title: Involvement of subchondral bone marrow in rheumatoid arthritis: lymphoid neogenesis and in situ relationship to subchondral bone marrow osteoclast recruitment.
abstract: OBJECTIVE
  To evaluate the presence and immunohistochemical characteristics of subchondral bone marrow inflammatory infiltrate in rheumatoid arthritis (RA) and to determine the in situ relationship between marrow inflammation and osteoclast recruitment.
  
  
  METHODS
  Bone samples and paired synovia from 8 RA patients undergoing joint surgery were analyzed by immunohistochemistry and in situ hybridization for specific lymphoid neogenetic features, such as T and B cell composition, follicular dendritic cell (FDC) networks, peripheral lymph node addressin (PNAd)-positive high endothelial venules, and lymphoid chemokine expression. Osteoclasts were identified as multinucleated tartrate-resistant acid phosphatase (TRAP)-positive and cathepsin K-positive cells adherent to the bone surface.
  
  
  RESULTS
  An inflammatory infiltrate with perivascular aggregates of variable size was detected in 7 (87.5%) of 8 synovial samples and in paired bone samples. Lymphoid neogenetic features typical of rheumatoid synovium were also recognized in the bone marrow. PNAd+ blood vessels were found in 4 of 8 patients, CD21+ FDC networks in 2 patients, CXCL13+ cells in 5 patients, and CCL21+ cells in 6 patients. TRAP-positive and cathepsin K-positive osteoclasts were identified on both the synovial and marrow sides of the bone surface. Bone marrow samples showing a higher degree of inflammation were characterized by a significantly increased number of osteoclasts adherent to the subchondral bone.
  
  
  CONCLUSIONS
  Our data demonstrate that lymphoid aggregates with lymphoid neogenetic features are detectable on the subchondral side of the joint in established RA. Moreover, the local inflammation/aggregation process appears to be related to osteoclast differentiation on the marrow side of subchondral bone, supporting a functional role of the bone compartment in local damage.
authors.affiliation: University of Pavia, IRCCS Policlinico S. Matteo, Piazzale Golgi 2, 27100 Pavia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Bugatti
authors.forename: Roberto
authors.initials: R
authors.lastname: Caporali
authors.forename: Antonio
authors.initials: A
authors.lastname: Manzo
authors.forename: Barbara
authors.initials: B
authors.lastname: Vitolo
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.forename: Carlomaurizio
authors.initials: C
authors.lastname: Montecucco
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology*; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D015207:Osteoarthritis, Hip / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; C515478:CCL21 protein, human; C110663:CXCL13 protein, human; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; D019742:Chemokines, CC; D019743:Chemokines, CXC