Parathyroid hormone-related peptide inhibits the expression of bone morphogenetic protein-4 mRNA through a cyclic AMP/protein kinase A pathway in mouse clonal chondrogenic EC cells, ATDC5

Abstract

The bone morphogenetic proteins (BMPs) play crucial roles in chondrogenic differentiation. Little is known, however, regarding the regulation of BMP gene expression. Here we examined the effect of parathyroid hormone-related peptide (PTHrP) (1-141), a full-length form of PTHrP molecules, on the expression of BMP-4 mRNA in clonal mouse chondrogenic EC cells, ATDC5. In differentiated ATDC5 cells, the expression of BMP-4 mRNA was inhibited by PTHrP (1-141), which stimulated cAMP accumulation and protein kinase A (PKA) activity in these cells. Dibutyryl cAMP, a permeable analog of cAMP, mimicked and H-89, a selective PKA inhibitor, blocked this effect of PTHrP (1-141). Moreover, actinomycin D attenuated the inhibition of BMP-4 mRNA expression by PTHrP (1-141). These results indicate that PTHrP (1-141) transcriptionally inhibits the expression of BMP-4 mRNA through a cAMP/PKA pathway in ATDC5 cells.

Regulation of Osteoprotegerin Gene Expression in Dental Follicle Cells

“…For example, activators of PKA, such as forskolin or dbcAMP, inhibit expression of OPG mRNA in primary osteoblasts (Takami et al, 2000), as well as reducing CSF-1 mRNA induced by IL-1␣ in a pancreatic carcinoma cell line (Kamthong et al, 2000). Inhibiting PKA activity also can inhibit the effect of PTHrP on enhancing gene expression, as seen in inhibition of the PTHrP-induced increase in IL-6 mRNA (Valin et al, 2001) and inhibition of the PTHrP-induced increase of BMP-4 mRNA (Ito et al, 2000). Activators of the PKC pathway such as PMA stimulate the expression of OPG mRNA in primary osteoblasts (Takami et al, 2000).…”

Simultaneous stimulation of EP2 and EP4 is essential to the effect of prostaglandin E2in chondrocyte differentiation

“…In contrast, Sylvia et al 21 have shown that the EP1 receptor subtype mediates various PGE 2 -induced cellular responses in chondrocytes derived from rat costochondral cartilage leading to decreased proliferation and enhanced differentiation. However, cAMP has been repeatedly reported to play a crucial role in chondrocyte differentiation 6,22,23 , and the functions of EP2 and EP4 remain to be clarified. We have screened compounds on a panel of the cloned receptors and developed agents that act specifically at each EP subtype 24 .…”

Parathyroid Hormone Related Protein (PTHrP)-Associated Molecular Signatures in Tissue Differentiation and Non-Tumoral Diseases

“…Several early lines of evidence have revealed that PTHrP opposes chondrogenic differentiation both in vitro and in vivo [44,45,46]. Ito et al [47] reported that, in mouse chondrogenic embryonic carcinoma ATDC5 cells, PTHrP negatively modulated the mRNA lev-…”

“…Several early lines of evidence have revealed that PTHrP opposes chondrogenic differentiation both in vitro and in vivo [44][45][46]. Ito et al [47] reported that, in mouse chondrogenic embryonic carcinoma ATDC5 cells, PTHrP negatively modulated the mRNA levels of bone morphogenetic protein 4 (BMP4), thus decreasing the amplitude of the chondrogenic signal. Moreover, in chick upper sternal chondrocytes cotreated with BMP2, PTHrP abrogated the expression of RUNX2, which, in the cartilage acts, as an inducer of chondrocyte maturation both in vitro and in vivo [48].…”