The mechanism of osteoclast differentiation induced by IL-1.
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.
Kim
Jung Ha
JH
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.
Jin
Hye Mi
HM
Kim
Kabsun
K
Song
Insun
I
Youn
Bang Ung
BU
Matsuo
Koichi
K
Kim
Nacksung
N
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
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