title: Articular damage is associated with intraosseous inflammation in the subchondral bone marrow of joints affected by experimental inflammatory arthritis and is modified by zoledronate treatment.
abstract: OBJECTIVE
  We studied histological changes in the cell populations of subchondral bone marrow resulting from inflammation in animal models of arthritis. Inflammation in intraosseous spaces and the effect of treatment with the aminobisphosphonate zoledronate were assessed.
  
  
  METHODS
  Peripheral blood, femoral bone marrow, and spleen cells were harvested from carrageenan-induced arthritis Sprague-Dawley rats; fluorescence stained for CD3, CD8, CD4, CD11b/c, anti-mononuclear phagocyte (MNP), CD3/CD8, CD3/CD4, and MNP/CD11b/c; and evaluated by flow cytometry. Arthritis was induced in New Zealand white rabbits in 5 treatment groups: normal, arthritis, zoledronate-treated from arthritis induction, or 2 or 4 weeks after induction. Animals were euthanized after 7 weeks and distal femoral condyles were decalcified, processed, sectioned, and stained. Sections were evaluated for several cell types and histological features relevant to inflammation, which were assigned a categorical grade from 0 (healthy morphology) to 3 (extensive inflammation). Tidemark was evaluated on a continuous scale.
  
  
  RESULTS
  Significantly elevated levels of CD3+CD4+ lymphocytes and CD11b/c+MNP+ monocytes were observed in the bone marrow of arthritic rats, consistent with intraosseous inflammation. No corresponding increase was observed in peripheral blood or spleen. In rabbits, the histology of lymphocytes, mononuclear cells, fibrocytes, fibrosis, lipocytes, and plasma cells varied significantly across treatment groups. Controls exhibited normal histology. In arthritis, these cell types and tissues displayed a shift of 1-2 grades higher (toward inflammation). Intact tidemark was reduced. Following zoledronate treatment, mononuclear cells, fibrocytes, fibrosis, and lipocytes were significantly altered toward normal, and tidemark shifted toward normal.
  
  
  CONCLUSIONS
  Intraosseous bone marrow inflammation was observed in carrageenan-induced inflammatory arthritis in rats and rabbits. Zoledronate administration diminished the intraosseous inflammatory response.
authors.affiliation: Department of Surgery, Li Ka Shing Knowledge Institute and Martin Family Centre for Arthritis Care and Research, Mobility Program, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. bogoche@smh.toronto.on.ca
authors.forename: Earl R
authors.initials: ER
authors.lastname: Bogoch
authors.forename: Todd C
authors.initials: TC
authors.lastname: Lee
authors.forename: Victor L
authors.initials: VL
authors.lastname: Fornasier
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Berger
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology*; D001855:Bone Marrow Diseases / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002351:Carrageenan; D004164:Diphosphonates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use*; D007249:Inflammation / Q000473:pathology; D007596:Joints / Q000276:immunology / Q000473:pathology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000276:immunology / Q000473:pathology; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D039481:CD11b Antigen; D017252:CD3 Complex; D015704:CD4 Antigens; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D002351:Carrageenan