title: Osteoblast-specific overexpression of amphiregulin leads to transient increase in femoral cancellous bone mass in mice.
abstract: The epidermal growth factor receptor ligand amphiregulin (AREG) has been implicated in bone physiology and in bone anabolism mediated by intermittent parathyroid hormone treatment. However, the functions of AREG in bone have been only incipiently evaluated in vivo. Here, we generated transgenic mice overexpressing AREG specifically in osteoblasts (Col1-Areg). pQCT analysis of the femoral metaphysis revealed increased trabecular bone mass at 4, 8, and 10weeks of age in Col1-Areg mice compared to control littermates. However, the high bone mass phenotype was transient and disappeared in older animals. Micro-CT analysis of the secondary spongiosa confirmed increased trabecular bone volume and trabecular number in the distal femur of 4-week-old AREG-tg mice compared to control littermates. Furthermore, μ-CT analysis of the primary spongiosa revealed unaltered production of new bone trabeculae in distal femora of Col1-Areg mice. Histomorphometric analysis revealed a reduced number of osteoclasts in 4-week-old Col1-Areg mice, but not at later time points. Cancellous bone formation rate remained unchanged in Col1-Areg mice at all time points. In addition, bone mass and bone turnover in lumbar vertebral bodies were similar in Col1-Areg and control mice at all ages examined. Proliferation and differentiation of osteoblasts isolated from neonatal calvariae did not differ between Col1-Areg and control mice. Taken together, these data suggest that AREG overexpression in osteoblasts induces a transient high bone mass phenotype in the trabecular compartment of the appendicular skeleton by a growth-related, non-cell autonomous mechanism, leading to a positive bone balance with unchanged bone formation and lowered bone resorption.
authors.affiliation: Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Research, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna 1210, Austria.
authors.forename: Mithila
authors.initials: M
authors.lastname: Vaidya
authors.affiliation: Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Research, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna 1210, Austria.
authors.forename: Diana
authors.initials: D
authors.lastname: Lehner
authors.affiliation: VetCore Facility for Research and Technology, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna 1210, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Handschuh
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Germany.
authors.forename: Freya F
authors.initials: FF
authors.lastname: Jay
authors.affiliation: Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Research, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna 1210, Austria.
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Germany. Electronic address: marlon.schneider@lmu.de.
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Schneider
mesh_terms: D066258:Amphiregulin / Q000096:biosynthesis*; D000818:Animals; D015152:Blotting, Northern; D015519:Bone Density / Q000502:physiology; D016723:Bone Remodeling / Q000502:physiology*; D005269:Femur / Q000000981:diagnostic imaging* / Q000378:metabolism; D061346:Laser Capture Microdissection; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: D066258:Amphiregulin
keywords: Amphiregulin; EGFR; Osteoblast; Osteoclast; Transgenic mice