title: Estrogen receptor α in osteocytes regulates trabecular bone formation in female mice.
abstract: Estrogens are well known steroid hormones necessary to maintain bone health. In addition, mechanical loading, in which estrogen signaling may intersect with the Wnt/β-catenin pathway, is essential for bone maintenance. As osteocytes are known as the major mechanosensory cells embedded in mineralized bone matrix, osteocyte ERα deletion mice (ERα(ΔOcy/ΔOcy)) were generated by mating ERα floxed mice with Dmp1-Cre mice to determine the role of ERα in osteocytes. Trabecular bone mineral density of female, but not male ERα(ΔOcy/ΔOcy) mice was significantly decreased. Bone formation parameters in ERα(ΔOcy/ΔOcy) were significantly decreased while osteoclast parameters were unchanged. This suggests that ERα in osteocytes exerts osteoprotective function by positively controlling bone formation. To identify potential targets of ERα, gene array analysis of Dmp1-GFP osteocytes sorted by FACS from ERα(ΔOcy/ΔOcy) and control mice was performed. Gene expression microarray followed by gene ontology analyses revealed that osteocytes from ERα(ΔOcy/ΔOcy) highly expressed genes categorized in 'Secreted' when compared to control osteocytes. Among them, expression of Mdk and Sostdc1, both of which are Wnt inhibitors, was significantly increased without alteration of expression of the mature osteocyte markers such as Sost and β-catenin. Moreover, hindlimb suspension experiments showed that trabecular bone loss due to unloading was greater in ERα(ΔOcy/ΔOcy) mice without cortical bone loss. These data suggest that ERα in osteocytes has osteoprotective functions in trabecular bone formation through regulating expression of Wnt antagonists, but conversely plays a negative role in cortical bone loss due to unloading.
authors: Laboratory of Epigenetic Skeletal Diseases, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors: Shino
authors: S
authors: Kondoh
authors: Laboratory of Epigenetic Skeletal Diseases, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Division of Integrative Pathophysiology, Proteo-Science Center, Graduate School of Medicine, Ehime University, Ehime, Japan; Department of Biological Resources, Integrated Center for Science, Ehime University, Ehime, Japan.
authors: Kazuki
authors: K
authors: Inoue
authors: Division of Cellular & Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.
authors: Katsuhide
authors: K
authors: Igarashi
authors: Division of Cardiovascular Regeneration, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors: Hiroe
authors: H
authors: Sugizaki
authors: Laboratory of Epigenetic Skeletal Diseases, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors: Yuko
authors: Y
authors: Shirode-Fukuda
authors: Laboratory of Epigenetic Skeletal Diseases, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors: Erina
authors: E
authors: Inoue
authors: Laboratory of Epigenetic Skeletal Diseases, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Division of Integrative Pathophysiology, Proteo-Science Center, Graduate School of Medicine, Ehime University, Ehime, Japan.
authors: Taiyong
authors: T
authors: Yu
authors: Division of Cardiovascular Regeneration, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; JST PRESTO, Japan.
authors: Jun K
authors: JK
authors: Takeuchi
authors: Division of Cellular & Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.
authors: Jun
authors: J
authors: Kanno
authors: Department of Oral Biology, School of Dentistry, University of Missouri at Kansas City, Kansas City, MO, USA.
authors: Lynda F
authors: LF
authors: Bonewald
authors: Laboratory of Epigenetic Skeletal Diseases, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan; Division of Integrative Pathophysiology, Proteo-Science Center, Graduate School of Medicine, Ehime University, Ehime, Japan. Electronic address: y-imai@m.ehime-u.ac.jp.
authors: Yuuki
authors: Y
authors: Imai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism*; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018390:Gene Targeting; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D000078792:Midkine; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D010641:Phenotype; D016474:Weight-Bearing; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D047628:Estrogen Receptor alpha; D036341:Intercellular Signaling Peptides and Proteins; C582105:Mdk protein, mouse; C483887:Sostdc1 protein, mouse; D000078792:Midkine
keywords: Bone formation; Estrogen; Estrogen receptor α; Osteocyte; Wnt signaling