title: The bone-sparing effects of estrogen and WNT16 are independent of each other.
abstract: Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16(-/-) mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females is WNT16-dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast-specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. Obl-Wnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L3. Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl-Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx Obl-Wnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16(-/-) mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16(-/-) and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16-targeted therapies might be useful for treatment of postmenopausal trabecular bone loss.
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden;
authors.forename: Sofia
authors.initials: S
authors.lastname: Movérare-Skrtic
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden;
authors.forename: Jianyao
authors.initials: J
authors.lastname: Wu
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden;
authors.forename: Petra
authors.initials: P
authors.lastname: Henning
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden;
authors.forename: Karin L
authors.initials: KL
authors.lastname: Gustafsson
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden;
authors.forename: Klara
authors.initials: K
authors.lastname: Sjögren
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden;
authors.forename: Sara H
authors.initials: SH
authors.lastname: Windahl
authors.affiliation: Unit of Cancer Research and Translational Medicine, MRC Oulu and Department of Anatomy and Cell Biology, University of Oulu, FI-90014 Oulu, Finland;
authors.forename: Antti
authors.initials: A
authors.lastname: Koskela
authors.affiliation: Unit of Cancer Research and Translational Medicine, MRC Oulu and Department of Anatomy and Cell Biology, University of Oulu, FI-90014 Oulu, Finland;
authors.forename: Juha
authors.initials: J
authors.lastname: Tuukkanen
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden; Rheumatology and Bone Diseases Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom;
authors.forename: Anna E
authors.initials: AE
authors.lastname: Börjesson
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden;
authors.forename: Marie K
authors.initials: MK
authors.lastname: Lagerquist
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden;
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Lerner
authors.affiliation: Institute of Biomedicine, Turku Center for disease modeling, Department of Physiology, University of Turku, FI-20520 Turku, Finland;
authors.forename: Fu-Ping
authors.initials: FP
authors.lastname: Zhang
authors.affiliation: Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204 jgustafsson@uh.edu Claes.Ohlsson@medic.gu.se.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden; Institute of Biomedicine, Turku Center for disease modeling, Department of Physiology, University of Turku, FI-20520 Turku, Finland;
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345 Gothenburg, Sweden; jgustafsson@uh.edu Claes.Ohlsson@medic.gu.se.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
mesh_terms: D000818:Animals; D015519:Bone Density / Q000502:physiology*; D004967:Estrogens; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D013131:Spine / Q000378:metabolism*; D051153:Wnt Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004967:Estrogens; D051153:Wnt Proteins; C585687:Wnt16 protein, mouse
keywords: WNT16; cortical bone; estrogen; trabecular bone; transgenic mice