Smpd3Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development
Sphingomyelin phosphodiesterase 3 (SMPD3), a lipid-metabolizing enzyme present in bone and cartilage, has been identified to be a key regulator of skeletal development. A homozygous loss-of-function mutation called fragilitas ossium (fro) in theSmpd3gene causes poor bone and cartilage mineralization resulting in severe congenital skeletal deformities. Here we show thatSmpd3expression in ATDC5 chondrogenic cells is downregulated by parathyroid hormone-related peptide through transcription factor SOX9. Furthermore, we show that transgenic expression ofSmpd3in the chondrocytes offro/fromice corrects the cartilage but not the bone abnormalities. Additionally, we report the generation ofSmpd3flox/floxmice for the tissue-specific inactivation ofSmpd3using the Cre-loxPsystem. We found that the skeletal phenotype inSmpd3flox/flox; Osx-Cremice, in which theSmpd3gene is ablated in both late-stage chondrocytes and osteoblasts, closely mimics the skeletal phenotype infro/fromice. On the other hand,Smpd3flox/flox;Col2a1-Cremice, in which theSmpd3gene is knocked out in chondrocytes only, recapitulate thefro/fromouse cartilage phenotype. This work demonstrates thatSmpd3expression in both chondrocytes and osteoblasts is required for normal endochondral bone development.