title: Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor.
abstract: OBJECTIVE
  Osteoclast differentiation factor (ODF; also known as osteoprotegerin ligand, receptor activator of nuclear factor kappaB ligand, and tumor necrosis factor-related activation-induced cytokine) is a recently described cytokine known to be critical in inducing the differentiation of cells of the monocyte/macrophage lineage into osteoclasts. The role of osteoclasts in bone erosion in rheumatoid arthritis (RA) has been demonstrated, but the exact mechanisms involved in the formation and activation of osteoclasts in RA are not known. These studies address the potential role of ODF and the bone and marrow microenvironment in the pathogenesis of osteoclast-mediated bone erosion in RA.
  
  
  METHODS
  Tissue sections from the bone-pannus interface at sites of bone erosion were examined for the presence of osteoclast precursors by the colocalization of messenger RNA (mRNA) for tartrate-resistant acid phosphatase (TRAP) and cathepsin K in mononuclear cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to identify mRNA for ODF in synovial tissues, adherent synovial fibroblasts, and activated T lymphocytes derived from patients with RA.
  
  
  RESULTS
  Multinucleated cells expressing both TRAP and cathepsin K mRNA were identified in bone resorption lacunae in areas of pannus invasion into bone in RA patients. In addition, mononuclear cells expressing both TRAP and cathepsin K mRNA (preosteoclasts) were identified in bone marrow in and adjacent to areas of pannus invasion in RA erosions. ODF mRNA was detected by RT-PCR in whole synovial tissues from patients with RA but not in normal synovial tissues. In addition, ODF mRNA was detected in cultured adherent synovial fibroblasts and in activated T lymphocytes derived from RA synovial tissue, which were expanded by exposure to anti-CD3.
  
  
  CONCLUSIONS
  TRAP-positive, cathepsin K-positive osteoclast precursor cells are identified in areas of pannus invasion into bone in RA. ODF is expressed by both synovial fibroblasts and by activated T lymphocytes derived from synovial tissues from patients with RA. These synovial cells may contribute directly to the expansion of osteoclast precursors and to the formation and activation of osteoclasts at sites of bone erosion in RA.
authors.affiliation: Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute, and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Gravallese
authors.forename: C
authors.initials: C
authors.lastname: Manning
authors.forename: A
authors.initials: A
authors.lastname: Tsay
authors.forename: A
authors.initials: A
authors.lastname: Naito
authors.forename: C
authors.initials: C
authors.lastname: Pan
authors.forename: E
authors.initials: E
authors.lastname: Amento
authors.forename: S R
authors.initials: SR
authors.lastname: Goldring
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D001859:Bone Neoplasms / Q000737:chemistry / Q000378:metabolism; D001862:Bone Resorption / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis*; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics; D015870:Gene Expression; D018212:Giant Cell Tumor of Bone / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D010010:Osteoclasts / Q000502:physiology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000737:chemistry*
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K