title: Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength.
abstract: This study was to determine if antibody against sclerostin (Scl-Ab) could prevent glucocorticoid (GC)-induced osteoporosis in mice. We found that Scl-Ab prevented GC-induced reduction in bone mass and bone strength and that the anabolic effects of Scl-Ab might be partially achieved through the preservation of osteoblast activity through autophagy.
  
  
  BACKGROUND
  Glucocorticoids (GCs) inhibit bone formation by altering osteoblast and osteocyte cell activity and lifespan. A monoclonal antibody against sclerostin, Scl-Ab, increased bone mass in both preclinical animal and clinical studies in subjects with low bone mass. The objectives of this study were to determine if treatment with the Scl-Ab could prevent loss of bone mass and strength in a mouse model of GC excess and to elucidate if Scl-Ab modulated bone cell activity through autophagy.
  
  
  METHODS
  We generated reporter mice that globally expressed dsRed fused to LC3, a protein marker for autophagosomes, and evaluated the dose-dependent effects of GCs (0, 0.8, 2.8, and 4 mg/kg/day) and Scl-Ab on autophagic osteoblasts, bone mass, and bone strength.
  
  
  RESULTS
  GC treatment at 2.8 and 4 mg/kg/day of methylprednisolone significantly lowered trabecular bone volume (Tb-BV/TV) at the lumbar vertebrae and distal femurs, cortical bone mass at the mid-shaft femur (FS), and cortical bone strength compared to placebo (PL). In mice treated with GC and Scl-Ab, Tb-BV/TV increased by 60-125 %, apparent bone strength of the lumbar vertebrae by 30-70 %, FS-BV by 10-18 %, and FS-apparent strength by 13-15 %, as compared to GC vehicle-treated mice. GC treatment at 4 mg/kg/day reduced the number of autophagic osteoblasts by 70 % on the vertebral trabecular bone surface compared to the placebo group (PL, GC 0 mg), and GC + Scl-Ab treatment.
  
  
  CONCLUSIONS
  Treatment with Scl-Ab prevented GC-induced reduction in both trabecular and cortical bone mass and strength and appeared to maintain osteoblast activity through autophagy.
authors.affiliation: Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA.
authors.forename: W
authors.initials: W
authors.lastname: Yao
authors.affiliation: Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA.|Science and Technology Experimental Center, Integrative Medicine Discipline, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: W
authors.initials: W
authors.lastname: Dai
authors.affiliation: Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA.
authors.forename: L
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA.
authors.forename: E Y-A
authors.initials: EY
authors.lastname: Lay
authors.affiliation: Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Department of Materials Science and Engineering, University of California at Berkeley, Berkeley, CA 94720, USA.
authors.forename: R O
authors.initials: RO
authors.lastname: Ritchie
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ke
authors.affiliation: Center for Musculoskeletal Health, Internal Medicine, University of California at Davis Medical Center, Sacramento, CA 95817, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Lane
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects* / Q000502:physiology; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005269:Femur / Q000503:physiopathology; D005938:Glucocorticoids / Q000008:administration & dosage / Q000633:toxicity*; D006023:Glycoproteins / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D008159:Lumbar Vertebrae / Q000503:physiopathology; D008297:Male; D008822:Mice, Transgenic; D010024:Osteoporosis / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D005938:Glucocorticoids; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse
keywords: Autophagy; Glucocorticoid-induced osteoporosis; Osteoblast; Sclerostin-antibody; dsRed-LC3 mouse