title: Elevated levels of the mediator of catabolic bone remodeling RANKL in the bone marrow environment link chronic heart failure with osteoporosis.
abstract: BACKGROUND
  Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and catabolic bone remodeling.
  
  
  RESULTS
  In a total cohort of 153 subjects (123 patients with CHF, 30 patients with coronary artery disease and preserved cardiac function) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of NF-κB ligand (RANKL), and its antagonist, osteoprotegerin were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/osteoprotegerin were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover C-telopeptide of type 1 collagen (r=0.6; P<0.001). Alterations in BM plasma levels of RANKL/osteoprotegerin were confirmed in a mouse model of postinfarction heart failure. Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts, and this effect was blocked by the RANKL inhibition.
  
  
  CONCLUSIONS
  CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifiers: NCT 00289822, NCT 00284713, NCT 00326989, NCT 00962364.
authors.affiliation: Department of Medicine III, Cardiology, Goethe University Frankfurt, Theodor-Stern-Kai, Frankfurt/Main, Germany.
authors.forename: David M
authors.initials: DM
authors.lastname: Leistner
authors.forename: Florian H
authors.initials: FH
authors.lastname: Seeger
authors.forename: Ariane
authors.initials: A
authors.lastname: Fischer
authors.forename: Tino
authors.initials: T
authors.lastname: Röxe
authors.forename: Jens
authors.initials: J
authors.lastname: Klotsche
authors.forename: Kazuma
authors.initials: K
authors.lastname: Iekushi
authors.forename: Timon
authors.initials: T
authors.lastname: Seeger
authors.forename: Birgit
authors.initials: B
authors.lastname: Assmus
authors.forename: Jörg
authors.initials: J
authors.lastname: Honold
authors.forename: Mahir
authors.initials: M
authors.lastname: Karakas
authors.forename: Klaus
authors.initials: K
authors.lastname: Badenhoop
authors.forename: Stefan
authors.initials: S
authors.lastname: Frantz
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
mesh_terms: D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001853:Bone Marrow / Q000378:metabolism*; D016723:Bone Remodeling / Q000502:physiology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D015331:Cohort Studies; D024042:Collagen Type I / Q000097:blood; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000453:epidemiology* / Q000378:metabolism*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010024:Osteoporosis / Q000453:epidemiology* / Q000378:metabolism*; D053244:Osteoprotegerin / Q000097:blood; D010455:Peptides / Q000097:blood; D053245:RANK Ligand / Q000097:blood* / Q000494:pharmacology; D012044:Regression Analysis
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D053244:Osteoprotegerin; D010455:Peptides; D053245:RANK Ligand; C505688:TNFSF11 protein, human; C505689:Tnfsf11 protein, mouse; C052929:collagen type I trimeric cross-linked peptide