title: Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice.
abstract: Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by bone fragility and deformity. OI type VI is unique owing to the mineralization defects observed in patient biopsies. Furthermore, it has been reported to respond less well to standard therapy with bisphosphonates [1]. Others and we have previously identified SERPINF1 mutations in patients with OI type VI. SERPINF1 encodes pigment epithelium derived factor (PEDF), a secreted collagen-binding glycoprotein that is absent in the sera of patients with OI type VI. Serpinf1 null mice show increased osteoid and decreased bone mass, and thus recapitulate the OI type VI phenotype. We tested whether restoration of circulating PEDF in the blood could correct the phenotype of OI type VI in the context of protein replacement. To do so, we utilized a helper-dependent adenoviral vector (HDAd) to express human SERPINF1 in the mouse liver and assessed whether PEDF secreted from the liver was able to rescue the bone phenotype observed in Serpinf1(-/-) mice. We confirmed that expression of SERPINF1 in the liver restored the serum level of PEDF. We also demonstrated that PEDF secreted from the liver was biologically active by showing the expected metabolic effects of increased adiposity and impaired glucose tolerance in Serpinf1(-/-) mice. Interestingly, overexpression of PEDF in vitro increased mineralization with a concomitant increase in the expression of bone gamma-carboxyglutamate protein, alkaline phosphatase and collagen, type I, alpha I, but the increased serum PEDF level did not improve the bone phenotype of Serpinf1(-/-) mice. These results suggest that PEDF may function in a context-dependent and paracrine fashion in bone homeostasis.
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, United States.
authors.forename: Abbhirami
authors.initials: A
authors.lastname: Rajagopal
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, United States.
authors.forename: Erica P
authors.initials: EP
authors.lastname: Homan
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, United States.
authors.forename: Kyu Sang
authors.initials: KS
authors.lastname: Joeng
authors.affiliation: Department of Medicine, Center for Cell and Gene Therapy, Baylor College of Medicine, United States.
authors.forename: Masataka
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, United States.
authors.forename: Terry
authors.initials: T
authors.lastname: Bertin
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, United States.
authors.forename: Racel
authors.initials: R
authors.lastname: Cela
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, United States.
authors.forename: Elda
authors.initials: E
authors.lastname: Munivez
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Dawson
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, United States.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Jiang
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Gannon
authors.affiliation: Department of Pathology, Saint Louis University, School of Medicine, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Crawford
authors.affiliation: Molecular and Human Genetics Department, Baylor College of Medicine, United States. Electronic address: blee@bcm.edu.
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
mesh_terms: D015055:1-Carboxyglutamic Acid / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000502:physiology*; D024042:Collagen Type I / Q000235:genetics; D005136:Eye Proteins / Q000097:blood* / Q000235:genetics*; D018014:Gene Transfer Techniques; D018149:Glucose Intolerance; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009414:Nerve Growth Factors / Q000097:blood* / Q000172:deficiency / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000503:physiopathology* / Q000628:therapy*; D010641:Phenotype; D015843:Serpins / Q000097:blood* / Q000172:deficiency / Q000235:genetics*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D015055:1-Carboxyglutamic Acid; D000469:Alkaline Phosphatase; D024042:Collagen Type I; D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: Gene transfer; Helper-dependent adenovirus; Osteogenesis imperfecta; PEDF; SerpinF1