Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients.
OBJECTIVE
To elucidate the direct role of human T cells in the induction of osteoclastogenesis in rheumatoid arthritis (RA), by studying human monocytes and the pathogenetic roles of receptor activator of nuclear factor kappaB ligand (RANKL), RANK, and osteoprotegerin (OPG).


METHODS
Synovial tissue obtained at total knee replacement was stained immunohistologically using anti-RANKL, CD3, and CD4 antibodies. Synovial fluid was obtained from patients with RA, osteoarthritis (OA), gout, or trauma. Concentrations of the soluble form of RANKL (sRANKL) and OPG in the synovial fluid were measured by enzyme-linked immunosorbent assay. Activated T cells from peripheral blood mononuclear cells (PBMC) of healthy volunteers were cultured with human monocytes from PBMC.


RESULTS
Immunostaining of the synovial tissue of RA patients demonstrated that RANKL-positive cells were detected in a subset of fibroblast-like synoviocytes and infiltrating mononuclear cells. Double immunostaining revealed that RANKL-positive cells were detected in a subset of CD3+ cells and CD4+ cells. An increased concentration of sRANKL and a decreased concentration of OPG were detected in synovial fluid from RA patients. The ratio of the concentration of sRANKL to that of OPG was significantly higher in synovial fluid of RA patients than in synovial fluid of patients with OA or gout. The activated T cells expressing RANKL induced osteoclastogenesis from autologous peripheral monocytes. The role of RANKL in this osteoclastogenetic process was confirmed by dose-dependent inhibition by OPG.


CONCLUSIONS
The present study is the first to demonstrate osteoclastogenesis using human-derived T cells and monocytes. In addition, the present findings suggest that excess production of RANKL by activated T cells increases the level of sRANKL in synovial fluid and may contribute to osteoclastic bone resorption in RA patients.
Kotake
S
S
Institute of Rheumatology, Tokyo Women's Medical University, Japan.
Udagawa
N
N
Hakoda
M
M
Mogi
M
M
Yano
K
K
Tsuda
E
E
Takahashi
K
K
Furuya
T
T
Ishiyama
S
S
Kim
K J
KJ
Saito
S
S
Nishikawa
T
T
Takahashi
N
N
Togari
A
A
Tomatsu
T
T
Suda
T
T
Kamatani
N
N
D000906:Antibodies; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology*; D017252:CD3 Complex / Q000032:analysis / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000276:immunology; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006023:Glycoproteins / Q000032:analysis / Q000276:immunology; D006073:Gout / Q000276:immunology / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D010003:Osteoarthritis / Q000276:immunology / Q000473:pathology; D010010:Osteoclasts / Q000276:immunology / Q000473:pathology*; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor; D013582:Synovial Fluid / Q000737:chemistry / Q000276:immunology
D000906:Antibodies; D017252:CD3 Complex; D015704:CD4 Antigens; D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human