The Negative Role of IDS in Osteoclastogenesis
Osteoclasts play an important role in bone metabolism by resorbing the bone matrix. These cells originate from hematopoietic precursors and share a common progenitor with macrophages and dendritic cells (DCs). Two essential cytokines, macrophage colony-stimulating factor (M-CSF) and TRANCE (also called RANKL, OPGL, and ODF), enable osteoclast differentiation from their monocyte/macrophage lineage precursors (Suda, Takahashi, Udagawa, et al. 1999; Yasuda, Shima, Nakagawa et al. 1998; Lacey, Timms, Tan, et al. 1998).
TRANCE, a TNF family member, supports osteoclast differentiation, survival, and activation. Binding of TRANCE to its receptor, receptor activator of nuclear factor κB (RANK), activates multiple signaling pathways mediated by TNF receptor-associated factors (TRAFs), including NF-κB, c-Jun N-terminal kinase (JNK), p38 MAP kinase, extracellular signal-related kinase (ERK), and AKT (Lee and Kim 2003; Boyle, Simonet and Lacey 2003).
It has been shown that TRANCE induces activation and/or induction of transcription factors such as Mitf, PU.1, and NFATc1 (Boyle, Simonet and Lacey 2003; Teitelbaum 2000; Teitelbaum and Ross 2003). Mitf is known to be important for osteoclastogenesis in vitro and in vivo (Holtrop, Cox, Eilon, et al. 1981; Thesingh and Scherft 1985; Luchin, Purdom, Murphy, et al. 2000).TRANCE activates Mitf via the MKK6/p38 signaling cascade. Subsequently, activated Mitf induces the expression of target genes, including TRAP, cathepsin K, and OSCAR, which are important for osteoclast differentiation or function (Luchin, Purdom, Murphy, et al. 2000; Motyckova, Weilbaecher, Horstmann, et al. 2001; Mansky, Sankar, Han, et al. 2002; So, Rho, Jeong, et al. 2003; Kim, Takami, Rho, et al. 2002), by binding to the canonical E-box sequence in the promoter region of those genes.
KeywordsPhagocytic Activity Osteoclast Differentiation bHLH Transcription Factor Regulate Osteoclast Differentiation OSCAR Gene
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