title: Amphiregulin lacks an essential role for the bone anabolic action of parathyroid hormone.
abstract: Although parathyroid hormone (PTH) has long been known to act as a bone anabolic agent when administered intermittently, the exact underlying mechanisms remain largely unknown. Amphiregulin (AREG), a ligand of the epidermal growth factor receptor, has been identified to be a PTH target gene in vitro and in vivo. Here, we used female global AREG knockout (AREG-KO) mice to explore the role of AREG in mediating the bone anabolic effects of PTH. AREG-KO mice were characterized by unchanged distal femoral cancellous bone mass and only subtle decreases in bone mineral density (BMD) and cortical thickness at the femoral midshaft at 3 and 8 months of age, relative to wildtype controls. AREG deficiency was associated with complex changes in the mRNA expression of other EGFR ligands in femoral cancellous bone osteoblasts in situ in 3-week-old mice. To examine the bone anabolic effects of PTH in the absence and presence of AREG, we injected 3-month-old AREG-KO females and wildtype control littermates with 80 μg/kg PTH or vehicle 5 times per week over 4 weeks. Intermittent PTH treatment of AREG-KO mice led to increases in femoral trabecular and cortical BMD, cortical thickness, endocortical and periosteal bone formation, cancellous bone formation rate, and serum osteocalcin, comparable to those observed in wildtype control mice. In conclusion, our data indicate that the bone anabolic effects of PTH do not require AREG, at least in 3-month-old female mice.
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, 1210 Vienna, Austria.
authors.forename: Mithila
authors.initials: M
authors.lastname: Vaidya
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Germany.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Porada
authors.affiliation: Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Research, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
authors.forename: Olena
authors.initials: O
authors.lastname: Andrukhova
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Germany.
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Schneider
authors.affiliation: Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Research, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria. Electronic address: Reinhold.Erben@vetmeduni.ac.at.
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
mesh_terms: D066258:Amphiregulin; D045930:Anabolic Agents / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D066255:EGF Family of Proteins / Q000172:deficiency / Q000235:genetics*; D005260:Female; D005269:Femur / Q000187:drug effects* / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055786:Gene Knockout Techniques; D051379:Mice; D015675:Osteocalcin / Q000097:blood; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D066258:Amphiregulin; D045930:Anabolic Agents; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D010281:Parathyroid Hormone; D015675:Osteocalcin
keywords: Amphiregulin; Bone; EGFR; Parathyroid hormone