Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 28, Issue 5, Pages 1160-1169Publisher
WILEY
DOI: 10.1002/jbmr.1834
Keywords
beta-CATENIN; LRP5; POSTNATAL BONE; OSX; TAMOXIFEN; OSTEOBLAST; ADIPOCYTE; OSTEOCLAST; BONE MARROW STROMAL CELLS
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Funding
- NIH [AR060456, AR055923, P30 AR057235]
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Genetic studies in the mouse have demonstrated multiple roles for -catenin in the skeleton. In the embryo, -catenin is critical for the early stages of osteoblast differentiation. Postnatally, -catenin in mature osteoblasts and osteocytes indirectly suppresses osteoclast differentiation. However, a direct role for -catenin in regulating osteoblast number and/or function specifically in the postnatal life has not been demonstrated. Addressing this knowledge gap is important because low-density lipoprotein receptor-related protein 5 (LRP5), a coreceptor for WNT signaling proposed to function through -catenin, controls osteoblast number and function in postnatal mice or humans. To overcome the neonatal lethality caused by embryonic deletion of -catenin in early-stage osteoblast-lineage cells, we use the Osx-CreERT2 mouse strain to remove -catenin in Osterix (Osx)-expressing cells by administering tamoxifen (TM) temporarily to postnatal mice. Lineage-tracing experiments in the long bones demonstrate that Osx-CreERT2 targets predominantly osteoblast-lineage cells on the bone surface, but also transient progenitors that contribute to bone marrow stromal cells and adipocytes. Deletion of -catenin by this strategy greatly reduces the bone formation activity of the targeted osteoblasts. However, the targeted osteoblasts rapidly turn over and are replaced by an excessive number of non-targeted osteoblasts, causing an unexpected increase in bone formation, but an even greater increase in osteoclast number and activity produces a net effect of severe osteopenia. With time, the mutant mice also exhibit a marked increase in bone marrow adiposity. Thus, -catenin in postnatal Osx-lineage cells critically regulates bone homeostasis by promoting osteoblast activity and suppressing osteoblast turnover, while restraining osteoclast and marrow fat formation. (c) 2013 American Society for Bone and Mineral Research.
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