title: Inactivation of the Progesterone Receptor in Mx1+ Cells Potentiates Osteogenesis in Calvaria but Not in Long Bone.
abstract: The effect of progesterone on bone remains elusive. We previously reported that global progesterone receptor (PR) knockout mice displayed high bone mass phenotype, suggesting that PR influences bone growth and modeling. Recently, Mx1+ cells were characterized to be mesenchymal stem cell-like pluripotent Cells. The aim of this study was to evaluate whether the PR in Mx1+ cells regulates osteogenesis. Using the Mx1-Cre;mT/mG reporter mouse model, we found that the calvarial cells exhibited minimal background Mx1-Cre activity prior to Cre activation by IFNα treatment as compared to the bone marrow stromal cells. IFNα treatment significantly activated Mx1-Cre in the calvarial cells. When the PR gene was deleted in the Mx1-Cre;PR-flox calvarial cells in vitro, significantly higher levels of expression of osteoblast maturation marker genes (RUNX2, Osteocalcin, and Dmp1) and osteogenic potential were detected. The PR-deficient calvariae exhibited greater bone volume, especially in the males. Although Mx1-Cre activity could be induced on the bone surface in vivo, the Mx1+ cells did not differentiate into osteocytes in long bones. Bone volumes at the distal femurs and the bone turnover marker serum Osteocalcin were similar between the Mx1-Cre;PR-flox mutant mice and the corresponding wild types in both sexes. In conclusion, our data demonstrates that blocking progesterone signaling via PRs in calvarial Mx1+ cells promoted osteoblast differentiation in the calvaria. Mx1+ was expressed by heterogeneous cells in bone marrow and did not differentiate into osteocyte during long bone development in vivo. Selectively inactivating the PR gene in Mx1+ cells affected the membrane bone formation but did not affect peripheral skeletal homeostasis.
authors.affiliation: Center for Musculoskeletal Health, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, United States of America.
authors.forename: Zhendong A
authors.initials: ZA
authors.lastname: Zhong
authors.affiliation: Center for Musculoskeletal Health, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, United States of America.
authors.forename: Weihua
authors.initials: W
authors.lastname: Sun
authors.affiliation: Center for Musculoskeletal Health, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, United States of America.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Center for Musculoskeletal Health, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, United States of America; Department of Emergency Medicine, The Second Xiangya Hospital of Central-South University, Hunan, Changsha, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for Musculoskeletal Health, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, United States of America.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
authors.affiliation: Center for Musculoskeletal Health, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, 95817, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
mesh_terms: D000818:Animals; D015415:Biomarkers; D001853:Bone Marrow / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000473:pathology; D003433:Crosses, Genetic; D005260:Female; D005269:Femur / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D006132:Growth Plate / Q000473:pathology; D019426:Integrases; D016898:Interferon-alpha / Q000494:pharmacology*; D008164:Luminescent Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D064547:Myxovirus Resistance Proteins / Q000235:genetics*; D009928:Organ Specificity; D010006:Osteoblasts / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D011374:Progesterone / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011980:Receptors, Progesterone / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012727:Sex Characteristics; D012886:Skull / Q000473:pathology*; D000097573:Red Fluorescent Protein
chemical_list: D015415:Biomarkers; D049452:Green Fluorescent Proteins; D019426:Integrases; D016898:Interferon-alpha; D008164:Luminescent Proteins; D064547:Myxovirus Resistance Proteins; D011374:Progesterone; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; D000097573:Red Fluorescent Protein; C579070:Mx1 protein, mouse; C045073:Cre recombinase