Abstract
Osteoclasts are multinucleated giant cells that play a critical role in bone resorption. It has been proposed that osteoblasts or bone marrow stromal cells are involved in osteoclastogenesis through a mechanism involving cell-to-cell contact with osteoclast precursors. This hypothesis was proved by the discovery of a new member of the TNF ligand family, receptor activator of nuclear factor-κB ligand (RANKL). Osteoclast precursors that express RANK, a TNF receptor family member, recognize RANKL and differentiate into osteoclast in the presence of macrophage colony-stimulating factor (M-CSF). The in vivo significance of RANKL-RANK signaling pathway has been verified by the observations that targeting disruption of either gene in mice results in severe osteopetrosis and a total lack of osteoclasts. Various pathological conditions which lead to excessive bone loss, such as rheumatoid arthritis, periodontal diseases and bone cancer have been shown to be influenced by cellular components e.g., T lymphocytes as well as by soluble factors produced by infiltrating lymphocytes. The term of "osteoimmunology" is an emerging concept that proposes that certain regulatory molecules link between bone metabolism and the immune system. For example, RANKL selectively induces NFATc1 expression via Ca^<2+> oscillations that lead to calcineurin-mediated activation of NFATc1, and therefore triggers a sustained NFATc1-dependent transcriptional program during osteoclast differentiation. NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts in response to RANKL stimulation, and that overexpression of NFATc1 causes precursor cells to undergo efficient differentiation without RANKL signaling. Thus, NFATc1 may represent a master regulator of terminal differentiation of osteoclasts. Another key molecule in this link between bone and immune responses is the transcription factor NF-κB. The targeting disruption of NF-κB p50/p52 was the first genetic model to reveal a direct link, but subsequently studies on IKK α and NIK deficient mice have further strengthened the evidence for this cross-talk. We have recently demonstrated that the NBD peptide, which selectively inhibits NF-κB activation can also efficiently inhibit osteoclastogenesis. It is now well accepted that NF-κB plays an essential role for osteoclast differentiation, however the molecular mechanism how does NF-κB regulate osteoclast differentiation remains unclear. It is still important to identify the target genes of NF-κB and define the molecular mechanisms through which NF-κB regulates osteoclast differentiation.
