Abstract
Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor (NF)-κB ligand (RANKL)-mediated osteoclast differentiation from monocyte/macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction. Protein inhibitor of activated STAT3 (PIAS3) was initially identified as a molecule that inhibits DNA binding of STAT3 and regulates many transcription factors through distinct mechanisms. To analyze PIAS3 function in osteoclasts in vivo, we have generated transgenic mice in which PIAS3 is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase (TRAP) gene promoter. PIAS3 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation. Overexpression of PIAS3 in RAW264.7 cells suppressed RANKL-induced osteoclastogenesis by inhibiting the expression of c-Fos and NFATc1. Interestingly, PIAS3 inhibits the transcriptional activity of microphthalmia-associated transcription factor (MITF) independent of sumoylation. Down-regulation of PIAS3 markedly enhances RANKL-mediated osteoclastogenesis in RAW264.7 cells. Furthermore, overexpression of PIAS3 in mouse primary osteoblast (POB), down-regulates RANKL expression induced by interleukin-6 (IL-6) cytokine family, and inhibits osteoclast formation from bone marrow macrophages (BMMs) in vitro coculture system. Down-regulation of PIAS3 leads to the accelerated expression of RANKL in POB stimulated with IL-6 and soluble IL-6 receptor (sIL-6R). Taken together, our results clearly indicate that PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts.
| Original language | English |
|---|---|
| Pages (from-to) | 2202-2212 |
| Number of pages | 11 |
| Journal | Blood |
| Volume | 113 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2009 Mar 5 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts. / Hikata, Tomohiro; Takaishi, Hironari; Jiro, Takito; Hakozaki, Akihiro; Furukawa, Mitsuru; Uchikawa, Shinichi; Kimura, Tokuhiro; Okada, Yasunori; Matsumoto, Masahito; Yoshimura, Akihiko; Nishimura, Riko; Reddy, Sakamuri V.; Asahara, Hiroshi; Toyama, Yoshiaki.
In: Blood, Vol. 113, No. 10, 05.03.2009, p. 2202-2212.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts
AU - Hikata, Tomohiro
AU - Takaishi, Hironari
AU - Jiro, Takito
AU - Hakozaki, Akihiro
AU - Furukawa, Mitsuru
AU - Uchikawa, Shinichi
AU - Kimura, Tokuhiro
AU - Okada, Yasunori
AU - Matsumoto, Masahito
AU - Yoshimura, Akihiko
AU - Nishimura, Riko
AU - Reddy, Sakamuri V.
AU - Asahara, Hiroshi
AU - Toyama, Yoshiaki
PY - 2009/3/5
Y1 - 2009/3/5
N2 - Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor (NF)-κB ligand (RANKL)-mediated osteoclast differentiation from monocyte/macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction. Protein inhibitor of activated STAT3 (PIAS3) was initially identified as a molecule that inhibits DNA binding of STAT3 and regulates many transcription factors through distinct mechanisms. To analyze PIAS3 function in osteoclasts in vivo, we have generated transgenic mice in which PIAS3 is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase (TRAP) gene promoter. PIAS3 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation. Overexpression of PIAS3 in RAW264.7 cells suppressed RANKL-induced osteoclastogenesis by inhibiting the expression of c-Fos and NFATc1. Interestingly, PIAS3 inhibits the transcriptional activity of microphthalmia-associated transcription factor (MITF) independent of sumoylation. Down-regulation of PIAS3 markedly enhances RANKL-mediated osteoclastogenesis in RAW264.7 cells. Furthermore, overexpression of PIAS3 in mouse primary osteoblast (POB), down-regulates RANKL expression induced by interleukin-6 (IL-6) cytokine family, and inhibits osteoclast formation from bone marrow macrophages (BMMs) in vitro coculture system. Down-regulation of PIAS3 leads to the accelerated expression of RANKL in POB stimulated with IL-6 and soluble IL-6 receptor (sIL-6R). Taken together, our results clearly indicate that PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts.
AB - Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor (NF)-κB ligand (RANKL)-mediated osteoclast differentiation from monocyte/macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction. Protein inhibitor of activated STAT3 (PIAS3) was initially identified as a molecule that inhibits DNA binding of STAT3 and regulates many transcription factors through distinct mechanisms. To analyze PIAS3 function in osteoclasts in vivo, we have generated transgenic mice in which PIAS3 is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase (TRAP) gene promoter. PIAS3 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation. Overexpression of PIAS3 in RAW264.7 cells suppressed RANKL-induced osteoclastogenesis by inhibiting the expression of c-Fos and NFATc1. Interestingly, PIAS3 inhibits the transcriptional activity of microphthalmia-associated transcription factor (MITF) independent of sumoylation. Down-regulation of PIAS3 markedly enhances RANKL-mediated osteoclastogenesis in RAW264.7 cells. Furthermore, overexpression of PIAS3 in mouse primary osteoblast (POB), down-regulates RANKL expression induced by interleukin-6 (IL-6) cytokine family, and inhibits osteoclast formation from bone marrow macrophages (BMMs) in vitro coculture system. Down-regulation of PIAS3 leads to the accelerated expression of RANKL in POB stimulated with IL-6 and soluble IL-6 receptor (sIL-6R). Taken together, our results clearly indicate that PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts.
UR - http://www.scopus.com/inward/record.url?scp=64049087213&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=64049087213&partnerID=8YFLogxK
U2 - 10.1182/blood-2008-06-162594
DO - 10.1182/blood-2008-06-162594
M3 - Article
C2 - 18952894
AN - SCOPUS:64049087213
VL - 113
SP - 2202
EP - 2212
JO - Blood
JF - Blood
SN - 0006-4971
IS - 10
ER -