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Research Article

Role of SMPD3 during Bone Fracture Healing and Regulation of Its Expression

Garthiga Manickam, Pierre Moffatt, Monzur Murshed
Garthiga Manickam
Faculty of Dentistry, McGill University, Montreal, Quebec, Canada
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Pierre Moffatt
Shriners Hospital for Children, McGill University, Montreal, Quebec, CanadaDepartment of Human Genetics, McGill University, Montreal, Quebec, Canada
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Monzur Murshed
Faculty of Dentistry, McGill University, Montreal, Quebec, CanadaShriners Hospital for Children, McGill University, Montreal, Quebec, CanadaDepartment of Medicine, McGill University, Montreal, Quebec, Canada
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DOI: 10.1128/MCB.00370-18
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ABSTRACT

Sphingomyelin phosphodiesterase 3 (SMPD3), a lipid-metabolizing enzyme present in bone and cartilage, has important roles in the developing skeleton. We previously showed that SMPD3 deficiency results in delayed extracellular matrix (ECM) mineralization and severe skeletal deformities in an inducible knockout mouse model, Smpd3flox/flox; Osx-Cre mice, in which Smpd3 was ablated in Osx-expressing chondrocytes and osteoblasts during early skeletogenesis. However, as shown in the current study, ablation of Smpd3 postnatally in 3-month-old Smpd3flox/flox; Osx-Cre mice resulted in only a mild bone mineralization defect. Interestingly, though, there was a marked increase of unmineralized osteoid in the fractured tibiae of 3-month-old Smpd3flox/flox; Osx-Cre mice. As was the case in the embryonic bones, we also observed impaired chondrocyte apoptosis at the fracture sites of Smpd3flox/flox; Osx-Cre mice. We further examined how Smpd3 expression is regulated in ATDC5 chondrogenic cells by two major regulators of chondrogenesis, bone morphogenetic protein 2 (BMP-2) and PTHrP. Our data show that BMP-2 positively regulates Smpd3 expression via p38 mitogen-activated protein kinase. Taken together, our findings show that SMPD3 plays a significant role in ECM mineralization and chondrocyte apoptosis during fracture healing. Furthermore, our gene expression analyses suggest that BMP-2 and PTHrP exert opposing effects on the regulation of Smpd3 expression in chondrocytes.

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Role of SMPD3 during Bone Fracture Healing and Regulation of Its Expression
Garthiga Manickam, Pierre Moffatt, Monzur Murshed
Molecular and Cellular Biology Feb 2019, 39 (4) e00370-18; DOI: 10.1128/MCB.00370-18

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Role of SMPD3 during Bone Fracture Healing and Regulation of Its Expression
Garthiga Manickam, Pierre Moffatt, Monzur Murshed
Molecular and Cellular Biology Feb 2019, 39 (4) e00370-18; DOI: 10.1128/MCB.00370-18
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KEYWORDS

BMP-2
chondrocytes
fracture
mineralization
PTHrP
SMPD3
Sox9
p38 MAPK

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