The balance between osteoblast-dependent bone formation and osteoclast-dependent bone resorption maintains bone homeostasis. In inflammatory conditions, this balance shifts toward bone resorption, causing osteolytic bone lesions observed in rheumatoid arthritis and periodontitis. A recently discovered family of cytokine IL-17 is widely reported to mediate diverse inflammatory processes. During the last decade, novel roles for IL-17 in skeletal homeostasis have been discovered indicating the potential importance of this cytokine in bone metabolism. This review will summarize and discuss the involvement of IL-17 during bone homeostasis in both physiologic and pathologic conditions. A better understanding of the role of IL-17 in skeletal systems warrants an advance in bone biology, as well as development of therapeutic strategies against bone-lytic diseases, such as rheumatoid arthritis and periodontitis. [BMB Reports 2013; 46(10): 479-483] IL-17 is a recently discovered family of cytokines composed of six members (1) . IL-17A was cloned in T cell hybridoma, as the first member of the new class of cytokine and generally entitled as IL-17 (2) . Additional isoforms homologous to IL-17A designated as IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F were discovered afterwards (3) . IL-17 is produced by a specialized subset of CD4+ T cells, called Th17 cells (4) . It is likely that the primary function of Th17 cells is to eliminate pathogens and IL-17 is a potent inducer of inflammation. The receptors for IL-17, IL-17R, constitute a distinct family of cytokine receptor (3) . In contrast to IL-17, IL17 receptor expression is ubiquitous, suggesting a possibility that IL-17 might affect the function of a wide variety of target cells. Until now, five members including IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE had been identified. IL-17RA is the founding member of this receptor family and binds to IL-17A (5) . The ligand-receptor specificity of IL-17-IL-17R interaction is yet to be fully unveiled. However, it has been demonstrated that IL-17RA and IL-17RC bind to IL-17A and IL-17F (6 , 7) . It has been shown that IL-17 can induce a wide variety of pro-inflammatory mediators in various types of cells involved in tissue damage, including macrophages. For example, IL-17 promoted the production of cytokines, such as IL-6, IL-1β, and TNF-α in mouse Kupffer cells (8) . IL-17 stimulated the production of IL-6 and TNF-α in human macrophages obtained from peripheral blood (9) . The increase of IL-6 following IL-17 treatment has also been reported in mouse microglia (10) . Similar induction of IL-6 was also reported in IL-17-stimulated human gingival fibroblasts (11) . Human peripheral blood mononuclear cell-derived macrophages responded to IL-17 to greatly enhance the production of IL-1β and TNF-α (11 , 12) . IL-17 is also known to trigger chemokine production. The most frequently reported chemokine instigated by IL-17 is IL-8, which was observed in human gingival fibroblasts (11 , 13) and human macrophages (9) . In mouse microglia, IL-17 also induced CXCL2 production (10) . In addition, IL-17 significantly elevated the expression of CCL2 in human macrophages (14) , CCL4 and CCL5 in mouse macrophages (15) , and CCL20 in human gingival fibroblasts (16) . IL-17 stimulated the production of prostaglandin E2 in MC3T3-E1 pre-osteoblasts (17 , 18) . Finally, IL-17 induced nitric oxide eneration in MC3T3-E1 cells (19) and in mouse astrocytes (20) . Bone homeostasis is intricately maintained by the coordination of bone formation by osteoblasts and bone resorption by osteoclasts. The role of IL-17 in the process of bone remodeling was first demonstrated in a study performed by Kotake et al . that showed IL-17, abundant in synovial fluids of rheumatoid arthritis patients, stimulated osteoclastogenesis in an osteo-blast-dependent manner (21) . Numerous following studies corroborated the pro-osteoclastogenic role of IL-17 both in vitro and in vivo . IL-17 stimulated bone resorption in combination with TNF-α in fetal mouse long bones (22) . However, whether IL-17 is directly working on osteoclast precursors or indirectly affecting osteoclast differentiation through stromal cells had not been clarified until Sato et al . revealed the role of Th17 cells on osteoclastogenesis (23) . In an effort to dissect the role of T cells in arthritic bone destruction, the authors discovered that IL-17 only stimulated the osteoclastogenesis in a co-culture of mouse osteoclasts and bone marrow macrophages (osteoclast precursors), while having no effect on the differentiation of a macrophage-only culture, suggesting that IL-17 induces the expression of RANKL (the osteoclast differentiation factor) in osteoclast-supporting cells, such as osteoblasts. Yet, the direct effect of IL-17 on osteoclast precursors is still controversial. IL-17 induced osteoclast differentiation from human monocytes in the absence of osteoblasts (24) . In contrast, Kitami et al . reported that IL-17 inhibited osteoclast differentiation from RAW264.7 cells (25) . Recently, it was reported that IL-17 inhibits osteoclastogenesis in mouse osteoblast-bone marrow cell co-culture by inducing the release of GM-CSF, an anti-osteoclastogenesis cytokine (26) . While the exact role of IL-17 in osteoclastogenesis still needs to be fully unveiled, it is likely that the effect of IL-17 on osteoclast differentiation is largely affected by multiple factors, such as the source of the osteoclast precursors, species, and culture conditions. 　Little is known about the role of IL-17 in osteoblast differentiation and bone formation. Huang et al . published that IL-17 stimulated the formation of the colony-forming unit-fibroblast (CFU-f) from both human and mouse bone marrow stromal cells, suggesting that IL-17 is a growth factor for mesenchymal stem cells (27) . Indeed, the CFU-f formation induced by CD4+ T cells was significantly reduced after bone marrow transplant in IL-17RA-deficient recipient mice. In line with these observations, IL-17 enhanced the proliferation, as well as osteogenic differentiation of human mesenchymal stem cells (28) . The IL-17-induced mesenchymal stem cell proliferation was dependent upon the generation of reactive oxygen species (ROS) mediated by NADPH oxidase 1 downstream of TRAF6 and Act1. Then, ROS activated the MEK-ERK pathway to stimulate mesenchymal stem cell proliferation. Importantly, IL-17 induced the expression of M-CSF and RANKL, crucial cytokines required for osteoclast survival and differentiation, potentiating the role for IL-17 in bone remodeling. IL-17F also stimulated osteogenic differentiation of MC3T3-E1 mouse pre-osteoblast cells, as well as primary mouse mesenchymal stromal cells (29) . In mouse myoblast cell line C2C12, IL-17 promoted osteogenic differentiation, while suppressing myogenic differentiation (30) . Interestingly, IL-17 has been widely accepted to inhibit adipogenesis (31) , suggesting that IL-17 may steer mesenchymal stem cells into an osteogenic fate ( Fig. 1 ). Since the first demonstration that IL-17 is crucially involved in bone resorption in rheumatoid arthritis patients (21) , scores of papers during the last decade confirmed the role of IL-17. The treatment of mice with anti-IL-17 antibody dramatically reduced not only the joint inflammation but also cartilage and bone destruction in a collagen-induced arthritis model (32) . The neutralization of endogenous IL-17 also significantly reduced bone erosion in a mouse methylated bovine serum albumin-induced experimental arthritis model by reducing the levels of RANKL, IL-1, and TNF-α (33) . By the same token, IL-17RA-deficient mice were clearly protected from cartilage destruction following arthritis induction by bacterial cell wall challenge (34) . These results strongly suggested that blocking the IL-17 signaling could be a strategy against rheumatoid arthritis. Indeed, Genovese et al . published that a humanized anti-IL-17 antibody successfully reduced the joint scores in a rheumatoid arthritis clinical study (35) . The usefulness of the anti-IL-17 therapy was further supported by recent studies that revealed the bone-protective effect of IL-17 blockade (36 - 38) . The aforementioned bone-destructive role of IL-17 is largely mediated by enhanced RANKL production by osteoblasts (21) , synovial cells (33 , 39) , and mesenchymal stem cells (28) . In addition, the IL-17-producing Th17 cells were proven to be the RANKL-expressing T cells (23) . In a recently published article, Kikuta et al . demonstrated that Th17 cells could activate mature osteoclasts into a bone-resorbing state (40) . Thus it is likely that Th17 cells in rheumatoid synovium, not only stimulate osteoclast differentiation by M-CSF and RANKL production in osteoclast-supporting cells via IL-17 secretion, but also directly activate osteoclast bone resorption via cell-cell contact as RANKL-producing T cells. Periodontitis is a panel of inflammatory diseases of the tissues surrounding teeth that leads to the destruction of alveolar bone. The bone loss associated with periodontitis is also mediated by osteoclasts (41) . In 2003, Oda et al . discovered that the surface antigens of Porphyromonas gingivalis , a gram-negative bacterium that causes periodontitis, significantly induced IL-17 expression in peripheral blood mononuclear cells (42) . Indeed, IL-17 mRNA was readily detected in tissue samples from periodontitis patients (43) . The increased amount of IL-17 protein was also detected in gingival crevicular fluid and cellular cultures of gingival tissues from periodontitis patients (44) . These early studies suggested that IL-17 might be also linked to periodontal diseases in a similar fashion observed in rheumatoid arthritis. However, Yu et al . reported that IL-17RAdeficient mice exhibited more severe alveolar bone loss upon challenge by P. gingivalis , suggesting a bone-protective role for IL-17 signaling (45) . The authors hypothesized that the IL-17 receptor-dependent signals are required for the neutrophil- mediated clearance of periodontal pathogens. Whether IL-17 stimulates bone destruction or protects bone in periodontitis is still an open question, although increasing evidence indicates that increased IL-17 expression in both chronic and aggressive periodontitis (46 - 48) . A newly identified family of cytokine IL-17 accelerates bone metabolism by stimulating osteogenic differentiation of mesenchymal stem cells and osteoblasts and promoting pro-osteoclastogenic molecules on these cells. In conjunction with the widely accepted pro-inflammatory role, numerous reports indicate that IL-17 is involved in inflammatory bone diseases, such as rheumatoid arthritis. Indeed anti-IL-17 therapy produced promising results in clinical trials among the rheumatoid arthritis patients. Several recent reports discovered potential association between IL-17 and periodontitis, although it is controversial whether IL-17 is a bone-protective or bone-destroying cytokine in alveolar bone during periodontitis. A better understanding on the physiologic, as well as pathologic role, for IL-17 in bone metabolism will provide greater insight into the osteolytic process during periodontitis and ensure future development of therapies against this bone-destructive disease.