Deletion of Smad4 in fibroblasts leads to defective chondrocyte maturation and cartilage production in a TGFβ type II receptor independent manner.

The transforming growth factor β (TGFβ) superfamily growth factors play vital roles during the development, homeostasis, and pathogenesis of multi-cellular organisms. Smad4 serves as an exclusive co-activating smad that elicits most of the transcription responses invoked by the TGFβ superfamily members. We used Cre recombinase driven by the Fsp1/S100A4 promoter to delete the Smad4 gene in fibroblasts. We show that Fsp1/S100A4 is expressed in the elastic and fibrocartilage, and demonstrate that the fsp1-Cre; Smad4 flox/flox mutants have normal body size, but exhibit a short ear phenotype due to the deletion of the Smad4 gene in the ear chondrocytes. In contrast, TGFβ type II receptor deletion using Fsp1-cre does not lead to this phenotype, supporting the notion that non-TGFβ mediated signaling via Smad4 is essential for proper formation of ear cartilage during development. Smad4 deficiency in Fsp1(+) fibroblasts leads to defective chondrocyte maturation and cartilage production, likely due to a deficiency in bone morphogenic protein 5 (BMP-5) mediated signaling via Smad4. Our results emphasize the importance of BMP signaling pathways in the maturation and function of certain lineages of chondrocytes and offer an insight into the heterogeneity of the chondrocyte population in the body.