Abstract
Parathyroid hormone (PTH) suppresses the expression of the bone formation inhibitor sclerostin (Sost) in osteocytes by inducing nuclear accumulation of histone deacetylases (HDACs) to inhibit the myocyte enhancer factor 2 (MEF2)-dependent Sost bone enhancer. Previous studies revealed that lipoprotein receptor–related protein 6 (LRP6) mediates the intracellular signaling activation and the anabolic bone effect of PTH. Here, we investigated whether LRP6 mediates the inhibitory effect of PTH on Sost using an osteoblast-specific Lrp6-knockout (LRP6-KO) mouse model. An increased level of Sost mRNA expression was detected in femur tissue from LRP6-KO mice, compared to wild-type littermates. The number of osteocytes expressing sclerostin protein was also increased in bone tissue of LRP6-KO littermates, indicating a negative regulatory role of LRP6 on Sost/sclerostin. In wild-type littermates, intermittent PTH treatment significantly suppressed Sost mRNA expression in bone and the number of sclerostin+ osteocytes, while the effect of PTH was much less significant in LRP6-KO mice. Additionally, PTH-induced downregulation of MEF2C and 2D, as well as HDAC changes in osteocytes, were abrogated in LRP6-KO mice. These data indicate that LRP6 is required for PTH suppression of Sost expression.
Original language | English (US) |
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Pages (from-to) | 62-73 |
Number of pages | 12 |
Journal | Annals of the New York Academy of Sciences |
Volume | 1364 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2016 |
Keywords
- HDAC
- LRP6
- MEF2
- PTH
- Sost
- osteocyte
- sclerostin
ASJC Scopus subject areas
- General Neuroscience
- General Biochemistry, Genetics and Molecular Biology
- History and Philosophy of Science