Back to Search
Start Over
Hormone-Independent Sexual Dimorphism in the Regulation of Bone Resorption by Krox20.
- Source :
-
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2019 Dec; Vol. 34 (12), pp. 2277-2286. Date of Electronic Publication: 2019 Sep 12. - Publication Year :
- 2019
-
Abstract
- Krox20/EGR2 is a zinc finger transcription factor, implicated in the development of the hindbrain, nerve myelination, and tumor suppression. In skeletal biology, we have demonstrated that Krox20 also regulates adult bone metabolism. We and others have characterized several functions of Krox20 in the osteoclast lineage, namely, preosteoclast proliferation and differentiation, and mature osteoclast apoptosis. We have previously reported that systemically Krox20-haploinsufficient mice have a low bone mass with increased bone resorption. However, new data have now revealed that this phenotype is restricted to females. In addition, we discovered that conditional knockout of Krox20 (cKO) restricted to osteoclast progenitors is sufficient to induce the same female-specific bone loss observed in systemic mutants. To test whether this sexual dimorphism results from an interaction between Krox20 and sex hormones, we examined the sex- and hormone-dependent role of Krox20 deficiency on proliferation and apoptosis in osteoclastic cells. Our results indicate that male and female sex hormones (dihydrotestosterone [DHT] and estradiol [E2], respectively) as well as Krox20 inhibit preosteoclast proliferation and augment osteoclast apoptosis. The observation that Krox20 expression is inhibited by DHT and E2 negates the hypothesis that the effect of sex hormones is mediated by an increase in Krox20 expression. Interestingly, the effect of Krox20 deficiency was observed only with cells derived from female animals, regardless of any sex hormones added in vitro. In addition, we have identified sexual dimorphism in the expression of several Krox20-related genes, including NAB2. This sex-specific epigenetic profile was established at puberty, maintained in the absence of sex hormones, and explains the female-specific skeletal importance of Krox20. The findings described in this study emphasize the medical importance of sex differences, which may be determined at the epigenetic level. © 2019 American Society for Bone and Mineral Research.<br /> (© 2019 American Society for Bone and Mineral Research.)
- Subjects :
- Animals
Apoptosis drug effects
Cell Differentiation drug effects
Cell Lineage
Cell Proliferation drug effects
Early Growth Response Protein 2 deficiency
Early Growth Response Protein 2 genetics
Female
Gene Expression Regulation drug effects
Haploinsufficiency genetics
Male
Mice, Knockout
Monocytes metabolism
Osteoclasts drug effects
Phenotype
Bone Resorption metabolism
Bone Resorption pathology
Early Growth Response Protein 2 metabolism
Gonadal Steroid Hormones metabolism
Sex Characteristics
Subjects
Details
- Language :
- English
- ISSN :
- 1523-4681
- Volume :
- 34
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
- Publication Type :
- Academic Journal
- Accession number :
- 31398266
- Full Text :
- https://doi.org/10.1002/jbmr.3847