ABSTRACT
OBJECTIVE: We have previously reported that stimulation of mouse bone marrow-derived macrophages with tumor necrosis factor (TNF) and interleukin-6 (IL-6) induces differentiation of osteoclast-like cells. We undertook this study to clarify the characterization and function of human TNF and IL-6-induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors. METHODS: Peripheral blood monocytes were cultured with a combination of TNF and IL-6, TNF alone, IL-6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL-6-induced osteoclasts or RANKL-induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole-body bone mineral density (BMD) was examined. RESULTS: Peripheral blood monocytes stimulated with a TNF and IL-6-induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL-6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL-6-induced osteoclast formation. Expression levels of IL1ß, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL-6-induced osteoclasts, but not in RANKL-induced osteoclasts. The number of TNF and IL-6-induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL-induced osteoclast numbers negatively correlated with the whole-body BMD of the same patients. CONCLUSION: Our results demonstrate that TNF and IL-6-induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA.
Subject(s)
Arthritis, Rheumatoid/immunology , Bone Resorption/immunology , Interleukin-6/immunology , Osteoclasts/immunology , Tumor Necrosis Factor-alpha/immunology , Aged , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/metabolism , Bone Density , Bone Resorption/diagnostic imaging , Bone Resorption/metabolism , Case-Control Studies , Cytokines/drug effects , Cytokines/immunology , Cytokines/metabolism , Female , Humans , Interleukin-12 Subunit p40/drug effects , Interleukin-12 Subunit p40/immunology , Interleukin-12 Subunit p40/metabolism , Interleukin-1beta/drug effects , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Interleukin-6/pharmacology , Male , Matrix Metalloproteinase 3/drug effects , Matrix Metalloproteinase 3/immunology , Matrix Metalloproteinase 3/metabolism , Middle Aged , NFATC Transcription Factors/drug effects , NFATC Transcription Factors/metabolism , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteogenesis/drug effects , Osteogenesis/immunology , RANK Ligand/metabolism , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
We describe pathohistological findings of the human femoral head after it was grafted with hydroxyapatite (HA) and allogenic bone. The femoral head was removed because of the recurrence of a giant cell tumor 15 months after the graft. Histological investigation revealed that the entire surface of the HA granules was completely surrounded by the bone in the periphery of the grafted area; in some areas granules were partly in contact with the existing bone, and the rest were surrounded by fibrous tissue. There was no intervening layer of fibrous tissue between the granule surface and the bone where they were in direct contact. Pores were completely filled with fibrous tissue, partially filled with bone in the periphery of the pores, or completely filled with bone. Undecalcified histology revealed the formation of osteoid and ossification at the site where fibrous tissue infiltrated the pores. These findings indicated continued ingrowth of new bone into the HA pores. Under a scanning electron microscope, the surfaces of the granules showed clear demarcation in vitro, but it became less smooth, indicating in vivo changes. Although no foreign body reaction to the HA was noted anywhere, the HA surface appeared to be subject to a biodegradation process.
