Involvement of subchondral bone marrow in rheumatoid arthritis: lymphoid neogenesis and in situ relationship to subchondral bone marrow osteoclast recruitment

Arthritis Rheum. 2005 Nov;52(11):3448-59. doi: 10.1002/art.21377.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology*
  • Biomarkers / metabolism
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology*
  • Bone Resorption / metabolism
  • Bone Resorption / pathology*
  • Chemokine CCL21
  • Chemokine CXCL13
  • Chemokines, CC / genetics
  • Chemokines, CC / metabolism*
  • Chemokines, CXC / genetics
  • Chemokines, CXC / metabolism*
  • Female
  • Humans
  • In Situ Hybridization
  • Male
  • Middle Aged
  • Osteoarthritis, Hip / metabolism
  • Osteoarthritis, Hip / pathology
  • Osteoclasts / metabolism
  • Osteoclasts / pathology*
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology


  • Biomarkers
  • CCL21 protein, human
  • CXCL13 protein, human
  • Chemokine CCL21
  • Chemokine CXCL13
  • Chemokines, CC
  • Chemokines, CXC