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Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells

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Kot A1, Zhong ZA1,2, Zhang H1,3, Lay YE1, Lane NE1, Yao W4. J Mol Endocrinol. 2017 Nov;59(4):351-363. doi: 10.1530/JME-17-0076. Epub 2017 Sep 4.

Abstract

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1 Center for Musculoskeletal HealthDepartment of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA.

2 Center for Cancer and Cell BiologyProgram in Skeletal Disease and Tumor Microenvironment, Van Andel Research Institute, Grand Rapids, Michigan, USA.

3 Department of Emergency MedicineCenter for Difficult Diagnoses and Rare Diseases, Second Xiangya Hospital of the Central-South University, Changsha, Hunan, China.

4 Center for Musculoskeletal HealthDepartment of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA yao@ucdavis.edu.

Abstract

Increasing peak bone mass is a promising strategy to prevent osteoporosis. A mouse model of global progesterone receptor (PR) ablation showed increased bone mass through a sex-dependent mechanism. Cre-Lox recombination was used to generate a mouse model of osteoprogenitor-specific PR inactivation, which recapitulated the high bone mass phenotype seen in the PR global knockout mouse mode. In this work, we employed RNA sequencing analysis to evaluate sex-independent and sex-dependent differences in gene transcription of osteoprogenitors of wild-type and PR conditional knockout mice. PR deletion caused marked sex hormone-dependent changes in gene transcription in male mice as compared to wild-type controls. These transcriptional differences revealed dysregulation in pathways involving immunomodulation, osteoclasts, bone anabolism, extracellular matrix interaction and matrix interaction. These results identified many potential mechanisms that may explain our observed high bone mass phenotype with sex differences when PR was selectively deleted in the MSCs.