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Li et al. LRP6 is necessary for the suppression of Sost by parathyroid hormone
DOI:10.1038/bonekey.2015.104
Lipoprotein receptor-related protein 6 (LRP6) is known to mediate activation of the intracellular signaling events that enable parathyroid hormone (PTH) to have its anabolic effect on bone. This study explored the role of LRP6 in more detail using osteoblast-specific Lrp6 knockout mice.
LRP6-KO mice were found to have large numbers of osteocytes that expressed sclerostin. LRP6-KO mice treated with PTH showed a reduction in sclerostin+ osteocytes but the impact of PTH was significantly reduced compared to its effect in wild type mice, indicating that the LRP6 deficiency abolished the suppression of Sost by PTH in osteocytes.
Analysis of the expression of myocyte enhancer factor 2 (MEF2), a transcription factor thought to mediate the suppression of Sost by PTH, revealed an increased number of MEF2C+ osteocytes in LRP6-KO mice compared to controls. Furthermore, Lrp6-KO mice showed upregulation of mRNA for Hdac2, Hdac3 and Hdac4, but not Hdac1 or Hdac5. Treatment with pulsed PTH did not reduce mRNA levels of Hdac 2, 3 or 4, as it did in wild type mice. The authors conclude that LRP6 regulates HDACs in osteocytes and is required for the suppression of Sost expression mediated by PTH.
Editor's comment: Another recent report demonstrated that HDACs regulate MEF2C-driven sclerostin expression in osteocytes. It is also notable that a large genome-wide association study meta-analysis has shown that variants in both HDAC5 and MEF2C are associated with the variance in human bone mineral density.
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