FGF18 Represses Noggin Expression and Is Induced by Calcineurin

Martina I Reinhold,Makoto Abe,Ravi M Kapadia,Zhixiang Liao,Michael C Naski

doi:10.1074/jbc.m404855200

Abstract

Fibroblast growth factors (FGFs) and bone morphogenetic proteins strongly regulate chondrogenesis and chondrocyte gene expression. The interactions of the signaling pathways initiated by these factors are central to the control of chondrocyte differentiation. Here we show that calcium-dependent signals induce expression of FGF18, an essential regulator of bone and cartilage differentiation. The induction of FGF18 expression required the calcium-dependent phosphatase, calcineurin. The activated forms of calcineurin or the calcineurin-dependent transcription factor, NFAT4 (nuclear factor of activated T-cell 4), induced FGF18 expression. FGF18 or a constitutive active FGF receptor suppressed noggin gene induction and thereby increased chondrocyte gene expression and chondrogenesis by facilitating bone morphogenetic protein-dependent signals. These findings reinforce the interdependence of bone morphogenetic protein and FGF signaling and provide a rational explanation for abnormal bone development occurring in humans or mice with constitutively active FGF receptors.

Highlights

The fibroblast growth factors (FGFs)1 and the fibroblast growth factor receptors (FGFRs) are important regulators of cartilage growth and development [1, 2]
We show that calcium-calcineurin signaling induces FGF18 expression, as does the calcineurin substrate nuclear factor of activated T-cell 4 (NFAT4)
The differentiation of immortalized chondrocytic cells (RCJ3.1C5.18) was stimulated by 1 ␮M ionomycin as shown by increased expression of the chondrocyte-specific gene, aggrecan (Fig. 1B). These data demonstrate that calcium-dependent signals stimulate chondrocyte differentiation, and in other work [30], we show that the calcium-dependent pathway requires calcineurin

Summary

Introduction

The fibroblast growth factors (FGFs)1 and the fibroblast growth factor receptors (FGFRs) are important regulators of cartilage growth and development [1, 2]. FGF18 or a constitutive active FGF receptor suppressed noggin gene induction and thereby increased chondrocyte gene expression and chondrogenesis by facilitating bone morphogenetic protein-dependent signals. We show that calcium-calcineurin signaling induces FGF18 expression, as does the calcineurin substrate nuclear factor of activated T-cell 4 (NFAT4).

Results

Conclusion