title: The mechanism of osteoclast differentiation induced by IL-1.
abstract: IL-1 is a potent cytokine that can induce bone erosion in inflammatory sites such as rheumatoid joint regions via activation of osteoclasts. Not only is IL-1 capable of activating osteoclasts, but it is also a key cytokine involved in the differentiation, multinucleation, and survival of osteoclasts. Herein, we show that IL-1 has the potential to drive osteoclast differentiation via a receptor activator of NF-kappaB ligand (RANKL)/RANK-independent mechanism. Although IL-1 has a synergistic effect on RANKL-induced osteoclast formation, IL-1 alone cannot induce osteoclast differentiation from osteoclast precursors (bone marrow-derived macrophages (BMMs)) due to a lack of IL-1 signaling potential in these cells. However, we demonstrate that overexpression of the IL-1RI receptor in BMMs or induction of IL-1RI by c-Fos overexpression enables IL-1 alone to induce the formation of authentic osteoclasts by a RANKL/RANK-independent mechanism. The expression of IL-1RI is up-regulated by RANKL via c-Fos and NFATc1. Furthermore, the addition of IL-1 to IL-1RI overexpressing BMMs (IL-1/IL-1RI) strongly activates NF-kappaB, JNK, p38, and ERK which is a hallmark gene activation profile of osteoclastogenesis. Interestingly, IL-1/IL-1RI does not induce expression of c-Fos or NFATc1 during osteoclast differentiation, although basal levels of c-Fos and NFATc1 seem to be required. Rather, IL-1/IL-1RI strongly activates MITF, which subsequently induces osteoclast-specific genes such as osteoclast-associated receptor and tartrate-resistant acid phosphatase. Together, these results reveal that IL-1 has the potential to induce osteoclast differentiation via activation of microphthalmia transcription factor under specific microenvironmental conditions.
authors: National Research Laboratory for Regulation of Bone Metabolism and Disease, Medical Research Center for Gene Regulation, Brain Korea 21, Chonnam National University Medical School, Gwangju, Korea.
authors: Jung Ha
authors: JH
authors: Kim
authors: Hye Mi
authors: HM
authors: Jin
authors: Kabsun
authors: K
authors: Kim
authors: Insun
authors: I
authors: Song
authors: Bang Ung
authors: BU
authors: Youn
authors: Koichi
authors: K
authors: Matsuo
authors: Nacksung
authors: N
authors: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000502:physiology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D051739:Microphthalmia-Associated Transcription Factor; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D053573:Receptors, Interleukin-1 Type I; C505687:Tnfrsf11a protein, mouse