title: Prolonged alendronate treatment prevents the decline in serum TGF-β1 levels and reduces cortical bone strength in long-term estrogen deficiency rat model.
abstract: BACKGROUND
  While the anti-resorptive effects of the bisphosphonates (BPs) are well documented, many questions remain about their mechanisms of action, particularly following long-term use. This study evaluated the effects of alendronate (Ale) treatment on TGF-β1 signaling in mesenchymal stem cells (MSCs) and osteocytes, and the relationship between prolonged alendronate treatment on systemic TGF-β1 levels and bone strength.
  
  
  METHODS
  TGF-β1 expression and signaling were evaluated in MSCs and osteocytic MLO-Y4 cells following Ale treatment. Serum total TGF-β1 levels, a bone resorption marker (DPD/Cr), three-dimensional microCT scans and biomechanical tests from both the trabecular and cortical bone were measured in ovariectomized rats that either received continuous Ale treatment for 360 days or Ale treatment for 120 days followed by 240 days of vehicle. Linear regression tests were performed to determine the association of serum total TGF-β1 levels and both the trabecular (vertebrae) and cortical (tibiae) bone strength.
  
  
  RESULTS
  Ale increased TGF-β1 signaling in the MSCs but not in the MLO-Y4 cells. Ale treatment increased serum TGF-β1 levels and the numbers of TGF-β1-positive osteocytes and periosteal cells in cortical bone. Serum TGF-β1 levels were not associated with vertebral maximum load and strength but was negatively associated with cortical bone maximum load and ultimate strength.
  
  
  CONCLUSIONS
  The increase of serum TGF-β1 levels during acute phase of estrogen deficiency is likely due to increased osteoclast-mediated release of matrix-derived latent TGF-β1. Long-term estrogen-deficiency generally results in a decline in serum TGF-β1 levels that are maintained by Ale treatment. Measuring serum total TGF-β1 levels may help to determine cortical bone quality following alendronate treatment.
authors.affiliation: Musculoskeletal Research Unit, Department of Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA.
authors.forename: Junjing
authors.initials: J
authors.lastname: Jia
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: Sarah
authors.initials: S
authors.lastname: Amugongo
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahnazari
authors.forename: Weiwei
authors.initials: W
authors.lastname: Dai
authors.forename: Yu-An E
authors.initials: YA
authors.lastname: Lay
authors.forename: Diana
authors.initials: D
authors.lastname: Olvera
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Zimmermann
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ritchie
authors.forename: Chin-Shang
authors.initials: CS
authors.lastname: Li
authors.forename: Tamara
authors.initials: T
authors.lastname: Alliston
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
mesh_terms: D019386:Alendronate / Q000627:therapeutic use*; D000818:Animals; D001696:Biomechanical Phenomena; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001842:Bone and Bones / Q000502:physiology*; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D007150:Immunohistochemistry; D023421:Models, Animal; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000097:blood*
chemical_list: D050071:Bone Density Conservation Agents; D004967:Estrogens; D053773:Transforming Growth Factor beta1; D019386:Alendronate