Expression of dominant negative TGF-β receptors inhibits cartilage formation in conditional transgenic mice

Although transforming growth factor-beta (TGF-beta) signaling has been implicated in cartilage formation in various studies, the exact role played by TGF-beta in this process remains controversial. TGF-beta signals are transduced through TGF-beta type II receptor (TGF-beta RI (TM) I (TM)) and type I receptor (ALK5). Col2a1-Cre-mediated deletion of Tgfbr2 did not cause obvious defects in long bone formation, suggesting that TGF-beta signals are dispensable for normal cartilage formation in the stage of condensing mesenchymal cells and chondrocytes or that related molecules can compensate for the lack of TGF-beta RI (TM) I (TM). In the present study, we established a conditional transgenic mouse in which a dominant negative form of TGF-beta RII (dnTGF-beta RII) is expressed in condensing mesenchymal cells and chondrocytes in limbs using the Cre/loxP system. Recombination at loxP sites and expression of dnTgfbr2 were monitored by the disappearance of LacZ expression. The conditional transgenic mice expressing dnTgfbr2 developed hypoplastic cartilage. The phenotype was much more severe than that of Col2a1-Cre-mediated Tgfbr2 conditional knockout mice, although the pattern of dnTgfbr2 expression appears similar to the pattern of Tgfbr2 deletion. These phenotypic differences suggest that the signaling through TGF-beta receptors is complex in cartilage.