TY - JOUR
T1 - IL-6 is produced by adipose-derived stromal cells and promotes osteogenesis
AU - Huh, Jeong Eun
AU - Lee, Soo Young
N1 - Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP ; No. 2013R1A2A1A05005153 ; R31-2008-000-10010-0 ; No. 2012R1A5A1048236 ; No. 2012M3A9C5048708 ). J.H. was supported by the second stage of the Brain Korea 21 Project .
PY - 2013/12
Y1 - 2013/12
N2 - Although Toll-like receptors (TLRs) have been implicated in the regulation of stem cell functions, their role in osteogenic differentiation of adipose-derived stromal cells (ASCs) has not been reported. We found that ASCs express a restricted subset of TLRs, including TLR1-TLR5, and that TLR agonists such as Pam3CSK4 (TLR1/2 agonist), polyinosinic:polycytidylic acid (TLR3 agonist), lipopolysaccharide (TLR4 agonist), and flagellin (TLR5 agonist), but not R848 (TLR7/8 agonist), consistently induced osteogenic differentiation in murine-derived ASCs, which coincided with the TLR expression pattern of ASCs. Cytokine expression profiles induced by TLR agonists and results from subsequent functional assays indicated that interleukin-6 (IL-6) together with soluble IL-6 receptor (sIL-6R) enhanced osteogenic differentiation of ASCs by activating STAT3. Small interfering RNA (siRNA)-mediated STAT3-silencing blunted osteogenesis and the expression of osteogenic markers, whereas STAT3 overexpression resulted in an increase in osteogenesis. Consistently, STAT3 inhibitor treatment reduced osteogenesis, STAT3 phosphorylation, and expression of osteogenic markers including osterix. Chromatin immunoprecipitation (ChIP) assays indicated that STAT3 binding to the STAT3-binding sites on the osterix promoter increased during IL-6-stimulated osteogenesis. Our results thus establish TLRs as novel regulators of ASCs which signal through IL-6/STAT3 pathway and induce osterix expression as a part of the osteogenesis.
AB - Although Toll-like receptors (TLRs) have been implicated in the regulation of stem cell functions, their role in osteogenic differentiation of adipose-derived stromal cells (ASCs) has not been reported. We found that ASCs express a restricted subset of TLRs, including TLR1-TLR5, and that TLR agonists such as Pam3CSK4 (TLR1/2 agonist), polyinosinic:polycytidylic acid (TLR3 agonist), lipopolysaccharide (TLR4 agonist), and flagellin (TLR5 agonist), but not R848 (TLR7/8 agonist), consistently induced osteogenic differentiation in murine-derived ASCs, which coincided with the TLR expression pattern of ASCs. Cytokine expression profiles induced by TLR agonists and results from subsequent functional assays indicated that interleukin-6 (IL-6) together with soluble IL-6 receptor (sIL-6R) enhanced osteogenic differentiation of ASCs by activating STAT3. Small interfering RNA (siRNA)-mediated STAT3-silencing blunted osteogenesis and the expression of osteogenic markers, whereas STAT3 overexpression resulted in an increase in osteogenesis. Consistently, STAT3 inhibitor treatment reduced osteogenesis, STAT3 phosphorylation, and expression of osteogenic markers including osterix. Chromatin immunoprecipitation (ChIP) assays indicated that STAT3 binding to the STAT3-binding sites on the osterix promoter increased during IL-6-stimulated osteogenesis. Our results thus establish TLRs as novel regulators of ASCs which signal through IL-6/STAT3 pathway and induce osterix expression as a part of the osteogenesis.
KW - Adipose-derived stromal cell
KW - IL-6
KW - Osteogenesis
KW - Osterix
KW - STAT3
KW - TLR
UR - http://www.scopus.com/inward/record.url?scp=84881084886&partnerID=8YFLogxK
U2 - 10.1016/j.bbamcr.2013.06.025
DO - 10.1016/j.bbamcr.2013.06.025
M3 - Article
C2 - 23830919
AN - SCOPUS:84881084886
SN - 0167-4889
VL - 1833
SP - 2608
EP - 2616
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 12
ER -