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Regulation of Indian hedgehog mRNA levels in chondrocytic cells by ERK1/2 and p38 mitogen-activated protein kinases

✍ Scribed by Lick Pui Lai; Kevin A. DaSilva; Jane Mitchell

Publisher
John Wiley and Sons
Year
2005
Tongue
English
Weight
327 KB
Volume
203
Category
Article
ISSN
0021-9541

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✦ Synopsis

Abstract

Indian hedgehog (Ihh) is produced by growth plate pre‐hypertrophic chondrocytes, and is an important regulator of endochondral ossification. However, little is known about the regulation of Ihh in chondrocytes. We have examined the role of integrins and mitogen‐activated protein (MAP) kinases in Ihh mRNA regulation in CFK‐2 chondrocytic cells. Cells incubated with the β~1~‐integrin blocking antibody had decreased Ihh mRNA levels, which was accompanied by decreases of activated extracellular signal‐regulated kinases (ERK1/2) and activated p38 MAPK. Ihh mRNA levels were also inhibited by U0126, a specific MEK1/2 inhibitor, or SB203580, a specific p38 MAPK inhibitor. Cells transfected with constitutively active MEK1 or MKK3 had increased Ihh mRNA levels, which were diminished by dominant‐negative MEK1, p38α or p38β. Stimulation of the PTH1R with 10^−8^ M rPTH (1–34) resulted in dephosphorylation of ERK1/2 that was evident within 15 min and sustained for 1 h, as well as transient dephosphorylation of p38 MAPK that was maximal after 25 min. PTH stimulation decreased Ihh mRNA levels, and this effect was blocked by transfecting the cells with constitutively active MEK1 but not by MKK3. These studies demonstrated that activation of ERK1/2 or p38 MAPK increased Ihh mRNA levels. Stimulation of the PTH1R or blocking of β~1~‐integrin resulted in inhibition of ERK1/2 and p38 MAPK and decreased levels of Ihh mRNA. Our data demonstrate the central role of MAPK in the regulation of Ihh in CFK‐2 cells. © 2004 Wiley‐Liss, Inc.

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