title: Sclerostin Antibody Administration Converts Bone Lining Cells Into Active Osteoblasts.
abstract: Sclerostin antibody (Scl-Ab) increases osteoblast activity, in part through increasing modeling-based bone formation on previously quiescent surfaces. Histomorphometric studies have suggested that this might occur through conversion of bone lining cells into active osteoblasts. However, direct data demonstrating Scl-Ab-induced conversion of lining cells into active osteoblasts are lacking. Here, we used in vivo lineage tracing to determine if Scl-Ab promotes the conversion of lining cells into osteoblasts on periosteal and endocortical bone surfaces in mice. Two independent, tamoxifen-inducible lineage-tracing strategies were used to label mature osteoblasts and their progeny using the DMP1 and osteocalcin promoters. After a prolonged "chase" period, the majority of labeled cells on bone surfaces assumed a thin, quiescent morphology. Then, mice were treated with either vehicle or Scl-Ab (25 mg/kg) twice over the course of the subsequent week. After euthanization, marked cells were enumerated, their thickness quantified, and proliferation and apoptosis examined. Scl-Ab led to a significant increase in the average thickness of labeled cells on periosteal and endocortical bone surfaces, consistent with osteoblast activation. Scl-Ab did not induce proliferation of labeled cells, and Scl-Ab did not regulate apoptosis of labeled cells. Therefore, direct reactivation of quiescent bone lining cells contributes to the acute increase in osteoblast numbers after Scl-Ab treatment in mice. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine and Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Sang Wan
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Williams
authors.affiliation: Henry M. Goldman School of Dental Medicine, Boston University, Boston, MA, USA.
authors.forename: Forest
authors.initials: F
authors.lastname: Lai
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine and Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Enishi
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Deepak H
authors.initials: DH
authors.lastname: Balani
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Marc N
authors.initials: MN
authors.lastname: Wein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000071538:Cortical Bone / Q000166:cytology / Q000378:metabolism*; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010521:Periosteum / Q000166:cytology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse
keywords: ANABOLICS; MOLECULAR PATHWAYS-REMODELING; OSTEOBLASTS; PRECLINICAL STUDIES; WNT/ß-CATENIN/LRPS