Smpd3 Expression 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 the Smpd3 gene causes poor bone and cartilage mineralization resulting in severe congenital skeletal deformities. Here we show that Smpd3 expression in ATDC5 chondrogenic cells is downregulated by parathyroid hormone-related peptide through transcription factor SOX9. Furthermore, we show that transgenic expression of Smpd3 in the chondrocytes of fro/fro mice corrects the cartilage but not the bone abnormalities. Additionally, we report the generation of Smpd3(flox/flox) mice for the tissue-specific inactivation of Smpd3 using the Cre-loxP system. We found that the skeletal phenotype in Smpd3(flox/flox); Osx-Cre mice, in which the Smpd3 gene is ablated in both late-stage chondrocytes and osteoblasts, closely mimics the skeletal phenotype in fro/fro mice. On the other hand, Smpd3(flox/flox); Col2a1-Cre mice, in which the Smpd3 gene is knocked out in chondrocytes only, recapitulate the fro/fro mouse cartilage phenotype. This work demonstrates that Smpd3 expression in both chondrocytes and osteoblasts is required for normal endochondral bone development.
Department of Medicine, McGill University, Montreal, Quebec, Canada.
Jingjing
J
Li
Faculty of Dentistry, McGill University, Montreal, Quebec, Canada.
Garthiga
G
Manickam
Faculty of Dentistry, McGill University, Montreal, Quebec, Canada.
Seemun
S
Ray
Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA.
Chun-do
CD
Oh
Department of Animal Biotechnology, Konkuk University, Seoul, Republic of Korea.
Hideyo
H
Yasuda
Shriners Hospital for Children, McGill University, Montreal, Quebec, Canada Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Pierre
P
Moffatt
Department of Medicine, McGill University, Montreal, Quebec, Canada Faculty of Dentistry, McGill University, Montreal, Quebec, Canada Shriners Hospital for Children, McGill University, Montreal, Quebec, Canada monzur.murshed@mcgill.ca.
Monzur
M
Murshed
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D015536:Down-Regulation; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*
D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; C491483:Smpd3 protein, mouse; D013108:Sphingomyelin Phosphodiesterase