EDITORIAL

www.nature.com/clinicalpractice/rheum Osteoimmunology: a new area of research Peter E Lipsky

Growing awareness of the close links between …osteo- CXC chemokine ligand–receptor pair CXCL12– the immune and skeletal systems has stimu lated CXCR4, as well as interactions involving Wnt development of a new field: osteoimmunology signaling. The marrow microenvironment (Walsh MC et al. [2006], Annu Rev Immunol 24: encompasses also provides survival niches for antibody- 33–63; Takayanagi H [2007], Nat Rev Immunol the analysis of secreting plasma cells and memory T and 7: 292–304). This discipline generally focuses developmental, B cells. These niches are primarily associated on three main topics. The first relates to develop- homeostatic with stromal cells and involve mental issues, especially the potential role of bone and pathologic several , chemokines and adhesion in the development of the immuno hemopoietic molecules. In addition, produce system; less attention has been devoted to the consequences large amounts of B-cell activating factor (also reciprocal relationship, because initial skeleto- of the known as TNF ligand superfamily member genesis seems to occur independently of the interactions 13B, or B-lymphocyte stimulator), which can . The second focus relates to of the immune enhance the survival of plasma cells and other the influence of the immune system on the B-lineage cells. skele tal system, and vice versa, during homeo- and skeletal Finally, pathologic damage to bone is medi- stasis, whereas the third area of focus concerns systems ated by the interaction of immune system the role of the immune system in bone pathology cells—in particular, by soluble products and the potential involvement of bone in immune derived from such cells—and bone cells, with system dysfunction. the development of bone erosion in rheuma- Several important observations provided toid (RA) providing a good example of the underpinnings of osteoimmunology. First, such damage. Bone damage in RA is medi- despite its superficially inert appearance, bone ated by increased differentiation is rapidly and continuously remodeled at a high and decreased function at sites of rate by bone-forming and bone- inflammation; proinflammatory cytokines, such resorbing osteoclasts. The latter differentiate as TNF, seem to be crucial for both processes. from myeloid cells of the immune system, which TNF increases the expression by osteoblasts of demonstrates the intimate relationship between receptor activator of nuclear factor κB ligand, bone and the immune system. Second, and and can thereby increase the local differentia- closely related to the first point, the functions of tion of bone-resorbing osteoclasts; this osteoclasts and osteoblasts are positively and also increases production of Dickkopf 1, which negatively influenced by a variety of cytokines inhibits Wnt signaling, and thereby decreases the and surface molecules, including tumor necrosis bone-synthetic activity of osteoblasts (Diarra D factor (TNF) and several , produced et al. [2007], Nat Med 13: 156–163). Conse- by cells of the immune system. Immune system quently, blocking TNF in RA exerts a powerful cells can, therefore, influence the balance inhibitory effect on the progression of bone between bone loss and bone matrix formation. damage, by suppressing osteoclast function PE Lipsky is the Third, cells residing in the bone marrow cavity, Editor-in-Chief and stimulating bone synthesis by osteoblasts. including osteoblasts and bone marrow stromal of Nature The new discipline of osteoimmunology cells, provide essential factors that influence the Clinical Practice encompasses the analysis of developmental, survival, self-renewal capacity and pluripotency Rheumatology. homeostatic and pathologic consequences of of hemopoietic stem cells. Interplay between interactions between the immune and skeletal osteoblasts and hemopoietic stem cells involves Competing interests systems. Understanding these complex inter- The author declared no a number of ligand–receptor interactions, competing interests. actions should provide new insights into the including N-cadherin–β-catenin, jagged–notch 1, functional regulation of both systems, and also www.nature.com/clinicalpractice angiopoietin 1–tyrosine kinase receptor 2, the doi:10.1038/ncprheum0764 uncover new targets for therapeutic inter vention.

MARCH 2008 VOL 4 NO 3 NATURE CLINICAL PRACTICE RHEUMATOLOGY 111