Why does bone respond so differently to inflammation in RA and SpA? Although the complex molecular networks have not been fully elucidated, Wnt signaling seems to play a crucial role in determining the effects of arthritis on bone. As described previously, low levels of Wnt activity yield low bone formation and high bone resorption in arthritis, while high levels of Wnt activity can increase bone formation and simultaneously block bone resorption. Indeed, studies indicate that patients with SpA show low levels of the Wnt inibitors Dkk-1 and sclerostin.13,20 Furthermore, Dickkopf-1 blockade can induce fusion of sacroiliac joints in experimental arthritis.21 In contrast, blockade of TNF-α does not appear to inf-luence new bone formation in SpA because TNF-α blockade neither halts new bone formation in experimental animal models of arthritis nor blocks new bone formation in patients with SpA.22 Importantly, TNF-α is a potent down-regulator of bone formation; it is therefore unlikely that blockade of TNF-α reduces new bone formation in SpA. Together, these findings point to a need for new therapeutics to target new bone formation and prevent the ankylosis of joints in SpA.
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Explore This IssueJuly 2011
Bone Marrow Niche
Until now, we have focused on the role of the immune system on bone pathology and the results of bone resorption or new bone formation. In addition to being a target of the immune system in arthritis, however, bone also may promote immunopathogenesis and serve as key player in the orchestra of cells that comprise the immune system.
Among its important direct effects on the immune system, bone provides a special micro-environment, the so-called “bone marrow niche,” a critical site for early B-cell differentiation as well as survival of long-lived B and plasma cells.23 In this context, pre-pro B cells (i.e., the earliest B-cell precursors) and mature plasma cells require CXC chemokine ligand (CXCL)–12 for homing. CXCL-12–expressing cells are a small population of stromal cells that are scattered throughout the bone marrow.24 Of note, these cells allow not only the homing of memory B cells and plasma cells to the marrow but also provide survival signals to increase longevity and promote their activity in establishing and maintaining immunological memory.
Bone seems to be the target and victim from damage inflicted at the hands of the immune system. Indeed, in inflammatory arthritis, bone erosion is the dreaded outcome of the immune system’s destructiveness. As is now realized, however, this view is too simplistic because bone can drive the immune system as well as withstand its blows.
As indicated by a series of intriguing experiments, plasma cells, by means of CXCL 12–induced chemotaxis, can traffic into survival niches in the bone marrow, where they produce antibodies and persist. If bone marrow homing of plasma cells is disturbed, however, a condition observed in murine lupus models where plasma cells are unresponsive to the effects of CXCL-12, a marked accumulation of plasma cells in the spleen, can occur.23 Furthermore, circulating B cells may only become memory B cells if they find appropriate survival conditions outside of the restimulating secondary lymphoid organs. Finally, recent findings on the role of osteoclast-derived cathepsin K in TH17 differentiation and toll-like receptor responses as well as on osteoclast-dependent mobilization of hematopoetic cells from the bone marrow are further evidence for an active role of bone in its duet with the immune system.25,26
In the past, we learned how the immune system can alter the structure and function of bone under physiologic conditions as well as during the course of inflammatory disease. These findings have led to the development of therapies for patients with rheumatic diseases that can reduce deleterious effects in the skeleton, whether bone erosion in the joint or periarticular bone loss and diffuse osteoporosis. We are now learning about the role of the other member of the duet and have gained important insights into how bone affects the immune system. Hopefully, the new knowledge of the roles of both members of the duet will deepen our understanding of the pathogenesis of rheumatic disease and lead to the development of new and more effective approaches to the treatment of the wide range of rheumatic diseases.