title: Sclerostin antibody (Scl-Ab) improves osteomalacia phenotype in dentin matrix protein 1(Dmp1) knockout mice with little impact on serum levels of phosphorus and FGF23.
abstract: Unlike treatments for most rickets, the treatment using 1,25-(OH)2 vitamin D3 has little efficacy on patients with hypophosphatemic rickets, a set of rare genetic diseases. Thus, understanding the local cause for osteomalacia in hypophosphatemic rickets and developing an effective treatment to restore mineralization in this rare disease has been a longstanding goal in medicine. Here, we used Dmp1 knockout (KO) mice (whose mutations led to the same type of autosomal recessive hypophosphatemic rickets in humans) as the model in which the monoclonal antibody of sclerostin (Scl-Ab) was tested in two age groups for 8weeks: the prevention group (starting at age 4weeks) and the treatment group (starting at age 12weeks). Applications of Scl-Ab greatly improved the osteomalacia phenotype (>15%) and the biomechanical properties (3-point bending, ~60%) in the treated long-bone group. Our studies not only showed improvement of the osteomalacia in the alveolar bone, which has the highest bone metabolism rate, as well as the long bone phenotypes in treated mice. All these improvements attributed to the use of Scl-Ab are independent of the change in serum levels of phosphorus and FGF23, since Scl-Ab had little efficacy on those parameters. Finally, we propose a model to explain how Scl-Ab can improve the Dmp1 KO osteomalacia phenotype, in which the sclerostin level is already low.
authors.affiliation: Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, TX, USA.
authors.forename: Yinshi
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, TX, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, China.
authors.forename: Xianglong
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, TX, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Medicine, University of Wisconsin-Madison and Geriatric Research and Education Center, Madison, WI, USA.
authors.forename: Baozhi
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Huazhu
authors.initials: H
authors.lastname: Ke
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, TX, USA. Electronic address: jfeng@bcd.tamhsc.edu.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D001696:Biomechanical Phenomena / Q000187:drug effects; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D055786:Gene Knockout Techniques; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D010018:Osteomalacia / Q000188:drug therapy* / Q000235:genetics; D010758:Phosphorus / Q000097:blood; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: DMP1; Hypophosphatemic rickets; Osteocytes; PDL; SOST; Sclerostin antibody