title: Stem cell antigen-1 positive cell-based systemic human growth hormone gene transfer strategy increases endosteal bone resorption and bone loss in mice.
abstract: BACKGROUND
  The present study assesses the effect of the stem cell antigen-1 positive (Sca-1(+) ) cell-based human growth hormone (hGH) ex vivo gene transfer strategy on endosteal bone mass in the mouse.
  
  
  METHODS
  Sublethally irradiated recipient mice were transplanted with Sca-1(+) cells transduced with lentiviral vectors expressing hGH or β-galactosidase control genes. Bone parameters were assessed by micro-computed tomography and histomorphometry.
  
  
  RESULTS
  This hGH strategy drastically increased hGH mRNA levels in bone marrow cells and serum insulin-like growth factor-I (IGF-I) (by nearly 50%, p < 0.002) in hGH recipient mice. Femoral trabecular bone volume of the hGH mice was significantly reduced by 35% (p < 0.002). The hGH mice also had decreased trabecular number (by 26%; p < 0.0001), increased trabecular separation (by 38%; p < 0.0002) and reduced trabecular connectivity density (by 64%; p < 0.001), as well as significantly more osteoclasts (2.5-fold; p < 0.05) and greater osteoclastic surface per bone surface (2.6-fold; p < 0.01).
  
  
  CONCLUSIONS
  Targeted expression of hGH in cells of marrow cavity through the Sca-1(+) cell-based gene transfer strategy increased circulating IGF-I and decreased endosteal bone mass through an increase in resorption in recipient mice. These results indicate that high local levels of hGH or IGF-I in the bone marrow microenvironment enhanced resorption, which is consistent with previous findings in transgenic mice with targeted bone IGF-I expression showing that high local IGF-I expression increased bone remodeling, favoring a net bone loss. Thus, GH and/or IGF-I would not be an appropriate transgene for use in this Sca-1(+) cell-based gene transfer strategy to promote endosteal bone formation. Published 2011 John Wiley & Sons, Ltd.
authors.affiliation: Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, CA, USA. susan.hall1@va.gov
authors.forename: Susan L
authors.initials: SL
authors.lastname: Hall
authors.forename: Shin-Tai
authors.initials: ST
authors.lastname: Chen
authors.forename: Jon E
authors.initials: JE
authors.lastname: Wergedal
authors.forename: Daila S
authors.initials: DS
authors.lastname: Gridley
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
authors.forename: K-H William
authors.initials: KH
authors.lastname: Lau
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000033:anatomy & histology / Q000166:cytology / Q000473:pathology; D005269:Femur / Q000033:anatomy & histology / Q000166:cytology; D018628:Gene Dosage; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D019382:Human Growth Hormone / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D011859:Radiography; D014161:Transduction, Genetic; D014916:Whole-Body Irradiation
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D019382:Human Growth Hormone