage lineage, osteoclast pro- 5). These include various endocrine disorders (such as type genitors express M-CSF receptor (CD115, cFms) and re- I and II diabetes, Cushing’s syndrome, hyperthyroidism, ceptor activator of nuclear factor-kB (RANK; also known hyperparathyroidism, hypogonadism and others), meta- as tumor necrosis factor receptor superfamily, member 11, bolic disorders (Marfan syndrome, Gaucher’s disease, TNFRSF11A), activation of which is crucial for their dif- galactosemia), rheumatologic and inflammatory diseases ferentiation and maturation (27). Excessive bone resorp- (systemic lupus erythematosus, rheumatoid arthritis, an- tion is an exclusive consequence of increased osteoclast kylosing spondylitis, inflammatory bowel disease), chronic activation, since the ability of macrophages and fibroblasts diseases (chronic obstructive pulmonary disease, celiac to degrade bone is weak (28). Osteoclasts are critically disease), neurologic, hematologic and oncologic diseases involved in skeletal functions such as bone remodeling, (2-6). It also includes medications such as glucocorticoids, fracture repair and pathological bone resorption associ- anticonvulsants, glitazones, heparine, cyclosporine and ated with inflammatory conditions(29). others. Iatrogenic secondary osteoporosis thus became a long-term complication of diseases treated with these Osteoporosis results from an imbalance in bone re- medications (4, 5). In this brief review we will particu- modeling, where bone resorption predominates over bone larly focus on mechanisms of bone loss associated with formation (5, 28). Subsequent changes in bone architec- inflammatory arthritides, characterized by chronic in- ture and a net loss of bone mass make bones weak and flammatory response as well as periarticular and general- incapable of bearing physiological load. In the most severe ized bone loss due to deregulation of bone metabolism – cases of osteoporosis even normal physical activities lead bone resorption by osteoclasts and bone formation by to pathologic fractures (30). Due to most common forms osteoblasts (7-11). of osteoporosis, the postmenopausal osteoporosis and se- nile osteoporosis, and well described effects of vitamin 3D , calcium and other nutritional deficiencies on bone struc- 2. BONE PATHOLOGY IN ture, the disease is usually classified as an endocrine or OSTEOPOROSIS metabolic disorder (4). Studies investigating secondary Bone remodeling is a well balanced, continuously on- osteoporosis, where chronic inflammatory diseases, re- going homeostatic process of osteoclast bone resorption gardless of the cause and primarily affected sites, are ac- and osteoblast bone formation, ensuring and adjusting companied by systemic bone loss and increased risk of 36 Period biol, Vol 117, No 1, 2015. Osteoporosis in the view of osteoimmunology Darja Flegar et al. Figure 1. Bone loss in rheumatoid arthritis is caused by the complex interplay between immune and bone cells. Immune cells, includ- ing macrophages, neutrophils, dendritic cells, and T and B lymphocytes, infiltrate the rheumatoid synovium that is constantly inflamed and invades adjacent tissue, resulting in joint destruction. These innate and adaptive immune cells vigorously drive differentiation of osteoclast progenitors by producing proinflammatory
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