title: The androgen receptor has no direct antiresorptive actions in mouse osteoclasts.
abstract: Androgen deficiency or androgen receptor knockout (ARKO) causes high-turnover osteopenia, but the target cells for this effect remain unclear. To examine whether AR in osteoclasts directly suppresses bone resorption, we crossed AR-floxed with cathepsin K-Cre mice. Osteoclast-specific ARKO (ocl-ARKO) mice showed no changes neither in osteoclast surface nor in bone microarchitecture nor in the response to orchidectomy and androgen replacement, indicating that the AR in osteoclasts is not critical for bone maintenance. In line with the lack of a bone phenotype, the levels of AR were very low in osteoclast-enriched cultures derived from bone marrow (BM) and undetectable in osteoclasts generated from spleen precursors. Since tibiae of ubiquitous ARKO mice displayed increased osteoclast counts, the role of AR was further explored using cell cultures from these animals. Osteoclast generation and activity in vitro were similar between ARKO and wildtype control (WT) mice. In co-culture experiments, BM stromal cells (BMSCs) were essential for the suppressive action of AR on osteoclastogenesis and osteoclast activity. Stimulation with 1,25(OH)2 vitamin D3 increased Rankl and decreased Tnfsf11 (osteoprotegerin, Opg) gene expression in BMSCs more than in osteoblasts. This increase in the Rankl/Opg ratio following 1,25(OH)2D3 stimulation was lower, not higher, in ARKO mice. Runx2 expression in BMSCs was however higher in ARKO vs. WT, suggesting that ARKO mice may more readily commit osteoprogenitor cells to osteoblastogenesis. In conclusion, the AR does not seem to suppress bone resorption through direct actions in osteoclasts. BMSCs may however represent an alternative AR target in the BM milieu.
authors.affiliation: Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Sinnesael
authors.affiliation: Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Ferran
authors.initials: F
authors.lastname: Jardi
authors.affiliation: Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Ludo
authors.initials: L
authors.lastname: Deboel
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Michaël R
authors.initials: MR
authors.lastname: Laurent
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dubois
authors.affiliation: Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Zajac
authors.affiliation: Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Davey
authors.affiliation: Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Claessens
authors.affiliation: Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium. Electronic address: dirk.vanderschueren@uzleuven.be.
authors.forename: Dirk
authors.initials: D
authors.lastname: Vanderschueren
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D002478:Cells, Cultured; D005269:Femur / Q000166:cytology / Q000378:metabolism; D007527:Isoenzymes / Q000097:blood; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D000071681:Tartrate-Resistant Acid Phosphatase; D013977:Tibia / Q000166:cytology / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D011944:Receptors, Androgen; D015675:Osteocalcin; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Androgen receptor; Androgens; Bone marrow stromal cell; Bone resorption; Osteoblast; Osteoclast