title: Adult-Onset Deletion of β-Catenin in (10kb)Dmp1-Expressing Cells Prevents Intermittent PTH-Induced Bone Gain.
abstract: β-Catenin (βcat) is a major downstream signaling node in canonical Wingless-related integration site (Wnt) signaling pathway, and its activity is crucial for canonical Wnt signal transduction. Wnt signaling has recently been implicated in the osteo-anabolic response to PTH, a potent calcium-regulating factor. We investigated whether βcat is essential for the anabolic action of intermittent PTH by generating male mice with adult-onset deletion of βcat in a subpopulation of bone cells (osteocytes and late-stage osteoblasts), treating them with an anabolic regimen of PTH, and measuring the skeletal responses. Male (10kb)Dmp1-CreERt2 transgenic mice that also harbored floxed loss-of-function βcat alleles (βcat(f/f)) were induced for Cre activity using tamoxifen, then injected daily with human PTH 1-34 (30 μg/kg) or vehicle for 5 weeks. Mice in which βcat was deleted showed either total lack of bone mineral density (BMD) gain, or BMD loss, and did not respond to PTH treatment. However, bone mass measurements in the trabecular compartment of the femur and spine revealed PTH-induced bone gain whether βcat was deleted or not. PTH-stimulated increases in periosteal and cancellous bone formation rates were not impaired by βcat deletion, but resorption markers and cortical porosity were significantly increased in induced mice, particularly induced mice treated with PTH. These results suggest that βcat is required for net-positive BMD effects of PTH therapy but that the anabolic effects per se of PTH treatment might not require osteocytic/osteoblastic βcat.
authors.affiliation: Department of Anatomy and Cell Biology (R.K., K.S.K., J.M.H., V.B., K.-E.L., D.H., A.G.R.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Molecular and Cell Biology (P.D.-P.), Boston University School of Dental Medicine, Boston, Massachusetts 02215; Department of Biomedical Engineering (A.G.R.), Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana 46202; and Richard L. Roudebush Veterans Affairs Medical Center (A.G.R.), Indianapolis, Indiana 46202.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kedlaya
authors.affiliation: Department of Anatomy and Cell Biology (R.K., K.S.K., J.M.H., V.B., K.-E.L., D.H., A.G.R.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Molecular and Cell Biology (P.D.-P.), Boston University School of Dental Medicine, Boston, Massachusetts 02215; Department of Biomedical Engineering (A.G.R.), Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana 46202; and Richard L. Roudebush Veterans Affairs Medical Center (A.G.R.), Indianapolis, Indiana 46202.
authors.forename: Kyung Shin
authors.initials: KS
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Cell Biology (R.K., K.S.K., J.M.H., V.B., K.-E.L., D.H., A.G.R.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Molecular and Cell Biology (P.D.-P.), Boston University School of Dental Medicine, Boston, Massachusetts 02215; Department of Biomedical Engineering (A.G.R.), Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana 46202; and Richard L. Roudebush Veterans Affairs Medical Center (A.G.R.), Indianapolis, Indiana 46202.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Hong
authors.affiliation: Department of Anatomy and Cell Biology (R.K., K.S.K., J.M.H., V.B., K.-E.L., D.H., A.G.R.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Molecular and Cell Biology (P.D.-P.), Boston University School of Dental Medicine, Boston, Massachusetts 02215; Department of Biomedical Engineering (A.G.R.), Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana 46202; and Richard L. Roudebush Veterans Affairs Medical Center (A.G.R.), Indianapolis, Indiana 46202.
authors.forename: Vidya
authors.initials: V
authors.lastname: Bettagere
authors.affiliation: Department of Anatomy and Cell Biology (R.K., K.S.K., J.M.H., V.B., K.-E.L., D.H., A.G.R.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Molecular and Cell Biology (P.D.-P.), Boston University School of Dental Medicine, Boston, Massachusetts 02215; Department of Biomedical Engineering (A.G.R.), Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana 46202; and Richard L. Roudebush Veterans Affairs Medical Center (A.G.R.), Indianapolis, Indiana 46202.
authors.forename: Kyung-Eun
authors.initials: KE
authors.lastname: Lim
authors.affiliation: Department of Anatomy and Cell Biology (R.K., K.S.K., J.M.H., V.B., K.-E.L., D.H., A.G.R.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Molecular and Cell Biology (P.D.-P.), Boston University School of Dental Medicine, Boston, Massachusetts 02215; Department of Biomedical Engineering (A.G.R.), Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana 46202; and Richard L. Roudebush Veterans Affairs Medical Center (A.G.R.), Indianapolis, Indiana 46202.
authors.forename: Daniel
authors.initials: D
authors.lastname: Horan
authors.affiliation: Department of Anatomy and Cell Biology (R.K., K.S.K., J.M.H., V.B., K.-E.L., D.H., A.G.R.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Molecular and Cell Biology (P.D.-P.), Boston University School of Dental Medicine, Boston, Massachusetts 02215; Department of Biomedical Engineering (A.G.R.), Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana 46202; and Richard L. Roudebush Veterans Affairs Medical Center (A.G.R.), Indianapolis, Indiana 46202.
authors.forename: Paola
authors.initials: P
authors.lastname: Divieti-Pajevic
authors.affiliation: Department of Anatomy and Cell Biology (R.K., K.S.K., J.M.H., V.B., K.-E.L., D.H., A.G.R.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Molecular and Cell Biology (P.D.-P.), Boston University School of Dental Medicine, Boston, Massachusetts 02215; Department of Biomedical Engineering (A.G.R.), Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana 46202; and Richard L. Roudebush Veterans Affairs Medical Center (A.G.R.), Indianapolis, Indiana 46202.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Robling
mesh_terms: D000367:Age Factors; D045930:Anabolic Agents / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016296:Mutagenesis; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology*; D051176:beta Catenin / Q000235:genetics*
chemical_list: D045930:Anabolic Agents; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D010281:Parathyroid Hormone; D051176:beta Catenin