Bone Morphogenetic Protein Signals Are Required for Cartilage Formation and Differently Regulate Joint Development During Skeletogenesis

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Abstract
The bone morphogenetic protein (BMP) family consists of a large number of members and has diverse biological activities during development. Various tissues express pleural BMP family members, which seem to cooperatively regulate developmental events. Here, multiple BMP signals were inactivated in chondrocytes to clarify the function of BMPs during skeletogenesis. To obtain tissue-specific inactivation, Noggin gene (Nog) was overexpressed in cartilage under the control of a2(XI) collagen gene (Collla2) promoter/enhancer sequences. The resultant transgenic mice lacked most of their cartilaginous components, suggesting that cartilage does not develop without BMP signals. These effects seem to be mediated through down-regulation of Sox9 expression. Conversely, specific BMP signals were activated in the skeleton by targeted expression of Bmp4 in cartilage and the resultant phenotype was compared with that of transgenic mice expressing growth and differentiation factor-5 (GDF-5), another BMP family member. Overactivity of Bmp4 in the skeleton caused an increase of cartilage production and enhanced chondrocyte differentiation, as GDF5 expression did, but it did not disturb joint formation as GDF5 did. During skeletogenesis, unique roles of each BMP may reside in the regulation of joint development. Together with the common effect on the cartilage overproduction by Bmp4 and GDF5 overactivation, loss of cartilage by inactivation of multiple BMPs in Noggin transgenic mice indicates that signals for cartilage production are reinforced by multiple BMPs exclusively. These conclusions may account for the reason why multiple BMPs are coexpressed in cartilage.