FGFR3 down-regulates PTH/PTHrP receptor gene expression by mediating JAK/STAT signaling in chondrocytic cell line.
The signaling axis comprising the parathyroid hormone (PTH)-related peptide (PTHrP), the PTH/PTHrP receptor and the fibroblast growth factor receptor 3 (FGFR3) plays a central role in chondrocyte proliferation. The Indian hedgehog (IHH) gene is normally expressed in early hypertrophic chondrocytes, and its negative feedback loop was shown to regulate PTH/PTHrP receptor signaling. In this study, we examined the regulation of PTH/PTHrP receptor gene expression in a FGFR3-transfected chondrocytic cell line, CFK2. Expression of IHH could not be verified on these cells, with consequent absence of hypertrophic differentiation. Also, expression of the PTH/PTHrP receptor (75% reduction of total mRNA) and the PTHrP (50% reduction) genes was reduced in CFK2 cells transfected with FGFR3 cDNA. Interestingly, we verified significant reduction in cell growth and increased apoptosis in the transfected cells. STAT1 was detected in the nuclei of the CFK2 cells transfected with FGFR3 cDNA, indicating predominance of the JAK/STAT signaling pathway. The reduction in PTH/PTHrP receptor gene in CFK2 cells overexpressing FGFR3 was partially blocked by treatment with an inhibitor of JAK3 (WHI-P131), but not with an inhibitor of MAPK (SB203580) or JAK2 (AG490). Altogether, these findings suggest that FGFR3 down-regulates PTH/PTHrP receptor gene expression via the JAK/STAT signaling in chondrocytic cells.
Li
Minqi
M
Center for Transdisciplinary Research, Niigata University, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Seki
Yukie
Y
Freitas
Paulo H L
PH
Nagata
Masaki
M
Kojima
Taku
T
Sultana
Sara
S
Ubaidus
Sobhan
S
Maeda
Takeyasu
T
Shimomura
Junko
J
Henderson
Janet E
JE
Tamura
Masato
M
Oda
Kimimitsu
K
Liu
Zhusheng
Z
Guo
Ying
Y
Suzuki
Reiko
R
Yamamoto
Tsuneyuki
T
Takagi
Ritsuo
R
Amizuka
Norio
N
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D015536:Down-Regulation; D053823:Hedgehog Proteins / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D053823:Hedgehog Proteins; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011799:Quinazolines; D044168:Receptor, Parathyroid Hormone, Type 1; D050791:STAT Transcription Factors; C116180:WHI P131; D051498:Receptor, Fibroblast Growth Factor, Type 3; D053612:Janus Kinases