title: Impact of sirolimus, tacrolimus and mycophenolate mofetil on osteoclastogenesis--implications for post-transplantation bone disease.
abstract: BACKGROUND
  Post-transplantation bone disease is associated with a high degree of morbidity including pain and fractures. Glucocorticoid-induced osteoporosis on top of pre-existing renal osteodystrophy is considered the major pathogenic factor, while the role of non-glucocorticoid immunosuppressants is less well defined.
  
  
  METHODS
  In this study, we investigated the influence of sirolimus (SRL) versus calcineurin inhibitor (CI)-based immunosuppressive regimens on biomarkers of bone resorption in renal transplant patients. In addition, the impact of SRL, tacrolimus and mycophenolate mofetil (MMF) on osteoclast activation and function was assessed in cell culture systems.
  
  
  RESULTS
  Using this approach, we demonstrated reduced serum levels of bone resorption markers in patients treated with SRL after kidney transplantation compared to a CI-based regimen. In line with this observation, we detected profoundly reduced osteoclast differentiation and subsequently diminished hydroxyapatite resorption in the presence of SRL compared to MMF and tacrolimus in vitro. Moreover, SRL significantly reduced osteoclast precursor proliferation in vitro compared to tacrolimus and led to augmented apoptosis in osteoclast precursors.
  
  
  CONCLUSIONS
  Taken together, SRL was shown to inhibit osteoclast formation in vivo and in vitro. SRL thus may have the potential to balance osteoclast promoting effects of glucocorticoids and CI, thereby counteracting the development of accelerated osteoporosis in renal transplant recipients.
authors.affiliation: Department of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany. ralf.westenfeld@med.uni-duesseldorf.de
authors.forename: Ralf
authors.initials: R
authors.lastname: Westenfeld
authors.forename: Georg
authors.initials: G
authors.lastname: Schlieper
authors.forename: Michael
authors.initials: M
authors.lastname: Wöltje
authors.forename: Alexander
authors.initials: A
authors.lastname: Gawlik
authors.forename: Vincent
authors.initials: V
authors.lastname: Brandenburg
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Rutkowski
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Markus
authors.initials: M
authors.lastname: Ketteler
mesh_terms: D000328:Adult; D000368:Aged; D001862:Bone Resorption; D002454:Cell Differentiation; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D010024:Osteoporosis / Q000209:etiology / Q000517:prevention & control; D053245:RANK Ligand / Q000096:biosynthesis; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus