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Interactions Between Bone and Immune Systems: a Focus on the Role of Inflammation in Bone Resorption and Fracture Healing

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Interactions Between Bone and Immune Systems: a Focus on the Role of Inflammation in Bone Resorption and Fracture Healing PERIODICUM BIOLOGORUM UDC 57:61 VOL. 116, No 1, 45–52, 2014 CODEN PDBIAD ISSN 0031-5362 Interactions between bone and immune systems: A focus on the role of inflammation in bone resorption and fracture healing Abstract TOMISLAV KELAVA1,2 ALAN ŠUĆUR1,2 Functional interactions between the immune system and bone tissues are SANIA KUZMAC2,3 reflected in a number of cytokines, chemokines, hormones and other media- 2,3 VEDRAN KATAVIĆ tors regulating the functions of both bone and immune cells. Investigations 1 Department of Physiology and Immunology of the mechanisms of those interactions have become important for the un- University of Zagreb School of Medicine derstanding of the pathogeneses of diseases like inflammatory arthritis, in- [alata 3b, Zagreb-HR 10000, Croatia flammatory bowel disease, periodontal disease and osteoporosis. This review 2 Laboratory for Molecular Immunology first addresses the roles of the inflammatory mediators and mechanisms by University of Zagreb School of Medicine which they cause inflammation-induced bone loss. In the second part of the [alata 12, Zagreb-HR 10000, Croatia review we stress the importance of proinflammatory mediators for normal 3 Department of Anatomy fracture healing. Defective bone remodeling underlying different patho- University of Zagreb School of Medicine logical processes may be caused by disturbed differentiation and function of [alata 3b, Zagreb-HR 10000, Croatia either osteoclast or osteoblast lineage cells. Understanding of the mechanisms governing enhanced differentiation and activation of osteoclast progenitors Correspondence: in the inflammatory conditions on the one hand, and the role of inflamma- Tomislav Kelava Department of Physiology and Immunology tion in the recruitment and differentiation of multipotent progenitors into University of Zagreb School of Medicine the skeletal lineage during the fracture healing on the other hand is a criti- [alata 3, 10000 Zagreb, Croatia cal first step in developing interventions that modulate bone regeneration E-mail: [email protected] processes and in designing novel pharmacological strategies. Key words: osteoimmunology, cytokine, Introduction inflammation, bone loss, fracture one growth and remodeling are essential processes, which create the Abbreviations: Bmarrow space for hematopoiesis, shape the bones during develop- IL – interleukin ment, adapt the bone tissue to changing biomechanical forces in the LPS – lypopolysaccharide adult life, enable tooth eruption as well as regulate calcium and phos- LTB4 – leukotriene B 4 phorus homeostasis. On average, during normal bone remodeling in the M-CSF – macrophage colony-stimulating factor adult human skeleton, 5–10% of the existing bone is replaced every year. PGE2 – prostaglandin E2 RANK – receptor activator of nuclear factor KB Deregulated bone remodeling is a feature of a number of pathological RANKL – receptor activator of nuclear factor KB states, including rheumatoid arthritis, hypercalcemia of malignancy, ligand Paget’s disease and osteopetrosis. A large number of cytokines, chemo- RAG1 – recombination activating gene 1 kines, hormones, tissue growth factors and other mediators are now TLR4 – Toll like receptor 4 known to influence bone cell functions and bone mass. TNF – tumor necrosis factor Bone cells Bone tissue constantly undergoes remodeling by bone-resorbing os- Received February 17, 2014. teoclasts and bone-forming osteoblasts in a tightly coordinated sequence of events referred to as coupling (1). T. Kelava et al. Inflammation in bone resorption and fracture healing Cells of the osteoblast lineage arise from the mesen- as well as by inhibition of osteoblast activity and bone chymal stem cells that have the ability to generate a diver- formation. Production of cytokines by immune cells has sity of lineages including osteoblasts, adipocytes, chon- been associated to human diseases such as rheumatoid drocytes, myocytes and cells that support hematopoiesis arthritis and osteoporosis, causing an inflammation-in- (2-6). During the process of osteoblastic differentiation, duced bone loss. On the other hand, some immune stim- an osteoprogenitor proliferates and undergoes a series of uli may support the osteoblast function and are important maturational steps before becoming a differentiated os- for the process of fracture healing and for the response of teoblast responsible for bone formation (7). Commitment bone to infections. of mesenchymal stem cells to the osteoblast lineage re- In the first part of the review we will discuss the in- quires the canonical Wnt/b-catenin pathway and associ- flammatory mediators and mechanism by which they ated proteins (8, 9). cause inflammation-induced bone loss, while in second Osteoclasts arise from hematopoietic progenitor cells we will stress the importance of proinflammatory media- of the monocyte/macrophage lineage that through a series tors for normal fracture healing. of differentiation stages generate large multinucleated, tartrate-resistant acid phosphatase (TRAP)-positive cells Inflammation-induced bone loss capable of resorbing the mineralized matrix (10). Com- Irreversible bone destruction, resulting from imbal- mitted osteoclast progenitors express the receptor activator anced remodeling processes, is a serious complication as- k of nuclear factor B (RANK) and can be matured in vitro sociated with localized bacterial infections of bones or into fully functional osteoclasts in the presence of macro- adjacent tissues, being a key feature of caries, periodonti- phage colony-stimulating factor (M-CSF) and receptor tis or osteomyelitis (22, 23). Bone loss is also observed in k activator of nuclear factor B ligand (RANKL) (11). other inflammatory processes such as rheumatoid arthri- Defective bone remodeling underlying different path- tis, certain malignancies, osteoporosis, chronic viral infec- ological processes may be caused by disturbed differen- tions and inflammatory bowel diseases (22-24). Mecha- tiation and function of either osteoclast or osteoblast nisms underlying inflammation-induced bone loss have lineage cells. Cell culture techniques and mouse models mainly been studied in various animal and in vitro mod- with altered bone metabolism have advanced our under- els. Application of various Streptococcus strains or other standing of molecular and cellular signals involved in the Gram-positive bacteria, which are the most often cause of regulation of bone homeostasis. osteomyelitis and posttraumatic infections, is a typical model used in studies of these diseases (25). On the other Osteoimmunology hand, periodontitis and the inflammatory milieu that causes a systemic bone loss, which will be the main topic It has been almost 40 years since the first observations of our review, are most often induced by application of that cells of the immune system affect the functions of lipopolysaccharide (LPS), a major component of the cell bone cells. Since then, we have greatly expanded our un- wall of Gram-negative bacteria that increases the produc- derstanding of the interactions between hematopoietic, tion of bone-resorptive factors and creates microenviron- immune, and bone cells, which is now known as the field ments that promote the differentiation of monocytes into of „osteoimmunology” (12). bone-resorbing osteoclasts causing enhanced bone resorp- Immune cells and bone cells both originate from bone tion (26). marrow environment and are closely functionally related. LPS exerts its effects through the activation of Toll like Crosstalk between the bone and the immune system is receptor 4 (TLR4), which is expressed on both principal important for bone homeostasis and physiological bone bone cell lineages: osteoblasts and osteoclasts (27-29). remodeling. Members of the tumor necrosis factor Studies in vitro suggest that LPS supports the survival of (13,14), (TNF)-related family of ligands and receptors as osteoclasts directly and, at least in part, independently of (15, 16), well as other cytokines colony stimulating factors the production of pro-osteoclastogenic cytokines, such as (17, 18), (19, 20) and signaling molecules are essential for interleukin (IL)-1b, TNF-a, and RANKL (28,30). How- normal development and function of both systems. This ever, Liu et al. demonstrated that LPS plays a bifunc- has been well documented in many experimental models tional role in osteoclastogenesis by inhibiting osteoclast and human diseases (13, 14, 17, 21). Moreover, it has been formation from naïve osteoclast precursors, but promot- shown that bone and immune cells may share the same ing osteoclastogenesis from precursors primed with progenitors and that their differentiation may be driven RANKL (31). Studies on culture models supportive for by the same support cells (19). Multiple complex interac- osteoblast differentiation have shown that activation of tions between hematopoietic and mesenchymal lineage TLR4 on osteoblast lineage cells induces gene expression cells define the bone marrow microenvironment(6,12). for RANKL in differentiating osteoblasts(32) and, at the Various immune mediators, particularly proinflamma- same time, has an inhibitory effect on late osteoblast dif- tory cytokines and chemokines, may cause bone loss by ferentiation (27, 33). In in vivo conditions, LPS has an stimulation of osteoclast formation and resorbing activity additional indirect effect in promoting bone destruction, 46 Period biol, Vol 116, No 1, 2014. Inflammation in bone resorption and fracture healing T. Kelava et al. by activation of macrophages and
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