such as "Introduction", "Conclusion"..etc
It has become clear over the past few years that the immunesystem plays an important role in bone biology; perhaps nowhereis this more evident than in the work of the Pacifici group.In this series, the Review by M. Neale Weitzmann and RobertoPacifici explores how estrogen deprivation leads to bone loss(80). In short, they report that estrogen, the main sex steroidregulating bone mass in both men and women (81), suppressesthe capacity of antigen-presenting cells to stimulate T cellactivation, an event that normally results in secretion of arange of proresorptive cytokines including TNF-, IL-6, and RANKL.Notably, in this circumstance RANKL is cleaved from the cellsurface. TNF- and IL-6 act on stromal cells and osteoclast precursorsto enhance bone resorption by regulating expression of pro-(i.e., RANKL and M-CSF) and antiosteoclastogenic (i.e., OPG)cytokines in the case of mesenchymal cells and by synergizingwith RANKL itself in the case of myeloid osteoclast precursors.
While these studies underscore the interface between bone andthe immune system, they represent only a fraction of the workin the "hot" new area of osteoimmunology. The elegant work ofTakayanagi and colleagues suggests that IFN- is an importantsuppressor of osteoclast formation and function (82). Nevertheless,these findings are in conflict with in vivo observations inhumans, including the report that IFN- treatment of childrenwith osteopetrosis ameliorates the disease (83) and the factthat a number of in vivo studies indicate that IFN- stimulatesbone resorption (ref. 84 and references therein). This conundrumhighlights again the need to discriminate between in vitro cultureexperiments using single cytokines and results in vivo. Manyadditional reports have implicated other cytokines in regulationof the osteoclast, including numerous ILs, GM-CSF, IFN-, stromalcell–derived factor 1, MIP-1, and MCP (85-88), but atthis time the results are either contradictory, as for GM-CSFin the murine versus human systems, or lack direct proof inhumans. Future studies are likely to clarify the currently confusingdata set. Finally, several groups have provided evidence thatmolecules traditionally considered as solely immune receptors,such as DNAX activating protein of 12 kDa (DAP12), FcR and triggeringreceptors expressed in myeloid cells, and their ligands on cellsof the stromal and myeloid/lymphoid lineages, are downstreamof RANKL and M-CSF signaling (89, 90). Mutations in DAP12 leadto a rare bone disease, Nasu-Hakola disease, in which patientsexhibit bone cysts and concomitant demyelination (91).
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