title: Skeletal unloading causes resistance of osteoprogenitor cells to parathyroid hormone and to insulin-like growth factor-I.
abstract: Skeletal unloading decreases bone formation and osteoblast number in vivo and decreases the number and proliferation of bone marrow osteoprogenitor (BMOp) cells in vitro. We tested the ability of parathyroid hormone (PTH) to stimulate BMOp cells in vivo by treating Sprague Dawley rats (n = 32) with intermittent PTH(1-34) (1 h/day at 8 microg/100 g of body weight), or with vehicle via osmotic minipumps during 7 days of normal weight bearing or hind limb unloading. Marrow cells were flushed from the femur and cultured at the same initial density for up to 21 days. PTH treatment of normally loaded rats caused a 2.5-fold increase in the number of BMOp cells, with similar increases in alkaline phosphatase (ALP) activity and mineralization, compared with cultures from vehicle-treated rats. PTH treatment of hind limb unloaded rats failed to stimulate BMOp cell number, ALP activity, or mineralization. Hind limb unloading had no significant effect on PTH receptor mRNA or protein levels in the tibia. Direct in vitro PTH challenge of BMOp cells isolated from normally loaded bone failed to stimulate their proliferation and inhibited their differentiation, suggesting that the in vivo anabolic effect of intermittent PTH on BMOp cells was mediated indirectly by a PTH-induced factor. We hypothesize that this factor is insulin-like growth factor-I (IGF-I), which stimulated the in vitro proliferation and differentiation of BMOp cells isolated from normally loaded bone, but not from unloaded bone. These results suggest that IGF-I mediates the ability of PTH to stimulate BMOp cell proliferation in normally loaded bone, and that BMOp cells in unloaded bone are resistant to the anabolic effect of intermittent PTH therapy due to their resistance to IGF-I.
authors.affiliation: Department of Medicine, University of California and Veterans Affairs Medical Center, San Francisco, California, USA; Department of Orthopedic Surgery, Boston University Medical Center, Boston Massachusetts, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: J
authors.initials: J
authors.lastname: Harris
authors.forename: B P
authors.initials: BP
authors.lastname: Halloran
authors.forename: R T
authors.initials: RT
authors.lastname: Turner
authors.forename: E R
authors.initials: ER
authors.lastname: Morey-Holton
authors.forename: D D
authors.initials: DD
authors.lastname: Bikle
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D002452:Cell Count / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004351:Drug Resistance; D006614:Hindlimb; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical; D016474:Weight-Bearing
chemical_list: D010281:Parathyroid Hormone; D007334:Insulin-Like Growth Factor I