Pb stimulates chondrogenesis and enhances the chondrogenic effect of BMP-2 and TGF-[beta] MSCs were placed in micromass culture and were treated with Pb in the presence and absence of BMP-2 (50 ng/mL) and TGF-[beta](5 ng/mL).
Pb induces Sox9, col2, and aggrecan expression and influences regulation of these genes by BMP-2 and TGF-[beta] To assess chondrogenesis in MSC cultures on the molecular level, the mRNA expression of Sox9, col2, and aggrecan were determined via real time RT-PCR.
Pb stimulates BMP-2-induced chondrogenesis in vivo.
These results demonstrate that Pb strongly inhibits BMP-2 signaling (which is opposite the effect of Pb on TGF-[beta] signaling) and suggest another mechanism by which Pb can affect the process of chondrogenesis.
Because Pb has no effect on basal TGF-[beta]-Smad and BMP-Smad signaling, and has opposite effects on these signaling pathways in the presence of their respective growth factors, it is unlikely that the induction of chondrogenesis by Pb is related to direct regulation of Smad signaling.
We have found that Pb affects neither basal BMP-2 nor TGF-[beta]signaling; thus it is unlikely that the effect of Pb on chondrogenesis is related to a direct alteration of these signaling pathways.
The complex regulation of the Smad signaling molecules makes it unlikely that the induction of chondrogenesis by Pb is cause by direct alteration of these pathways.
AP-1 activation has been shown to inhibit chondrogenesis, so it is possible that the inhibition of AP-1 could be involved in the induction of chondrogenesis by Pb (Hwang et al.
The induction of chondrogenesis by Pb in the current study is consistent with findings observed in an in vivo murine model of fracture healing (Carmouche et al.
At the same time, this finding implies that lead's influence on chondrogenesis operates independently of Smad signaling.
Given the importance of cartilage both in embryonic development and in fracture repair later in life, stimulation of chondrogenesis seems like a good thing; but if lead triggers the formation of too much cartilage at the wrong time, or prevents its further maturation into bone, this could explain lead's crippling effects on the skeleton.