1. Krox20/EGR2 deficiency accelerates cell growth and differentiation in the monocytic lineage and decreases bone mass.
- Author
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Gabet Y, Baniwal SK, Leclerc N, Shi Y, Kohn-Gabet AE, Cogan J, Dixon A, Bachar M, Guo L, Turman JE Jr, and Frenkel B
- Subjects
- Animals, Base Sequence, Bone Resorption etiology, Bone Resorption genetics, Bone Resorption metabolism, Bone Resorption pathology, Cell Cycle, Cell Differentiation genetics, Cell Differentiation physiology, Cell Proliferation, DNA Primers genetics, Disease Models, Animal, Early Growth Response Protein 2 genetics, Female, Haploinsufficiency, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteoblasts metabolism, Osteoblasts pathology, Osteoclasts metabolism, Osteoclasts pathology, Osteogenesis, Osteoporosis genetics, Osteoporosis metabolism, Osteoporosis pathology, RNA, Small Interfering genetics, Signal Transduction, Bone and Bones metabolism, Early Growth Response Protein 2 deficiency, Monocytes cytology, Monocytes metabolism, Osteoporosis etiology
- Abstract
Krox20/EGR2, one of the 4 early growth response genes, is a highly conserved transcription factor implicated in hindbrain development, peripheral nerve myelination, tumor suppression, and monocyte/macrophage cell fate determination. Here, we established a novel role for Krox20 in postnatal skeletal metabolism. Microcomputed tomographic analysis of 4- and 8-week-old mice revealed a low bone mass phenotype (LBM) in both the distal femur and the vertebra of Krox20(+/-) mice. This was attributable to accelerated bone resorption as demonstrated in vivo by increased osteoclast number and serum C-terminal telopeptides, a marker for collagen degradation. Krox20 haploinsufficiency did not reduce bone formation in vivo, nor did it compromise osteoblast differentiation in vitro. In contrast, growth and differentiation were significantly stimulated in preosteoclast cultures derived from Krox20(+/-) splenocytes, suggesting that the LBM is attributable to Krox20 haploinsufficiency in the monocytic lineage. Furthermore, Krox20 silencing in preosteoclasts increased cFms expression and response to macrophage colony-stimulating factor, leading to a cell-autonomous stimulation of cell-cycle progression. Our data indicate that the antimitogenic role of Krox20 in preosteoclasts is the predominant mechanism underlying the LBM phenotype of Krox20-deficient mice. Stimulation of Krox20 expression in preosteoclasts may present a viable therapeutic strategy for high-turnover osteoporosis.
- Published
- 2010
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