Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development

被引：24

作者：

Li, Jingjing ^{[1
]}

Manickam, Garthiga ^{[2
]}

Ray, Seemun ^{[2
,7
]}

Oh, Chun-do ^{[3
]}

Yasuda, Hideyo ^{[4
]}

Moffatt, Pierre ^{[5
,6
]}

Murshed, Monzur ^{[1
,2
,5
]}

机构：

[1] McGill Univ, Dept Med, Montreal, PQ, Canada

[2] McGill Univ, Fac Dent, Montreal, PQ, Canada

[3] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA

[4] Konkuk Univ, Dept Anim Biotechnol, Seoul, South Korea

[5] McGill Univ, Shriners Hosp Children, Montreal, PQ, Canada

[6] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[7] Univ Giessen, Lab Expt Trauma Surg, Fac Med, Giessen, Germany

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2016年 / 36卷 / 17期

基金：

加拿大健康研究院;

关键词：

NEUTRAL SPHINGOMYELINASE 2; SPHINGOLIPID METABOLISM; SOX9; MECHANISM; MOUSE; PHOSPHODIESTERASE-3; DIFFERENTIATION; MINERALIZATION; OSSIFICATION; CARTILAGE;

D O I：

10.1128/MCB.01077-15

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2282 / 2299

页数：18