title: RANKL is a marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis.
abstract: RANKL is an essential mediator of bone erosions, but the role of RANKL in systemic bone loss had not been studied in arthritis. RANKL protein was increased in rat joint extracts and serum at the earliest stages of arthritis. Osteoprotegerin (OPG) treatment reversed local and systemic bone loss, suggesting that RANKL is both a marker and mediator of bone loss in arthritis.
  
  
  BACKGROUND
  RANKL is well established as an essential mediator of bone erosions in inflammatory arthritis, but the role of RANKL in systemic bone loss in arthritis had not been studied. We hypothesized that serum RANKL could serve as both a mediator and as a novel biomarker for local and systemic bone loss in arthritis. We challenged this hypothesis in two established rat models of inflammatory arthritis. We sought to determine whether serum RANKL was elevated early in disease progression and whether RANKL suppression could prevent both local and systemic bone loss in these models.
  
  
  METHODS
  Detailed time-course studies were conducted in animals with collagen-induced (CIA) or adjuvant-induced (AIA) arthritis to evaluate the onset and progression of inflammation (paw swelling), bone erosions, osteoclast numbers, and RANKL protein levels in arthritic joints and in serum. Additional CIA and AIA rats (n=8/group) received placebo (PBS) or recombinant OPG (3 mg/kg three times weekly) for 10 days beginning 4 days after disease onset (first macroscopic evidence of hind paw erythema and edema) to assess the role of RANKL in local and systemic bone loss.
  
  
  RESULTS
  RANKL protein was significantly elevated in the joints and serum of CIA and AIA rats within 1-2 days of disease onset. Increased RANKL levels were associated with local (hind paw) and systemic (vertebral) osteopenia in both models. The RANKL inhibitor OPG prevented local and systemic osteopenia in both models of established disease.
  
  
  CONCLUSIONS
  RANKL protein is significantly increased both locally and systemically during the earliest stages of inflammatory arthritis in rats, suggesting that serum RANKL might have prognostic value for bone erosions and systemic osteopenia in this condition. RANKL inhibition through OPG prevented local and systemic bone loss in these arthritis models, suggesting that RANKL inhibition is a promising new approach for treating bone loss in arthritis.
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, California 91320, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.forename: Stephen
authors.initials: S
authors.lastname: Adamu
authors.forename: Mike
authors.initials: M
authors.lastname: Ominsky
authors.forename: Denise
authors.initials: D
authors.lastname: Dwyer
authors.forename: Frank
authors.initials: F
authors.lastname: Asuncion
authors.forename: Zhaopo
authors.initials: Z
authors.lastname: Geng
authors.forename: Scot
authors.initials: S
authors.lastname: Middleton
authors.forename: Heather
authors.initials: H
authors.lastname: Brown
authors.forename: Jim
authors.initials: J
authors.lastname: Pretorius
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Brad
authors.initials: B
authors.lastname: Bolon
authors.forename: Ulrich
authors.initials: U
authors.lastname: Feige
authors.forename: Debra
authors.initials: D
authors.lastname: Zack
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D015415:Biomarkers / Q000097:blood; D001851:Bone Diseases, Metabolic / Q000097:blood* / Q000188:drug therapy / Q000209:etiology; D002352:Carrier Proteins / Q000097:blood*; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000188:drug therapy; D007596:Joints / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D053244:Osteoprotegerin; D053245:RANK Ligand; D051381:Rats; D011917:Rats, Inbred Lew; D018160:Receptors, Cytoplasmic and Nuclear / Q000008:administration & dosage; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506032:Tnfrsf11b protein, rat