1. Lipoprotein receptor-related protein 6 is required for parathyroid hormone-induced Sost suppression.
- Author
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Li, Changjun, Wang, Weishan, Xie, Liang, Luo, Xianghang, Cao, Xu, and Wan, Mei
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SCLEROSTIN , *IMMUNOSUPPRESSION , *LIPOPROTEIN receptors , *PARATHYROID hormone , *OSTEOCYTES , *PROTEIN expression , *CELLULAR signal transduction - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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